Most patients with Barrett’s esophagus derive no increase in life expectancy from expensive and invasive programs for early detection or prevention of malignancy because they will not develop cancer (10
). By identifying patient subsets with different incidences of cancer, our study should improve management of the malignant risk in Barrett’s esophagus. A baseline endoscopic biopsy protocol using histology and flow cytometry identified a large, benign subset, comprising 66% of our patients, with a low risk for cancer. No patient with negative, indefinite, or LGD whose biopsies had neither aneuploidy nor increased 4N developed cancer within 5 yr. This benign subset may constitute greater percentages of Barrett’s patients in practices with fewer high-risk referrals. Counseling, reassurance, and lengthened surveillance intervals for these low-risk patients could reduce patient anxiety and decrease cost of medical care. There is no evidence that such low-risk patients will benefit from endoscopic ablative therapies or antireflux surgeries intended, in theory, to diminish the risk of esophageal adenocarcinoma (44
), and such interventions do not seem to be indicated in the routine clinical setting at the present time. Conversely, patients without HGD but with aneuploidy or increased 4N had a substantial risk for developing cancer (RR = 19). Baseline increased 4N, aneuploidy, and HGD had 5-yr cumulative cancer incidences of 56%, 43%, and 59%, respectively. Adjusting for age and sex did not influence the estimated relationship of histological and cytometric measures to cancer outcome.
The risk of cancer in HGD seems to be variable, and comparison of our results with those of Sontag et al.
and Weston et al.
indicates that the risk of baseline HGD may vary among centers (47
). Some HGD patients remain free of cancer indefinitely, whereas others progress rapidly. Sontag et al.
found a lower risk of cancer in baseline HGD (prevalent HGD) and in follow-up (incident HGD). Our study design evaluated only baseline predictors of progression to cancer. However, in 27 incident HGD patients, we found a 5-yr cumulative incidence of cancer of 31% (95% CI = 14, 60), which was lower than our baseline HGD (p
= 0.01) and seemed closer to the results of Sontag et al.
and Weston et al.
, although theirs were not presented with time-dependent analyses (data not shown). Abnormal cytometric results at the time of HGD diagnosis were more frequent in baseline (65%) than incident HGD (27%) (p
< 0.001) but were not statistically significant predictors of cancer in either category of HGD. Patients who had aneuploidy or increased 4N in baseline (prevalent) and incident HGD had 3-yr cancer incidences of 61% (95% CI = 44, 78) and 58% (95% CI = 16, 99), respectively, compared to 42% (95% CI = 23, 68) and 7.7% (95% CI = 1.1, 43) for baseline and incident HGD without cytometric abnormalities, respectively. It is clear that there is a great incentive to find biomarkers that distinguish the subset of HGD patients who will progress from those who will not, and there is considerable evidence that not all HGD patients should be subjected to invasive intervention (47
). The higher cancer incidence in our baseline HGD patients might be due to lead-time bias or referral of high-risk cases because our center has been one of the few willing to survey HGD.
Endoscopic surveillance based on a five-tiered classification system for dysplasia and cancer has been recommended for clinical management of Barrett’s esophagus, but this classification has not been shown to be reproducible in formal, blinded studies (26
). For example, reanalysis of data from eight readers in a previous study (26
) showed an average, pair-wise agreement of 48% in a five-tiered classification. Pending validation of the reproducibility of our classification criteria in formal, blinded multicenter studies, we recommend caution in therapeutic interventions for diagnoses other than cancer, based on our observations of HGD outcome, because there is evidence that other centers may have different rates of progression depending on diagnostic criteria or other factors (47
). In the absence of consensus, we recommend that HGD be confirmed by at least two experienced pathologists on at least two endoscopic evaluations before considering therapeutic intervention.
Future studies may refine histological criteria for dysplasia by using progression to cancer as a “gold standard,” but flow cytometry presently complements histology in risk assessment. For example, observer agreement seems to be highest (86%) when the diagnoses of negative, indefinite, and LGD are combined (26
), and flow cytometry separates these patients into low- and high-risk subsets with 5-yr cancer incidences of 0% and 28%, respectively. It might be suggested only patients with LGD need flow-cytometric analysis, but this ignores the potential for low reproducibility of this histological diagnosis, and many of our LGD patients might be diagnosed differently by other observers (26
). Our data, as well as previously published data (12
), are equivocal as to whether or not LGD is a significant predictor of cancer. However, Sontag et al.
recently reported a 19-yr prospective study in which only 18 of 848 patients (2.1%) with LGD progressed to cancer (49
). Thus, the data from both this and our own prospective studies suggest that only a small subset of patients with LGD will progress to cancer in cases of Barrett’s esophagus.
Four studies over more than a decade have shown little progress in resolving sources of histological irreproducibility, especially in biopsies that are less than high grade (26
). We are more hopeful that flow cytometry can be performed as an objective measure. There is an extensive body of literature on reducing sources of interlaboratory variation in flow cytometry, including sample handling, preparation, instrumentation, computer analysis, and histogram interpretation (50
). Recent studies have shown that flow cytometry can be reproducible; for example, one large study found 94% interlaboratory agreement in a five-tiered classification system of ploidy (53
). We are optimistic that interlaboratory differences in instrumentation will not be insurmountable, as we have found excellent agreement between ICP-22 (Partec GmbH, Münster, Germany) and Coulter Elite instruments (Beckman Coulter, Fullerton, CA) (data not shown). Furthermore, our finding of a 6% threshold for elevated 4N fractions associated with histological abnormalities has been reproduced by another laboratory (33
), and another laboratory also observed, during a prospective study of 30 patients, that individuals without flow cytometric aneuploidy did not progress to cancer during 5 yr (36
). Although observer variation in flow-cytometric histogram interpretation seems to be less than for the diagnosis of dysplasia (54
), we recommend confirmation of aneuploidy or increased 4N by a laboratory experienced in flow-cytometric analyses of Barrett’s samples. We do not recommend surgical or endoscopic ablative therapy based solely on flow-cytometric findings. However, patients with aneuploidy or increased 4N may benefit from more frequent surveillance.
Our results demonstrate that aneuploidy, increased 4N fractions, and HGD are predictors of progression to cancer in Barrett’s esophagus and that a four-quadrant biopsy protocol is superior to a more limited protocol. We and others have shown that endoscopic biopsy surveillance detects early, curable Barrett’s adenocarcinomas (8
), and 95% of the cancers detected in the present study were T1 lesions. However, there is debate concerning optimal patient management because mortality from esophagectomy varies among institutions (55
), alternative therapies have not been shown to be superior in preventing or curing cancer, and prospective studies provide apparently different estimates of rates of progression (47
). Our data support use of flow cytometry with histology in the evaluation of cancer risk in Barrett’s esophagus. Patients who undergo our biopsy protocol and have negative, indefinite, or LGD biopsies without increased 4N or aneuploidy may have subsequent surveillance deferred for up to 5 yr. More frequent surveillance can be reserved for patients with cytometric abnormalities, and management of HGD can be individualized based on careful risk–benefit calculations (9