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Biologic Characteristics of Esophageal Epithelial Dysplasia Assessed by Proliferating Cell Nuclear Antigen

read with interest the paper by Koga et al.' Their study indicated I that the proliferating cell nuclear antigen (PCNA) may be a useful biomarker for esophageal dysplasia. It therefore follows that the pres- ence of PCNA should be taken as seriously as the clinical diagnosis of esophageal carcinoma. I write to give a pharmacologic perspective on this important conclusion.

There i,s good evidence that nonsteroidal antiinflammatory drugs (NSAIDs), such as aspirin, reduce the risk of esophageal carcinoma.* NSAIDs inhibit prostaglandin E2 (PGE2) synthesis and PGE2 synthesis also appears to be proportional to the rate of esophageal mucosal pr~liferation.~ The protective mechanism of NSAIDs may thus be re- lated to the inhibition of carcinostimulant PGE2 that is produced in excessive amounts by precancerous esophageal lesions. NSAID chem- oprevention may therefore be viduable in patients at high risk of esophageal carcinoma, and the dysplastic PCNA patients described by Koga et al. represent a good trial cohort. Despite this, PCNA and PGE2 activities have not been simultaneously measured in patients with esophageal dysplasia and I believe such studies are warranted. The results of studies that correlate PCNA and PGE2 activities could provide strong justification for randomized NSAID chemoprevention trials in patients with esophageal dysplasia.

REFERENCES 1. Koga Y, Kuwano H, Sugimachi K. Biological characteristics of esophageal epi-

thelial dysplasia assessed by proliferating cell nuclear antigen. Cancer

Morgan GP. NSAIDs and the chemoprevention of colorectal and oesophageal cancer. Guf 1996;38:646-8. Morgan GP. Deleterious effects of prostaglandin E2 in reflux esophagitis. Med Hypothe~~es 1996; 46:42- 4.

1996; 77:237-44. 2.

3.

Gareth Morgan, M.D. Pharmaceutical Department

West Glamorgan Health Authority

Swansea, South Wales Wales

Author Reply e appreciate the useful comments of Dr. Morgan on our article. W In clinical studies of esophageal lesions, esophagitis,' Barrett's

esophagus,' and dysplasia3 were suggested to be precancerous condi- tions of the esophagus. In a high incidence area of esophageal carci-

0 1996 American Cancer Society

Correspondence 151 5

noma in the Republic of China, the incidence of esophagitis and dysplasia coexistent with esophageal caircinoma was found to be quite high.' There was a close relationship between dysplasia and esophagitis and esophageal carcinoma, and inflammatory esopha- geal change was one of the causes of esophagitis and esophageal dysplasia. Our serial studies revealed that esophageal dysplasia was closely correlated with ma- lignancy, using cytophotometric DNA analysis4 and immunohistochemical proliferating cell nuclear anti- gen (PCNA)' analysis to assess esophageal lesions. We ha.ve mentioned that esophageal epithelial dysplasia, especially severe dysplasia, could be considered as se- rious a lesion as carcinoma.

It is of great interest that nonsteroidal antiin- flammatory drugs (NSAIDs), such as aspirin, may re- duce the incidence of esophageal mucosal prolifera- tion and be protective regarding esophageal carci- noma. As Dr. Morgan recommended, assay of carcinostimulant prostaglandin E2 (PGE2) for patients with esophagitis or esophageal dysplasia would be good cohort studies. We do not have the preliminary data regarding a relationship between PCNA expres- sions on precancerous esophageal lesions and PGE2 activities. Thus, we would like to measure PCNA inten- sity and PGE2 activities in patients with esophagitis or dysplasia and evaluate the effects of NSAID chemo- prevention for esophageal carcinoma.

Thank you for the opportunity to respond to Dr. Morgan's comments.

REFERENCES 1.

2.

3.

4.

5.

Qiu S, Yang G. Precursor lesions of esophageal cancer in high-risk populations in Henan Province, China. Cancer

Hameeteman W, Tytgat GNJ, Houthoff HJ, Tweel JG. Barrett's esophagus: development of dysplasia and adenocarcinoma. Gastroenterolo~~ 1989; 96:1249-56. Jacob P, Kahrilas PJ, Desai T, Hidvegi D, Walloch J, Yokoo H, et al. Natural history and significance of esophageal squa- mous cell dysplasia. Cancer 1990;65:273 1-9. Koga Y, Sugimachi K, Kuwano H, Mori M. Matsufuji H. Cyto- photometric DNA analysis of esophageal dysplasia and car- cinoma induced in rats by N-methyl-N-amylnitrosamine. Eur J Cancer Clin Oiicol 1988;24:643-51. Koga Y, Kuwano H, Sugimachi K. Biologic characteristics of esophageal epithelial dysplasia assessed by proliferating cell nuclear antigen. Carzcer 1996;77:237-44.

1988; 62:551-7.

Yoshihiko Koga, M.D. Hiroyuki Kuwano, M.D. Keizo Sugimachi, M.D.

Department of Surgery I1 Faculty of Medicine

Kyushu University Fukuokn, Japan

Risk Factors for Gallbladder Cancer

An International Collaborative Case- Control Study

n interesting case-control study on gallbladder can- A cer, conducted in Bolivia and Mexico, two high inci- dence countries for this cancer, appeared recently in Cancer.' Aymara race was postulated to be the main risk factor and constitutes a challenging finding, espe- cially its correlation with language. Unfortunately, Na- tive American ancestry cannot be examined in most case-control studies around the The differing risk between Quechuas and Aymaras could be due to differences in education, disease perception, or accessi- bility to medical care, resulting in delays in the diagnosis and treatment of gallstones, a widely accepted risk fac- tor? Race may be considered a marker variable, like poverty, so we would like to know more about the ap- parent lack of correlation of gallbladder cancer with ed- ucation. Educational attainment appeared so relevant in a recent Polish study that all other variables were adjusted to it.3 Two Chilean articles also suggest low educational attainment as a risk factor,'^^ probably due to its relationship to lower socioeconomic status and delayed access to cholecystectomy. There is evidence that low rates of cholecystectomy in a population are associated with high mortality for gallbladder cancer.'- '' We agree with Dr. Strom et al. that sample size may have limited the power of the analysis in some cases.

Chile has the highest mortality rate for gallbladder cancer in the Moreover, mortality trends in Chile document a sharp and constant increase over the last two decades, a very unusual behavior for a chronic disease.I3 The two above-mentioned Chilean case-con- trol studies postulate as risk factors for gallbladder can- cer, in addition to low education or delayed disease recognition, parity and duration of unoperated gall- stones. One of the studies, with 90 cases,' also found chili pepper consumption to have an odds ratio (OR) of 3.17 (95% confidence interval [CI] 1.79-5.63), and a similar association recently has been found with gastric cancer.I4 A final analysis with 114 cases is in progress.

We would like Dr. Strom et al. to clarify whether mothers who breast fed one child did exactly that, or did they have only one delivery? Why was parity not an issue? Was chili consumption evaluated? Could the authors expand their reasons for not exploring gallstone disease as a risk factor for gallbladder cancer? We think that it would be useful to analyze separately in certain cases both types of controls, with and without gall- stones, despite their similarity, to better clarify the role of gallstones. In our series, patients who had a ne-