THE EPIDEMIOLOGY of NASOPHARYNGEAL CARCINOMA Chee Khoon Chan, M.S. a Thesis Submitted to the Faculty of the Harvard School of L'
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THE EPIDEMIOLOGY OF NASOPHARYNGEAL CARCINOMA Chee Khoon Chan, M.S. A Thesis Submitted to the Faculty of The Harvard School of l'ublic Health ; -. ., . .~ !. in Partial Fulfillment of the Requirements for the Degree of Doctor of Science in the Field of Epidemiology Boston, Massachusetts December 1990 ~692~6 \2-C- 't((O r'~ ~lf ~v ii This thesis has been read and approved by -----~~~--------- ___ 1)_~---~~~---------- -----~---~~------- iii Preface .... Greatly mourned by his wife but without children, Law had died in a private hospital of the nasopharyngeal cancer so prevalent on the southern coast, caused by a lifetime's inordinate consumption of the dried salt fish he had loved so much ..... Timothy Mo, in Sour Sweet (p. 43, Abacus, 1983) Novelists rush in where epidemiologists fear to tread. The point of the above quote is not just to note that literary license provides for a degree of freedom not available to epidemiologists, but also that the salted fish hypothesis in NPc·etiology was sufficiently known, if not among the general populace of southern China, then at least among the literary public. This may not have had much impact on the case-control findings on salted fish consumption, but it does argue for some caution in appraising that literature. I wish to record my appreciation and gratitude to Dr. Nancy Mueller, my thesis committee chairperson, and to Dr. Walter Willett and Dr. Anastasios Tsiatis, who also served on iv the committee. Their support and counsel, together with that of Dr. Dimitrios Trichopoulos, Dr. Fran Cook, Dr. c.c. Hsieh, and other friends in the Epidemiology Department, were crucial in seeing me through the more difficult moments of this thesis. I am grateful to the Science University of Malaysia for a staff training fellowship which supported me through 4 years of doctoral studies. The Insti tut Pasteur de Lyon also provided generous support for a year's research work in France. Chee Khoon Chan v Table of contents Title Page ................................... i Preface . ..................................... iii Table of Contents ........•...........•........ v List of Figures . ............................. vi List of Tables . .............................. vii Epstein-Barr virus antibody titers preceding the diagnosis of nasopharyngeal carcinoma............ 1 Dietary risk factors for nasopharyngeal carcinoma A case-control study in Zangwu County, Guangxi Autonomous Region, People's Republic of China... 26 The epidemiology of nasopharyngeal carcinoma A review. 66 vi List of Figures Epstein-Barr virus antibody patterns preceding the diagnosis of nasopharyngeal carcinoma Figure 1 Anti-VCA/IgG antibody titers preceding diagnosis of nasopharyngeal carcinoma Figure 2 Anti-VCA/IgA antibody titers preceding diagnosis of nasopharyngeal carcinoma vii List of Tables Epstein-Barr virus antibody patterns preceding the diagnosis of nasopharyngeal carcinoma Table 1 Epstein-Barr virus antibody titers of NPC patients and matched controls Table 2 Prevalence of elevated titers and geometric mean titers of antibodies against Epstein Barr virus among NPC patients and controls Table 3 Summary of findings of previous studies on EBV serology in NPC patients prior to diagnosis of nasopharyngeal carcinoma Dietary risk factors for nasopharyngeal carcinoma A case-control study in Zangwu County, Guangxi Autonomous Region, People's Republic of China Table 1 Childhood living conditions, current income & risk for NPC Table 2 Weaning foods & risk for NPC Table 3 Childhood diet (age 2-10 yrs) & risk for NPC Table 4 Childhood dietary risks for NPC -- Estimates for subjects with living parent(s) compared to all-subject estimates Table 5 Adult diet (two decades ago) & risk for NPC Table 6 Multivariate analysis of dietary risk factors for NPC viii The epidemiology of nasopharyngeal carcinoma A review Table 1 Age-standardised NPC incidence rates for selected countries Table 2 HLA antigens associated with risk for NPC Table 3 Epstein-Barr virus antigens detected in nasopharyngeal carcinoma Table 4 Salted fish consumption & risk for NPC Table 5 Environmental inhalants & risk for NPC Table 6 EBV antibody titers preceding diagnosis of NPC Epstein-Barr Virus Antibody Patterns Preceding the Diagnosis of Nasopharyngeal Carcinoma 1 2 Chee Khoon Chan, Ms • 1 3 Nancy Mueller, ScD ' Alfred Evans, MD, MPH4 Nancy L. Harris, MD5 and members of the EBV-NPC collaboration (in alphabetical order) George W. Comstock, MD, DrPH6 Egil Jellum, MD7 Knut Magnus, PhD8 Norman Orentreich, MD9 B. Frank Polk, MD6 ·* Joseph Vogelman, PhD6 1. Department of Epidemiology, Harvard School of Public Health, 677 Huntington Ave., Boston, MA 02115. 2. Science University of Malaysia. 3. To whom reprints requests should be addressed. 4. Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT. 5 Department of Pathology, Massachusetts General Hospital, Boston, MA. 6 Department of Epidemiology, School of Hygiene & Public Health, Johns Hopkins University, Baltimore, MD. 7. University Institute for Clinical Biochemistry, Rikshospitalet, Oslo, Norway. 8. Cancer Registry of Norway, Oslo, Norway. 9. The Orentreich Foundation for the Advancement of Science, New York, NY. * Deceased This study was supported by PHS grants CA31747, CA30433, BRSG RR05446, BRSG RR05443, National Institutes of Health, Department of Health & Human Services and by a staff training fellowship from the Science University of Malaysia to C.K. Chan. The follow-up of the HDFP study population is supported by PHS grant CA34937. 2 Acknowledgements We are indebted to Dr. Diana Petitti of the Division of Research, Permanente Medical Group for her participation in this study. We also wish to thank Mrs. Rose Udin and Mrs. Sylvia Feinson at Harvard and Ms Linda Cenabra and Ms Betty Olson at Yale, and Dr. Robert Chambers, former Director of Laboratories, Washington County Hospital. 3 Abstract Nasopharyngeal carcinoma (NPC) patients have elevated IgG and IgA antibody titers against the Epstein-Barr viral capsid antigen (VCA) and the diffuse component of the early antigen complex (EA-D) at diagnosis. Several studies have implied that the presence of anti-VCA-lgA can be used as a screening marker for early NPC. To evaluate this further, we undertook a serologic case-control study based on four serum banks which together had specimens from over 240,000 persons. Seven cases of undifferentiated or poorly differentiated NPC were diagnosed in the period after serum collection ranging from 26 months to 154 months. Two controls per case matched on serum bank, age, sex, race, and date of serum collection were selected by a pre-determined random process. For anti-VCA-IgG, the geometric mean titer for cases (88.3) was significantly higher than that for controls (75.5) (p < 0.05). The difference was greatest among the Asian patients. No significant differences were found for anti-VCA-IgA, anti-EA-D, anti-EA-R or anti EBNA. No time effects were evident when titers were plotted against time of blood collection preceding diagnosis. Our results do not suggest EBV activation in the period preceding NPC diagnosis, nor that detectable IgA antibody against VCA is a marker for early disease. key words Nasopharyngeal carcinoma, Epstein-Barr virus, serological screening 4 The Epstein-Barr virus (EBV) has been consistently associated with the occurrence of undifferentiated and poorly differentiated nasopharyngeal carcinoma (NPC). NPC patients from around the world, at or following diagnosis, often have high IgG titers against the viral capsid antigen (VCA) and the diffuse component of the EBV early antigen complex (EA-D) but not the restricted (EA-R) (de Schryver et al., 1969, 1974; Henle, w. et al., 1970, 1973; Lin et al., 1971; Henderson et al., 1974). In contrast, patients with carcinomas of the oropharynx or hypopharynx or tumors of the nasopharynx other than carcinomas usually have much lower titers. IgA titers against the VCA and the EA-D are also markedly elevated in the sera and saliva of NPC patients (Wara et al., 1975; Henle, G. et al., 1977). Elevated titers against an EBV-specific DNase has also been reported (Cheng et al., 1980). Nucleic acid hybridization consistently demonstrated the presence of EBV-DNA in NPC biopsies (zur Hausen et al., 1970, 1974; Nonoyama et al., 1973), and specifically in the anaplastic or poorly differentiated carcinoma cells (Wolf et al., 1973, 1975; Desgranges et al., 1975). Biopsies from carcinomas at other sites of the head and neck and from other types of tumors of the nasopharynx have been mostly negative for EBV-DNA (Andersson-Anvret et al., 1977). The EBV-associated nuclear 5 antigen (EBNA) is also detected in anaplastic NPC cells, but not in the lymphoid elements of the tumor (Wolf et al., 1973, 1975; Huang et al., 1974; Klein et al., 1974; Desgranges et al., 1975). These findings have prompted much interest in the potential of EBV serologic markers -- in particular IgA antibodies against VCA -- as screening aids in early detection of NPC (Zeng, 1985). The data on EBV serology prior to diagnosis is sparse, and the temporal relationship between altered EBV serological profile and emergence of disease remains obscure. One clinical report, and three other studies have yielded conflicting results (Ho et al., 1978; Lanier et al., 1980; Zeng et al., 1985; Chen et al., 1985). The purpose of this study is to evaluate the pattern of pre-diagnosis EBV antibodies in a series of NPC patients. MATERIALS AND METHODS The study population and selection process as well as details of the serologic assays have been previously described (Mueller et al., 1990). Two controls were identified for each case. Biopsy slides were requested for all NPC cases for review by one of us (NLH). The slides were reviewed without knowledge of the previous diagnosis or clinical findings. 6 statistical Analyses The relative risk (RR) associated with elevated anti EBV titers, for subsequent occurrence of nasopharyngeal carcinoma, was estimated using conditional logistic regression. The criteria for elevation were taken at the 80th (or closest) percentile for titer distributions of controls.