Affiliations of authors: The VA Outcomes Group, White River Junction, VT (HP, HGW); and the Center for the Evaluative Clinical Sciences, Dartmouth Medical School, Hanover, NH (HGW)
Correspondence to: Heiko Pohl, MD, VA Outcomes Group (111B), Department of Veterans Affairs Medical Center, White River Junction, VT 0500 (e-mail: heiko.pohl{at}dartmouth.edu and h.gilbert.welch{at}dartmouth.edu)
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ABSTRACT |
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INTRODUCTION |
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Could overdiagnosis or reclassification explain the observed increase in the incidence of esophageal adenocarcinoma? It is possible that increased diagnostic intensity, particularly with the rapid rise in the use of upper endoscopy for patients with dyspepsia, gastroesophageal reflux disease, or Barrett esophagus (8,9), has resulted in overdiagnosis. Further, an incidence increase of in situ and localized disease (10) and a decrease in distant disease at the time of diagnosis have recently been reported (10,11), suggesting a shift in stage distribution toward earlier stages, raising the possibility of overdiagnosis. Reclassification, for instance, of gastric adenocarcinoma of the cardia, has also been considered (4,1214).
In this study, we examine the incidence, stage distribution, and disease-specific mortality of esophageal adenocarcinoma, and the incidence of adjacent cancers to determine whether the observed increase in incidence of esophageal adenocarcinoma over the past 25 years represents overdiagnosis or reclassification. For this analysis, we used data from the National Cancer Institutes Surveillance, Epidemiology, and End Result (SEER1) database.
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SUBJECTS AND METHODS |
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We performed a population-based study using data from the SEER 9 program. This group of nationwide cancer registries collects information on all malignancies newly diagnosed within the states of Connecticut, Hawaii, Iowa, New Mexico, and Utah and the cities of Atlanta, Detroit, San Francisco, and Seattle and represents approximately 10% of the U.S. population. Our analysis included data from all available years (19732001). Although we focused on patients with histologically confirmed esophageal adenocarcinoma, we also selected patients with other malignancies to provide context and to assess the problem of reclassification.
Analysis
We first examined the change in the age-adjusted incidence of esophageal adenocarcinoma, defined anatomically as being in the esophagus (International Classification of Diseases for Oncology, third edition [ICD-O-3] codes 150159) and histologically as adenocarcinoma (ICD-O-3 codes 81408573). In addition, we retrieved information on the incidence of esophageal squamous cell carcinoma using the same anatomic codes and histologic ICD-O-3 codes 80508082 and on the incidence of adenocarcinoma of the gastric cardia (ICD-O-3 codesanatomic code 160 and histologic codes 81408573). To provide a perspective on incidence trends, we also examined other common malignancies as reported annually and defined by SEER.
The possibility of histologic reclassification was evaluated by examining the incidence trends after categorizing all esophageal cancers into one of three different anatomic locations: upper third of the esophagus (ICD-O-3 anatomic code 150 "cervical" and 153 "upper third"), middle third (154 "middle third"), and lower third (152 "abdominal" and 155 "lower third"). Cancer cases coded as "thoracic esophagus" (151) may include upper, middle, and lower thirds of the esophagus. Therefore, cancer cases that were coded as "thoracic esophagus" (151) were combined with cases that were coded as "overlapping" (158) and "not otherwise specified" (159) into a single category, "not clearly categorized."
To examine whether overdiagnosis may be responsible for the observed increase of esophageal adenocarcinoma, we retrieved information on the change in incidence of each stage at diagnosis using the SEER historic stage A (in situ, localized, regional, and distant). Although newer staging systems are available for several cancers, e.g., tumornodemetastasis (TNM) staging, stage IIV, SEER does not provide more detailed stage information for esophageal cancer.
We also examined the issue of overdiagnosis by determining the annual mortality from esophageal adenocarcinoma using the recently constructed incidence-based mortality database maintained by SEER. This database makes it possible to isolate mortality by histologic type, which is not possible with U.S. mortality data from the National Death Index.
Statistical Analysis
We reported an incidence increase using a relative ratethe ratio of incidence in each year to the incidence at baseline. Because the incidence of esophageal adenocarcinoma was low in the 1970s and therefore unstable, we used the average incidence from 1973 to 1975 as the baseline. The same approach (i.e., the use of rates relative to a 19751973 baseline) was used to describe changes in mortality.
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RESULTS |
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During the same period (19752001), the incidence of the other major esophageal cancer, squamous cell carcinoma, fell from 31 to 19 per million (Fig. 2). Thus, it is possible that some of the rise in the observed incidence of esophageal adenocarcinoma could be explained by histologic reclassificationin other words, if what was once called squamous cell carcinoma is now called adenocarcinoma. However, this is unlikely. For histologic reclassification to be a plausible explanation, one would expect to find a relatively stable anatomic distribution of all esophageal cancers. Instead, the anatomic distribution has changed over time (Fig. 3). The only site with increased incidence has been the lower third of the esophagus, near the gastroesophageal junction, the site where adenocarcinomas most commonly arise (Fig. 3).
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Increased diagnostic intensity could lead to the detection of formerly undiagnosed cancers and a shift to earlier stages at diagnosis. However, we found only a small increase over time in the proportion of early-stage disease at diagnosis (in situ and localized cancers rose from 25% of all esophageal adenocarcinomas diagnosed in 1975 to 31% in 2001). Furthermore, the incidence of regional and distant disease has risen just as rapidly as that of local disease (Fig. 5).
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DISCUSSION |
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The argument that the incidence increase is real is based on the lack of evidence to support alternative explanations. Specifically, we did not find evidence for either histologic reclassification of esophageal squamous cell carcinoma or anatomic reclassification of adenocarcinoma of the gastric cardia. We also did not find evidence for overdiagnosis; the incidence of all stages increased simultaneously, and mortality increased in parallel with incidence.
It may be questioned how evaluating incidence in specific anatomic locations can clarify whether increased incidence can be explained by histologic reclassification. We believe it can, because squamous cell carcinoma originates from squamous cell epithelium and may develop anywhere in the esophagus. Adenocarcinoma, in contrast, always arises from columnar epithelium. Most esophageal adenocarcinomas develop from Barrett esophagusintestinal metaplasia that originates at the gastroesophageal junction and extends to the lower third and, less commonly, the middle and upper thirds of the esophagus. Therefore, the majority of adenocarcinomas are located in the lower third of the esophagus. We indeed found an increase in the incidence of esophageal cancers only in the lower third of the organthe site where most adenocarcinomas arise. Thus, histologic reclassification of squamous cell carcinoma represents a very unlikely explanation for the increased incidence of esophageal adenocarcinoma.
Similarly, our analysis of incidence of adenocarcinoma of the gastric cardia argues against anatomic reclassification of this cancer as a possible explanation for the increased incidence of esophageal adenocarcinoma. We found, as have others (3,5,15), that incidence of adenocarcinoma of the gastric cardia rose substantially in the 1970s and 1980s and has since stabilized. Because incidence of adenocarcinoma of the gastric cardia did not fall as that of esophageal adenocarcinoma rose, reclassification is, again, unlikely.
We believe that the pattern of the change in incidence also makes reclassification an unlikely explanation. Changes in diagnostic practice or in pathologic classification that lead to reclassification would be expected to be adopted and implemented in a relatively limited period (i.e., less then 10 years). What we observed was not a discrete change in incidence but a steady rise over the past three decades.
Another possible limitation to our study is missing or incomplete data. Of all patients with esophageal cancers, we selected only those who had a histologic diagnosis for esophageal adenocarcinoma or squamous cell carcinoma. However, these diagnoses made up 82% of all esophageal cancers in 1975 and 89% in 2001. Thus, the proportion of esophageal cancers that received other histologic diagnosis was small (18% in 1975 to 11% in 2001) and cannot explain the rising incidence in esophageal adenocarcinoma.
This study also shares the limitations of all investigations using the SEER data. The SEER 9 regions represent only approximately 10% of the U.S. population. On the other hand, these data include a broad cross-section of the population and are, without a doubt, the most representative cancer incidence data in the United States. This study also shares the limitations of any investigation using secondary data. Our inferences are wholly dependent on the quality of the underlying dataa reality that leads SEER to provide extensive training for cancer registrars and to conduct regular audits to evaluate both the quality and completeness of the data being reported (16).
Our results strongly indicate that the increase in esophageal adenocarcinoma represents a true increase in disease burden. In fact, this cancer constitutes the fastest rising malignancy in the United States. Changes in the prevalence of commonly reported risk factors [i.e., gastroesophageal reflux disease (17), increased body mass index (18,19), and low fruit and vegetable intake (18,20)] or of Helicobacter pylori infection (21,22) have been discussed as possible explanations for the increase in incidence. To explain a rise of this magnitude, however, the prevalence of a strong risk factor must also rise dramaticallyas was the case for smoking and lung cancer. Such a risk factor has not yet been identified and defining it should be a priority.
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NOTES |
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We acknowledge the contribution of our colleagues in the VA Outcomes Group. Their feedback enhanced both our thinking and the presentation of our results. H. Pohl was supported by a Veterans Affairs Special Fellowship Program in Outcomes Research. This study was also supported by a Research Enhancement Award from the Department of Veterans Affairs to investigate the harms from excessive medical care. The views expressed herein do not necessarily represent the views of the Department of Veterans Affairs.
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REFERENCES |
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1 Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E, et al. Cancer statistics, 2004. CA Cancer J Clin 2004;54:829.
2 Devesa SS, Blot WJ, Fraumeni JF Jr. Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer 1998;83:204953.[CrossRef][ISI][Medline]
3 El-Serag HB, Mason AC, Petersen N, Key CR. Epidemiological differences between adenocarcinoma of the oesophagus and adenocarcinoma of the gastric cardia in the USA. Gut 2002;50:36872.
4 Blot WJ, Devesa SS, Kneller RW, Fraumeni JF Jr. Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA 1991;265:12879.[Abstract]
5 Brown LM, Devesa SS. Epidemiologic trends in esophageal and gastric cancer in the United States. Surg Oncol Clin North Am 2002;11:23556.[Medline]
6 Black WC. Overdiagnosis: an underrecognized cause of confusion and harm in cancer screening. J Natl Cancer Inst 2000;92:12802.
7 Etzioni R, Penson DF, Legler JM, di Tommaso D, Boer R, Gann PH, et al. Overdiagnosis due to prostate-specific antigen screening: lessons from U.S. prostate cancer incidence trends. J Natl Cancer Inst 2002;94:98190.
8 Schwartz LM, Woloshin S, Welch HG. Trends in diagnostic testing following a national guideline for evaluation of dyspepsia. Arch Intern Med 1996;156:8735.[Abstract]
9 Benhamiche AM, Faivre J, Tazi AM, Couillault C, Villing AL, Rat P. Time trends in diagnostic strategy, treatment, and prognosis of gastric cancer in the elderly: a population based study. Eur J Cancer Prev 1997;6:717.[ISI][Medline]
10 Eloubeidi MA, Mason AC, Desmond RA, El-Serag HB. Temporal trends (19731997) in survival of patients with esophageal adenocarcinoma in the United States: a glimmer of hope? Am J Gastroenterol 2003;98:162733.[ISI][Medline]
11 Younes M, Henson DE, Ertan A, Miller CC. Incidence and survival trends of esophageal carcinoma in the United States: racial and gender differences by histological type. Scand J Gastroenterol 2002;37:135965.[CrossRef][ISI][Medline]
12 El-Serag HB. The epidemic of esophageal adenocarcinoma. Gastroenterol Clin North Am 2002;31:42140, viii.[ISI][Medline]
13 Botterweck AA, Schouten LJ, Volovics A, Dorant E, van Den Brandt PA. Trends in incidence of adenocarcinoma of the oesophagus and gastric cardia in ten European countries. Int J Epidemiol 2000;29:64554.
14 Ekstrom AM, Signorello LB, Hansson LE, Bergstrom R, Lindgren A, Nyren O. Evaluating gastric cancer misclassification: a potential explanation for the rise in cardia cancer incidence. J Natl Cancer Inst 1999;91:78690.
15 Kubo A, Corley DA. Marked multi-ethnic variation of esophageal and gastric cardia carcinomas within the United States. Am J Gastroenterol 2004;99:5828.[CrossRef][ISI][Medline]
16 Available at http://seer.cancer.gov/training/ and http://seer.cancer.gov/about/quality.html.
17 Lagergren J, Bergstrom R, Lindgren A, Nyren O. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 1999;340:82531.
18 Cheng KK, Sharp L, McKinney PA, Logan RF, Chilvers CE, Cook-Mozaffari P, et al. A case-control study of oesophageal adenocarcinoma in women: a preventable disease. Br J Cancer 2000;83:12732.[CrossRef][ISI][Medline]
19 Lagergren J, Bergstrom R, Nyren O. Association between body mass and adenocarcinoma of the esophagus and gastric cardia. Ann Intern Med 1999;130:88390.
20 Brown LM, Swanson CA, Gridley G, Swanson GM, Schoenberg JB, Greenberg RS, et al. Adenocarcinoma of the esophagus: role of obesity and diet. J Natl Cancer Inst 1995;87:1049.[Abstract]
21 Blaser MJ. Hypothesis: the changing relationships of Helicobacter pylori and humans: implications for health and disease. J Infect Dis 1999;179:152330.[CrossRef][ISI][Medline]
22 Graham DY. The changing epidemiology of GERD: geography and Helicobacter pylori. Am J Gastroenterol 2003;98:146270.[CrossRef][ISI][Medline]
Manuscript received July 16, 2004; revised November 17, 2004; accepted November 26, 2004.
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