Subjects and Methods. Results

Transcription

1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2006;4: ORIGINAL ARTICLES Familial Risk for Esophageal Cancer: An Updated Epidemiologic Study From Sweden JIANGUANG JI* and KARI HEMMINKI*, *Department of Bioscience at Novum, Karolinska Institute, Huddinge, Sweden; and Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany Background & Aims: Familial risks for esophageal cancer are not well known, especially for specific histologic types. Methods: We used the nationwide Swedish Family-Cancer Database to examine familial risks for esophageal cancer in offspring. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were used to calculate the risk. Age standardized incidence rates for specific histology types of esophageal cancer were available from Swedish Cancer Registry. Results: The incidence of male squamous cell carcinoma (SCC) reached its peak rate in 1985 and decreased afterwards. The incidence of adenocarcinoma exceeded that of SCC in 2000 among men. The SIR for offspring esophageal cancer was significantly increased when a parent presented with esophageal cancer (SIR, 2.60). The SIRs for adenocarcinoma were 4.05 and 3.52 when a parent was diagnosed with SCC and any esophageal cancer, respectively; from maternal probands the SIRs were and 7.74, respectively. The familial SIR was above unity but not significant for SCC. For associations with other cancer sites, SCC showed a significantly increased risk when a sibling had lung cancer (SIR, 2.52). Conclusions: The present study showed that adenocarcinoma became the major histologic type of esophageal cancer in Swedish men around For the first time we could show that familial risks of esophageal adenocarcinoma were increased when parents presented with esophageal cancer (particularly SCC). The high risk for adenocarcinoma in such families might be due to heritable effects. However, because of the limited number of familial cases, the results should be interpreted with caution. Esophageal cancer has been referred to as one of the least studied and deadliest cancers worldwide. 1 More than 90% of esophageal cancers are either squamous cell carcinomas (SCCs) or adenocarcinomas. 2 Other neoplasms, such as melanomas, leiomyosarcomas, and carcinoids, might develop in the esophagus on rare occasions. The incidence of SCC varies greatly worldwide, which might be explained mostly by smoking, alcohol drinking, and nutritional imbalances. 3 The incidence of adenocarcinoma has increased about 450% in the United States among white men and 50% among black men during the past 20 years, 4,5 and in some European countries, with an average annual increase of 1.5% in Sweden. 6 Barrett s esophagus, recurring symptoms of reflux, obesity, and smoking are the main risk factors for esophageal adenocarcinoma. 7 Because of the decreasing incidence of SCC, the overall incidence of esophageal cancer has been relatively stable in Sweden at about 7 per 100,000 in men and 2 per 100,000 in women. 8 Familial aggregation of esophageal cancer has been observed in the high incidence areas of China, with a 2-fold to 3-fold increased risk for first-degree relatives, but the roles of shared environmental factors or inherited susceptibility remain unknown Familial clustering was also noted in Sweden on the basis of the older version of the Swedish Family-Cancer Database. 12 However, negative reports on both SCC and adenocarcinoma were noted in some other studies conducted in the United States and Sweden. 13,14 Reliability of reporting might be a general problem in case-control studies for family history. 15 To examine this issue further, we examined familial risks of esophageal cancer on the basis of the newest update of the nationwide Swedish Family-Cancer Database, which covered offspring aged from 0 70 years and their parents. It offers unique possibilities for reliable estimation of familial risks because the data on family relationships and cancers were obtained from registered sources with almost complete coverage. Compared with the previous familial esophageal cancer study from this database, 12 an extended population and more familial esophageal cancer cases are available, allowing Abbreviations used in this paper: CI, confidence interval; ICD-7, International Classification of Diseases, 7th revision; SCC, squamous cell carcinoma; SIR, standardized incidence ratio 2006 by the American Gastroenterological Association Institute /06/$32.00 doi: /j.cgh

2 July 2006 FAMILIAL ESOPHAGEAL CANCER 841 analysis by specific histologic types. Associations with other cancer sites were also analyzed. To our knowledge, our study is by far the largest cohort study of familial esophageal cancer published to date. To interpret familial risks in histologic types of esophageal cancer, we assessed also the national histology-specific incidence trends of esophageal cancer. Subjects and Methods The Swedish Cancer Registry was established in According to the instructions by the National Board of Health and Welfare, all physicians in hospitals and other establishments for medical treatment under public or private admission in Sweden must report all cases of cancer (clinical report) to the Cancer Registry. Furthermore, pathologists and cytologists report every cancer diagnosis on surgically removed tissues, biopsies, cytologic specimens, bone marrow aspirates, and autopsies (pathology report) to the Registry. Thus the majority of cases are notified twice in separate reports; cancer registration is currently considered to be close to 100%. 8 Incidences of histology-specific esophageal cancers, standardized according to the Swedish standard population as of December 31, 2000, were available in the Swedish Cancer Registry from years Statistics Sweden maintains a Multigeneration Register in which children, offspring, born in Sweden in 1932 (maximally 70 years old) and later are registered with their parents, and they are organized as families. It is worth pointing out that the parents are registered at the time of birth of the child, and it is possible to track biological parents, despite divorce and remarriage. 16 Of course, false paternity cannot be excluded, but, if present, results would be biased toward null. The Multigeneration Register was linked by using the individually unique national registration number to the Cancer Registry to establish the Swedish Family-Cancer Database. All data in the Family-Cancer Database were accrued by register linkages, and thus reporting bias, common in interview studies, was not present. Information on the Database is also available at the Nature Genetic website as Supplementary information to reference. 17 The Database was updated in 2004 and included cancer cases from The data on families and cancers have a complete coverage, barring some groups of deceased offspring, which affected those born during the 1930s and those who died before Although this small group of offspring with missing links to parents has a negligible effect on the estimate of familial risk, 18 we limited the present study to offspring whose parents were known to eliminate the possibility of bias. A 4-digit diagnosis code according to the 7th revision of the International Classification of Diseases (ICD-7) has been used. The following ICD-7 codes were grouped: upper aerodigestive tract cancer codes 161 (larynx) and (lip, mouth, pharynx), except for code 142 (salivary glands); non-hodgkin s lymphoma codes 200 and 202; and leukemia codes (leukemias), 208 (polycythemia vera), and 209 (myelofibrosis). Rectal cancer, ICD-7 code 154, was subdivided into the anus (squamous cell carcinoma, 154.1) and mucosal rectum (154.0). Basal cell carcinoma of the skin is not registered in the Cancer Registry. Only the first primary esophageal cancer was considered in the present study. According to ICD-7 classification, lymphomas, including esophageal lymphomas, are classified as lymphomas irrespective of the site at which they occur. The histologic classification was used to define adenocarcinoma, pathologic anatomic diagnosis code 096, and SCC, code 146. Information on family history was collected on all firstdegree relatives (parents, siblings, and children), but only parent-offspring relationship was used for concordant esophageal cancer because of the lack of affected sibling pairs. Sibling relationship was used for discordant cancer sites. Standardized incidence ratios (SIRs) were used to measure the cancer risks for offspring according to the occurrence of cancers in their families. The follow-up was started for each offspring at birth, immigration, or on January 1, 1961, whichever was the latest time. Follow-up was terminated at the diagnosis of first cancer, death, emigration, or the closing date of the study on December 31, Parents ages were not limited, but offspring were 0 70 years of age. SIRs were calculated as the ratio of observed (O) to expected (E) number of cases. The expected numbers were calculated from 5-year age-specific, gender-specific, tumor type specific, period-specific, socioeconomic status specific (6 groups), and residential area specific (3 groups) standard incidence rates for all offspring lacking a family history. 19 Confidence intervals (95% CIs) were calculated by assuming a Poisson distribution, and they were rounded to the nearest 2 decimals. 19 Risks for siblings were calculated by using the cohort method in this study, which considers each sibling separately and is practically independent of the number of siblings. 20 Results The incidence trends for the 2 common histologyspecific esophageal cancers, SCC and adenocarcinoma, from the Swedish Cancer Registry are shown in Figure 1 for years The incidence of male SCC reached its peak rate in 1985 and decreased afterwards. Adenocarcinoma became the main histologic type in 2000 among men because of its continually increasing rate, but the rates fluctuated somewhat. The trends for women showed a pattern similar to men, but the changes in rates were more moderate. In 2003, there was a 2.6-fold male excess in SCC and 5.3-fold excess in adenocarcinoma. The Swedish Family-Cancer Database, which covered , included 866 esophageal cancer cases in offspring (0 70 years) and 6141 cases in parents (Table 1). SCC accounted for 65.5% and adenocarcinoma for 23.2% in parents, whereas in offspring the proportions were 54.9% and 37.6%, respectively. The median ages of onset were almost identical for SCC and adenocarcinoma;

3 842 JI AND HEMMINKI CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 7 6 Incidence rate/ person years Diagnosis year Figure 1. Age standardized incidence of esophageal adenocarcinoma and SCC in men and women from Swedish Cancer Registry for , Male adenocarcinoma;, male SCC;, female adenocarcinoma;, female SCC. however, the offspring generation with the truncated age structure showed an earlier age of onset than the parental generation (56 years in offspring vs 68 years in parents). Histology-specific familial risk for esophageal cancer was analyzed by using parents as proband (Table 2). The data in this and subsequent tables were adjusted for age, period, residential area, sex, and socioeconomic status. The overall SIR was significantly increased when a parent presented with esophageal cancer (SIR, 2.60). The risk for esophageal cancer was higher (3.81) when mothers were probands compared with paternal probands (2.14). The SIRs for esophageal adenocarcinoma were 4.05 and 3.52 when a parent was diagnosed with SCC and any esophageal cancer, respectively. These risks were mainly due to maternal probands with an SIR of and 7.74, respectively; 2 of the offspring cases were male patients. The SIR for SCC was not significant, although it was above unity. No sibling pairs with concordant esophageal cancer were observed. Associations for discordant cancer sites were further analyzed by using parents as probands, but because no association was significant, data are not shown. Associations between discordant sites in siblings are shown in Table 3. Only those cancer sites with at least 3 offspring esophageal cancers are listed. A significantly increased risk for esophageal cancer was noted when a sibling had lung cancer (SIR, 2.18), particularly SCC (2.52). Discussion One of the most notable changes for esophageal cancer is the increasing incidence of adenocarcinoma in many Western countries during the past 2 decades. 6,7,21 The male-to-female ratio for adenocarcinoma is extremely high, with a reported ratio of about 7:1 4 ; in our study, the ratio was about 5:1 in The number of patients with adenocarcinoma exceeded that of patients with SCC in 1994 for the first time in the United States Table 1. Number of Cases for Specific Histologic Types of Esophageal Cancer Parent Offspring Father Mother All Son Daughter All Histologic types No. % age (y) SCC Adenocarcinoma Others All

4 July 2006 FAMILIAL ESOPHAGEAL CANCER 843 Table 2. SIR for Specific Histologic Types of Esophageal Cancer in Offspring of Parental Proband a Histologic types in proband SCC Adenocarcinoma All types O SIR 95% CI O SIR 95% CI O SIR 95% CI Father proband SCC Adenocarcinoma All types Mother proband SCC Adenocarcinoma All types Parental proband SCC Adenocarcinoma All types NOTE. Boldface shows that 95% CIs do not overlap with O, observed. a All expected numbers were calculated on age, gender, period, residence, and socioeconomic level specific incidence. according to the Johns Hopkins tumor registry data. 22 A subsequent article from the National Cancer Institute s Surveillance, Epidemiology and End Results program confirmed that the incidence of adenocarcinoma among white men has surpassed that of SCC. 5 In Sweden, according to the present data from the population-based Cancer Registry, adenocarcinoma became the most common histologic type of esophageal cancer among men around It has been suggested that gastroesophageal reflux, with medications that might cause reflux and obesity, could explain the increasing incidence. 7 However, the large sex difference in esophageal adenocarcinoma cannot be rationalized by the major risk factors listed above. The incidence rate of SCC has been steady or declining in the geographical areas listed above. 5,21 In Sweden, the incidence of SCC has decreased greatly among men since 1985, but the rate remained relatively stable among women. Epidemiologic evidence suggests that lifestyle modifications, such as a reduction of alcohol and tobacco use and an increased dietary use of fruits and Table 3. Risk for Esophageal Cancer in Siblings a SCC Adenocarcinoma All cancer Cancer site in siblings O SIR 95% CI O SIR 95% CI O SIR 95% CI Upper aerodigestive tract Stomach Corpus Cardia Colon Rectum Pancreas Lung Breast Cervix Endometrium Prostate Urinary bladder Melanoma Skin Nervous system Endocrine glands Non-Hodgkin s lymphoma Leukemia All NOTE. Boldface shows that 95% CIs do not overlap with O, observed. a All expected numbers were calculated on age, gender, period, residence, and socioeconomic level specific incidence.

5 844 JI AND HEMMINKI CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 7 vegetables, would decrease the incidence of SCC. 21 Among these risk factors, tobacco smoking has reduced greatly in Swedish men but not in women. 23 Familial risk of esophageal cancer was examined in the present population up to age 70 years. The markedly increased incidence of esophageal adenocarcinoma and decreased incidence of SCC during the study period might be a source of bias, but the adjustment for period should have minimized this problem. Other limitations of the present study were the small number of familial patients and the lack of data on Barrett s esopahgus. Familial clustering of esophageal cancer might be the result of heredity, shared environmental effects, or a combination of the two. 24 The effect of the shared environment has been assessed by comparing cancer risks between spouses from this database; spouse concordance was only noted for stomach and lung cancers, and melanoma and pancreatic cancer if diagnosed at an early age, 25 suggesting that shared environmental effects were small between spouses for esophageal cancer. Lifestyles are likely to differ more between parents and offspring than between spouses. 26 On the basis of these data, we can speculate that familial aggregation of esophageal cancer is unlikely to be due to environmental factors alone. The risk to offspring was significantly increased, 2.60, from concordant parental esophageal cancer. The magnitude of increase agreed with the data from the high incidence area in China. 9 However, the histology types were not reported in the Chinese study, but they were probably SCC because of the prevalence of this histologic type in north China. 27 In the present study, the familial risk for SCC was not significant, although the SIR was Familial risk of esophageal cancer was mainly attributable to adenocarcinoma in our study. The SIRs for adenocarcinoma were significantly increased when a parent presented with SCC (4.05) and any esophageal cancer (3.52). The risk was mainly attributable to maternal probands (10.47 for mothers SCC and 7.74 for all types of esophageal cancer); however, the SIRs were based on 3 mother-offspring pairs only. Although none of the affected parents were diagnosed with adenocarcinoma, familial risk might be independent of parental histologic types, because earlier studies have shown that there appeared to be no large difference in familial risks for lung, breast, and testicular carcinomas between the different histologic types Moreover, because of the major changes in histologic types, the offspring generation has few SCCs, and, conversely, the parental generation has few adenocarcinomas. Most esophageal adenocarcinomas are thought to originate from Barrett s esophagus. 31 Clusters of Barrett s esophagus and esophageal adenocarcinoma in multi-generation families have been reported earlier In a recent study familial risks were reported for combined diagnoses of Barrett s esophagus, esophageal adenocarcinoma, and esophagogastric junctional adenocarcinoma. 35 Unfortunately, we had no data on Barrett s esophagus. Previous studies have suggested that an autosomal dominant gene is responsible for familial Barrett s esophagus. 32,33,36 Several molecular changes have been identified for Barrett s esophagus and esophageal adenocarcinoma. 37 Associations with discordant cancer sites were also tested. With an increasing number of tests, chance findings might be unavoidable. Biologic plausibility and consistency with previous findings might be used to exclude chance associations. No parent-offspring aggregation was found for discordant cancer sites. Only SCC showed an increased risk when a sibling was diagnosed with lung cancer, probably explainable by smoking. In conclusion, the present study showed that adenocarcinoma became the major histologic type of esophageal cancer among men about 2000 because of the continuously increasing incidence. Familial risks for specific histologic types showed a significantly increased risk for esophageal adenocarcinoma, a novel observation, and a nonsignificant risk for SCC. The high risk for adenocarcinoma, with an SIR of 4.05 and 3.52 when a parent was diagnosed with SCC and any esophageal cancer, respectively, might be due to heritable effects, assuming that shared environmental effects were small, and familial risk was not histology-specific. However, the small number of familial cases is an essential limitation even for this nationwide study. References 1. Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med 2003; 349: Daly JM, Fry WA, Little AG, et al. Esophageal cancer: results of an American College of Surgeons Patient Care Evaluation Study. J Am Coll Surg 2000;190: Hamilton SR, Aaltonen LA. World Health Organization classification of tumours: pathology and genetics of tumours of the digestive system. Lyon, France: IARC Press, Blot WJ, Devesa SS, Kneller RW, et al. Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA 1991; 265: Devesa SS, Blot WJ, Fraumeni JF Jr. Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer 1998;83: Hansson LE, Sparen P, Nyren O. Increasing incidence of both major histological types of esophageal carcinomas among men in Sweden. Int J Cancer 1993;54: Lagergren J. Adenocarcinoma of oesophagus: what exactly is the size of the problem and who is at risk? Gut 2005;54(Suppl 1):i1 i5. 8. Center for Epidemiology. Cancer incidence in Sweden 2000.

6 July 2006 FAMILIAL ESOPHAGEAL CANCER 845 Stockholm, Sweden: The National Board of Health and Welfare, Chang-Claude J, Becher H, Blettner M, et al. Familial aggregation of oesophageal cancer in a high incidence area in China. Int J Epidemiol 1997;26: Wang YP, Han XY, Su W, et al. Esophageal cancer in Shanxi Province, People s Republic of China: a case-control study in high and moderate risk areas. Cancer Causes Control 1992;3: Li JY, Ershow AG, Chen ZJ, et al. A case-control study of cancer of the esophagus and gastric cardia in Linxian. Int J Cancer 1989; 43: Hemminki K, Jiang Y. Familial and second esophageal cancers: a nation-wide epidemiologic study from Sweden. Int J Cancer 2002; 98: Lagergren J, Ye W, Lindgren A, et al. Heredity and risk of cancer of the esophagus and gastric cardia. Cancer Epidemiol Biomarkers Prev 2000;9: Dhillon PK, Farrow DC, Vaughan TL, et al. Family history of cancer and risk of esophageal and gastric cancers in the United States. Int J Cancer 2001;93: Hemminki K, Rawal R, Chen B, et al. Genetic epidemiology of cancer: from families to heritable genes. Int J Cancer 2004;111: Hemminki K, Li X, Plna K, et al. The nation-wide Swedish familycancer database: updated structure and familial rates. Acta Oncol 2001;40: Hemminki K, Granstrom C. Risk for familial breast cancer increases with age. Nat Genet 2002;32: Dong C, Hemminki K. Modification of cancer risks in offspring by sibling and parental cancers from 2,112,616 nuclear families. Int J Cancer 2001;92: Esteve J, Benhamou E, Raymond L. Statistical methods in cancer research. Lyon, France: IARC, Hemminki K, Vaittinen P, Dong C, et al. Sibling risks in cancer: clues to recessive or X-linked genes? Br J Cancer 2001;84: Pera M. Recent changes in the epidemiology of esophageal cancer. Surg Oncol 2001;10: Heitmiller RF, Sharma RR. Comparison of prevalence and resection rates in patients with esophageal squamous cell carcinoma and adenocarcinoma. J Thorac Cardiovasc Surg 1996;112: Li X, Mutanen P, Hemminki K. Gender-specific incidence trends in lung cancer by histological type in Sweden, Eur J Cancer Prev 2001;10: Petersen GM. Familial aggregation: sorting susceptibility from shared environment. J Natl Cancer Inst 2000;92: Hemminki K, Dong C, Vaittinen P. Cancer risks to spouses and offspring in the Family-Cancer Database. Genet Epidemiol 2001;20: Hemminki K, Jiang Y. Cancer risks among long-standing spouses. Br J Cancer 2002;86: Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of eighteen major cancers in Int J Cancer 1993;54: Hemminki K, Li X. Familial risk for lung cancer by histology and age of onset: evidence for recessive inheritance. Exp Lung Res 2005;31: Hemminki K, Li X. Familial risk in testicular cancer as a clue to a heritable and environmental aetiology. Br J Cancer 2004;90: Hemminki K, Granstrom C. Familial breast carcinoma risks by morphology: a nationwide epidemiologic study from Sweden. Cancer 2002;94: Cameron AJ, Lomboy CT, Pera M, et al. Adenocarcinoma of the esophagogastric junction and Barrett s esophagus. Gastroenterology 1995;109: Eng C, Spechler SJ, Ruben R, et al. Familial Barrett esophagus and adenocarcinoma of the gastroesophageal junction. Cancer Epidemiol Biomarkers Prev 1993;2: Fahmy N, King JF. Barrett s esophagus: an acquired condition with genetic predisposition. Am J Gastroenterol 1993;88: Jochem VJ, Fuerst PA, Fromkes JJ. Familial Barrett s esophagus associated with adenocarcinoma. Gastroenterology 1992;102: Chak A, Lee T, Kinnard MF, et al. Familial aggregation of Barrett s oesophagus, oesophageal adenocarcinoma, and oesophagogastric junctional adenocarcinoma in Caucasian adults. Gut 2002; 51: Poynton AR, Walsh TN, O Sullivan G, et al. Carcinoma arising in familial Barrett s esophagus. Am J Gastroenterol 1996;91: Souza RF, Meltzer SJ. The molecular basis for carcinogenesis in metaplastic columnar-lined esophagus. Gastroenterol Clin North Am 1997;26: Address requests for reprints to: Jianguang Ji, MD, Department of Bioscience at Novum, Karolinska Institute, Huddinge, Sweden. jianguang.ji@biosci.ki.se; fax: Supported by Deutsche Krebshilfe, the Swedish Cancer Society and the EU, LSHC-CT The Family-Cancer Database was created by linking registers maintained at Statistics Sweden and the Swedish Cancer Registry.