Case 1 -

Barrett's Esophagus with High-Grade Dysplasia and Possible Intramucosal Adenocarcinoma John R. Goldblum The Cleveland Clinic Cleveland Clinic Lerner College of Medicine Cleveland, Ohio

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Case History 63-year-old male with a long history of "heartburn." Eventually, the patient underwent an EGD and was found to have a 4-cm length of columnar-lined esophagus. Four-quadrant biopsy specimens were obtained for every cm of columnar-lined esophagus. Case 1 - Figure 1 - Low-magnification view of this esophageal biopsy. There is a vaguely villiform architecture, and rare goblet cells can be seen. At low magnification, there is a complex glandular pattern associated with overt cytologic atypia, which is identifiable even from this magnification. The cytologic atypia clearly extends onto the surface epithelium. Case 1 - Figure 2 - Different area of this same biopsy specimen. Again, cytologic atypia is identifiable at low magnification, including on the surface. There is a complex glandular architecture with "back-to-back" glands. Case 1 - Figure 3 - Higher-magnification view of a focus of crowded atypical glands. There is little, if any, lamina propria between the glands. Case 1 - Figure 4 - In addition to the larger rounded glands, there are smaller "abortive" glands, including glands with intraluminal necrotic debris. Case 1 - Figure 5 - At the base of the biopsy specimen, there is an enlarged dilated atypical gland that infiltrates into the superficial aspect of the muscularis mucosae. Case 1 - Figure 6 - Scattered dilated atypical glands with intraluminal necrotic debris were identified. Diagnosis Barrett's Esophagus with High-grade Dysplasia and Possible Intramucosal Adenocarcinoma Discussion Barrett's esophagus (BE) is a complication of chronic gastroesophageal reflux disease (GERD), and most patients who develop BE have severe, chronic GERD as defined by a weak lower esophageal sphincter pressure, decreased amplitude of contraction in the distal esophagus, increased acid exposure, increased bile acid exposure and the presence of a hiatal hernia. [1] The average age of BE diagnosis is approximately 55 years. For unknown reasons, BE occurs primarily in Caucasian males. [2, 3, 4] The importance of diagnosing BE is related to its association with the subsequent development of esophageal adenocarcinoma, the frequency of which has rapidly increased over the past several decades. [5, 6] The Diagnosis of BE In most cases, the diagnosis of BE is established by the examination of biopsy specimens obtained during endoscopic evaluation of the esophagus. Endoscopically, columnar epithelium in the esophagus can be readily identified by its characteristic red color and velvet-like texture. These features sharply contrast with the pale, glossy appearance of the adjacent squamous epithelium. Endoscopists usually suspect that BE is present when they see long segments of columnar epithelium extending up the esophagus well above the esophagogastric junction (EGJ). However, the diagnosis must be confirmed by biopsy specimens procured from the columnar-lined esophagus, and histologically, there must be evidence of specialized columnar epithelium (goblet cells) to confirm a diagnosis of BE. [7] Cytologically, goblet cells have distended, mucin-filled cytoplasm with a barrel-shaped configuration. Histochemically, goblet cells contain acid mucins that stain positively with Alcian blue at pH 2.5. [8] The columnar cells in between the goblet cells may resemble either gastric-type foveolar cells or intestinal-type absorptive cells. [9] However, unlike normal gastric foveolar cells, which contain neutral mucins, the columnar cells in BE may contain Alcian blue-positive acid mucins, although the intensity of staining is not as great as is seen in goblet cells. The presence of Alcian blue-positive non-goblet columnar cells (so-called "columnar blues") is not considered to be diagnostic of BE. [10] Barrett's Esophagus and Cancer Risk It has been well established that BE predisposes to esophageal adenocarcinoma, although the exact magnitude of this risk is unknown. [11, 12, 13] Approximately 10% of patients with symptomatic GERD who undergo endoscopy are found to have BE. [14] However, this is certainly an underestimate of the prevalence of BE, as many patients are asymptomatic. It has been estimated that approximately 10% of patients have adenocarcinoma at the time of initial diagnosis of BE (prevalent cancers). [15] The estimated risk of developing adenocarcinoma (incident cancers) ranges from 1 in 52 to 1 in 441 patient years, which translates to an approximately 30-125-fold increased risk over the general population. [16] Risk Factors for Barrett's-related Adenocarcinoma Although all patients with BE are at an increased risk for developing adenocarcinoma, some patients are at higher risk than others. Epidemiologic data suggest that elderly white males are much more commonly affected than any other group of patients. [16] There is also evidence to support the contention that only those patients with specialized columnar epithelium are at an increased risk of developing Barrett's-related adenocarcinoma. [17, 18] The presence of epithelial dysplasia, particularly high-grade dysplasia, is also a risk factor for synchronous or metachronous adenocarcinoma. A number of studies suggest that high-grade dysplasia (HGD) in this condition often progresses to malignancy. For example, Hameeteman described 8 patients with HGD in BE, 5 of whom had invasive cancer detected within one year of the discovery of the HGD. [19] In a more recent study by Levine et al, 7 of 29 patients (24%) with HGD were found to progress to invasive cancer during a follow-up of 2 to 46 months. [20, 21] The data of Drewitz et al found that among the 4 patients developing adenocarcinoma of the esophagus after a diagnosis of BE, all had dysplasia. [22] Furthermore, among patients who have had esophageal resections performed because endoscopic examination revealed only HGD in BE, approximately one-third have been found to have an inapparent malignancy in the resected specimen. As discussed below, for these reasons, many authorities recommend esophageal resection for patients with BE-related HGD. Unfortunately, the mortality rate for esophageal resection is approximately 4% to 10%, and there can be substantial long-term morbidity for those who survive this surgery. [23, 24, 25] Cancer Surveillance in Barrett's Esophagus Although cancer surveillance is performed in most institutions once a diagnosis of BE is rendered, the true cost/benefit ratio of this endeavor is still essentially unknown. In fact, there are actually very few patients with BE who ultimately progress to adenocarcinoma. Although this issue has yet to be fully resolved, at our institution, patients are placed into a cancer surveillance program once a diagnosis of BE has been clearly established, with the surveillance goal being the identification of epithelial dysplasia in a biopsy specimen, before carcinoma has intervened. We essentially follow the protocol as proposed by Reid et al with four-quadrant biopsies taken at intervals of 2 cm or less throughout the length of the BE segment, with additional biopsies of any endoscopic lesions, using large forceps. [26] Histopathologic Diagnosis of Dysplasia Dysplasia can be defined as the presence of neoplastic epithelium that is confined within the basement membrane of the glands within which it arises. [27] However, unlike inflammatory bowel disease-associated dysplastic lesions, most BE-related dysplastic lesions do not closely resemble colonic adenomas. Rather, the typical form of BE-related dysplasia arises in glands that retain their normal configuration and often lack nuclear stratification. Using the criteria as defined by Riddell et al for dysplasia arising in IBD, dysplasia in BE can be classified as either low-grade (LGD) or high-grade (HGD) based upon the degree of the abnormality present. Thus, the classification for BE-related dysplasia includes 1) negative for dysplasia; 2) positive for dysplasia, either LGD or HGD; or 3) indefinite for dysplasia. [27] In LGD, crypt architecture tends to be preserved with only minimal distortion, and cytologically atypical nuclei are generally limited to the basal half of the crypts. The nuclei tend to show variable hyperchromasia, overlapping cell borders with nuclear crowding and irregular nuclear contours. Dystrophic goblet cells may be seen, although typically goblet cell numbers are markedly reduced. Separation of LGD from regenerative atypia can be extremely difficult, as all pathologists know. Simply put, HGD shows more severe cytologic and architectural changes than are present in LGD, and in some cases this distinction is quite difficult. Architecturally, there tends to be more crypt distortion in HGD, sometimes with a villiform configuration of the mucosal surface and/or branched or cribriform crypts. Cytologically, the cells show more nuclear pleomorphism and hyperchromatism than is seen in LGD, and there is often nuclear stratification to the crypt luminal surface. A diagnosis of "indefinite for dysplasia," much to our clinical colleagues' dismay, is a legitimate diagnosis. The differentiation of regenerative changes from true dysplasia, particularly in a background of inflammation or ulceration, is at times difficult, if not impossible. Thus, if the pathologist is unsure as to whether the epithelial changes are regenerative or truly dysplastic, a diagnosis of indefinite for dysplasia should be made. Observer Variability in the Diagnosis of Dysplasia One of the major problems in using dysplasia as the marker of increased cancer risk in BE is the problem of observer variability. Given the subtle gradation of changes from baseline atypia to LGD to HGD, it is not surprising that such variation exists. Reid et al found that this variation was most striking at the low end of the spectrum -- in other words, distinguishing negative for dysplasia from LGD or indefinite for dysplasia. [28] A more recent study using kappa statistics (which accounts for agreement that occurs by chance alone) has confirmed a high degree of intra- and interobserver variation in the separation of these diagnoses at the low end of the spectrum, even among pathologists with a special interest in gastrointestinal pathology. [29] However, as discussed below, there are essentially no data that have evaluated the extent of observer variability in separating "bad from worse" -- that is, HGD versus intramucosal adenocarcinoma (IMC) or submucosal adenocarcinoma (SMC). Management of BE-related Dysplasia The management of patients with BE-related dysplasia is controversial and varies from institution to institution. Given the paucity of prospective data on the natural history and time course of the dysplasia-carcinoma sequence in this disease, there is no standard way to manage these patients. At our institution, the current management plan is a modification of the recommended guidelines proposed by Reid et al. [26] Once a diagnosis of BE is established, patients are followed with yearly endoscopy with biopsy. If a diagnosis of indefinite or LGD is made, patients are generally placed on anti-reflux therapy in order to reduce the intensity of inflammation and associated reactive epithelial changes that could be misinterpreted as dysplasia. Following anti-reflux therapy, our gastroenterologists generally repeat endoscopy with biopsy in 3-6 months. If the repeat biopsies are also negative, we repeat endoscopy with biopsy at 3- to 6-month intervals until two consecutive negative interpretations are encountered, followed by a return to yearly surveillance. However, if indefinite or LGD persists, we continue a program of 3- to 6-month surveillance intervals until dysplasia progresses. The management of HGD is controversial and serves as the basis for this discussion. At our institution, we consider esophagectomy if a diagnosis of HGD is confirmed, provided the patient is a surgical candidate. At the Cleveland Clinic, we found that approximately one-third of patients have unsuspected adenocarcinoma in resection specimens from patients who had a preoperative diagnosis of HGD without an endoscopic abnormality. [30] Given our relatively low mortality rate from esophagectomy, we believe this procedure is indicated in operative candidates with HGD. However, there are alternative methods of handling patients with BE-related HGD, including continued endoscopic surveillance, which seems to be growing in popularity in the United States. At least in part, this has occurred because of the study by Schnell and colleagues from the Hines VA in Chicago. [31] This study is quite unique in that all of the authors have worked closely together for a long period of time studying a large cohort of patients with BE. The gastroenterologists have essentially worked with a single GI pathologist over this period, and they clearly have established a close working relationship. In this study of almost 1,100 patients with BE, the authors followed 79 patients with BE and HGD. As an important sidenote, approximately 60% of the patients in this cohort were found to have LGD, a number that is far higher than any other published series. Of the 79 patients with BE and HGD, 4 patients were found to have cancer within the first year of discovery of HGD and, as such, probably had carcinoma which was undetected at the time of detection of HGD. Of the remaining 75 patients with BE and HGD, only 12 (16%) progressed to carcinoma over a mean surveillance period of 7.3 years, a strikingly low number. Thus, the authors recommended close endoscopic surveillance with biopsy in patients with BE and HGD but without detectable carcinoma within the first year, since there was a relatively low rate of progression to carcinoma. The authors also recommended reserving esophagectomy for those patients with "cancer" in their preoperative specimens. Of course, this strategy implies that pathologists are completely reliable at distinguishing HGD from IMC/SMC in preoperative biopsy specimens, which is essentially the point of the case utilized for this presentation. Observer Variability in Separating HGD from IMC/SMC in Biopsy Specimens There are very little published data that have looked at observer variability at the upper end of the spectrum -- that is, distinguishing HGD from IMC/SMC. One prior study by Ormsby and colleagues evaluated observer variability (HGD vs IMC vs SMC) in 75 esophagectomy specimens with superficial esophageal adenocarcinoma. [32] Interestingly, even when evaluating esophagectomy specimens, GI pathologists had only fair agreement in distinguishing between these diagnosis, which was not substantially improved on subsequent re-evaluation following establishment of uniform histologic criteria. It is not unreasonable to assume that observer agreement would be even less when evaluating preoperative biopsy specimens, and as such, Mendelin et al performed a study to this end. [33] Pre-resection biopsy specimens from 168 patients with BE and at least HGD who ultimately underwent esophagectomy were reviewed. A single slide showing the most severe abnormalities was selected from each patient by 2 GI pathologists. At a multi-headed microscope, all study GI pathologists evaluated 5 representative slides and developed a consensus set of histologic criteria defining 4 diagnostic categories (Table 1): 1-HGD; 2-HGD with marked glandular architectural distortion; cannot exclude intramucosal adenocarcinoma (HGD-MAD); 3-intramucosal adenocarcinoma (IMC); and 4-submucosal adenocarcinoma (SMC). To establish a diagnosis of IMC, we required one or more of the following criteria -- single cell invasion in more than one focus; sheets of cells obliterating the lamina propria; small angulated, so-called abortive glands invading the lamina propria; or a "never-ending" anastomosing glandular pattern similar to that encountered in endometrial adenocarcinomas of endometrioid type. Only one criterion was required to establish a diagnosis of SMC -- that is, unequivocal stromal desmoplasia. Although the category of HGD-MAD is used as a diagnosis by several of the study pathologists in their clinical practices for problematic biopsies where the histologic abnormalities fall between HGD and IMC, it is not an established diagnostic category, per se. However, we did attempt to establish criteria for this diagnosis, which included one or more of the following -- glandular crowding resulting in glands that are essentially back-to-back; cribriform (gland-in-gland) growth; or at least 3 dilated glands with intraluminal debris. Table 1: Consensus Histologic Criteria Diagnostic Category Criteria 1. High-grade dysplasia (HGD) ~Severe cytologic atypia extending to the surface `Glandular distortion 2. High-grade dysplasia with marked glandular architectural distortion, cannot exclude intramucosal adenocarcinoma (HGD-MAD) ~Marked glandular crowding with back-to-back glands `Cribriform growth ("gland-in-gland") `At least 3 dilated glands with intraluminal debris 3. Intramucosal Adenocarcinoma (IMC) ~Single cell invasion in more than one focus `Sheets of cells obliterating the lamina propria `Abortive, angulated glands `Never-ending/anastomosing gland pattern 4, Submucosal Aadenocarcinoma (SMC) Unequivocal stromal desmoplasia There was complete agreement among all 7 pathologists in only 7.4% of the cases (12/163) (Table 2). The level of agreement for the remaining cases was: 86% agreement (6/7 pathologists) in 20.2% of cases (33/163), 71% (5/7 pathologists) in 28.2% of cases (46/163), 57% agreement (4/7 pathologists) in 30.1% of cases (49/163) and 43% agreement (3/7 pathologists) in 14.1% of cases (23/163). Among the 12 cases with 100% agreement, 2 cases were interpreted as HGD and 10 cases were interpreted as HGD-MAD by all pathologists. Of the 33 cases with near-perfect agreement (6/7 pathologists), 14 cases were interpreted as HGD, 16 as IMC and 3 as HGD-MAD. Overall, a majority of the pathologists, or at least 4 of 7, agreed in 85.9% of cases. Table 2: Observer agreement in 163 cases of BE-related HGD/IMC or SMC Agreement (No. of pathologists) No. of cases % 7/7 (100%) 12   2 HGD   10 HGD-MAD 7.4 6/7 (86%) 33   14 HGD   3 HGD-MAD   16 IMC 20.2 5/7 (71%) 46   7HGD   16 HGD-MAD   22 IMC   1 SMC 28.2 4/7 (57%) 49 30.1 3/7 (43%) 23 14.1 When analyzed using kappa statistics (Table 3), the overall kappa score for all 4 diagnostic categories was 0.30 (fair agreement). Cases interpreted as HGD showed the highest degree of agreement (kappa = 0.47; moderate agreement), while cases interpreted as HGD-MAD and IMC had kappa values of 0.21 and 0.30, respectively (fair agreement). The lowest kappa score was among cases interpreted as SMC (kappa = 0.17; poor agreement). Table 3: Kappa statistics assessing observer variability Diagnosis Overall Kappa Individual Kappa P 95% CI Interpretation   0.30   <0.001 0.28 - 0.32 Fair HGD   0.47 <0.001 0.44 - 0.51 Moderate HGD-MAD   0.21 <0.001 0.18 - 0.25 Fair IMC   0.30 <0.001 0.26 - 0.33 Fair SMA   0.17 <0.001 0.14 - 0.21 Poor Kappa Interpretation (Altman): <0.20 poor; 0.21-0.40 fair; 0.41-0.60 moderate; 0.61-0.80 good; 0.81-1.00 very good We also analyzed the data by grouping cases interpreted as HGD-MAD with those interpreted as HGD, as well as those interpreted as IMC, after which kappa scores were recalculated for the combined categories (Tables 4 and 5). By combining cases interpreted as HGD-MAD with either HGD or IMC, the kappa scores for the combined categories were not significantly different from the initial uncombined scores. Specifically, the kappa score for HGD went from 0.47 to 0.50 (both moderate agreement) when combined with HGD-MAD, while the kappa score for IMC shifted from 0.3 to 0.28 (both fair agreement). Table 4: Kappa statistics assessing observer variability grouping HGD-MAD with HGD category Diagnosis Overall Kappa Individual Kappa P 95% CI Interpretation   0.37   <0.001 0.34 - 0.40 Fair HGD + HGD-MAD   0.50 <0.001 0.48 - 0.54 Moderate IMC   0.30 <0.001 0.26 - 0.33 Fair SMC   0.17 <0.001 0.14 - 0.21 Poor Kappa Interpretation (Altman): <0.20 poor; 0.21-0.40 fair; 0.41-0.60 moderate; 0.61-0.80 good; 0.81-1.00 very good Table 5: Kappa statistics assessing observer variability grouping HGD-MAD with IMC category Diagnosis Overall Kappa Individual Kappa P 95% CI Interpretation   0.37   <0.001 0.34 - 0.40 Fair HGD + HGD-MAD   0.50 <0.001 0.48 - 0.54 Moderate IMC   0.30 <0.001 0.26 - 0.33 Fair SMC   0.17 <0.001 0.14 - 0.21 Poor Kappa Interpretation (Altman): <0.20 poor; 0.21-0.40 fair; 0.41-0.60 moderate; 0.61-0.80 good; 0.81-1.00 very good The results of this study call into question treatment regimens that are based on the assumption that HGD, IMC and SMC can reliably be distinguished from one another in biopsy specimens. 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