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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Hisada, M. Articles by Travis, L. B. Search for Related Content PubMed PubMed Citation Articles by Hisada, M. Articles by Travis, L. B. Related Collections Brief Reports Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 September 2001, Vol. 98, No. 6, pp. 1979-1981 BRIEF REPORT Solid tumors after chronic lymphocytic leukemia Michie Hisada, Robert J. Biggar, Mark H. Greene, Joseph F. Fraumeni Jr, and Lois B. Travis From the Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.     Abstract Top Abstract Introduction Study design Results and discussion References Prior reports indicate that patients with chronic lymphocytic leukemia (CLL) may be at increased risk of subsequent neoplasms. This study quantified the risk of second cancers among 16 367 patients with CLL in the population-based Surveillance, Epidemiology and End Results Program. Overall, the observed/expected ratio (O/E) was 1.20 (95% confidence interval [CI], 1.15-1.26). Second cancer risks for patients who received chemotherapy only as the first course of treatment (O/E = 1.21) were similar to risks for those who received no treatment initially (O/E = 1.19). Significant excesses were found for Kaposi sarcoma (O/E = 5.09), malignant melanoma (O/E = 3.18), and cancers of the larynx (O/E = 1.72) and the lung (O/E = 1.66). Increased risks were also found for brain cancer among men (O/E =1.91) and for cancers of the stomach (O/E = 1.76) and bladder (O/E = 1.52) among women. Additional investigations of cancers after CLL are needed to explore the role of immunologic impairment and/or other etiologic influences. (Blood. 2001;98:1979-1981) © 2001 by The American Society of Hematology.     Introduction Top Abstract Introduction Study design Results and discussion References Chronic lymphocytic leukemia (CLL) is a malignancy of mature B lymphocytes of unknown etiology.1 Prior studies have reported that site-specific excesses of second cancer may exist among patients with CLL.2,3 Patterns of subsequent neoplasms in these individuals may provide insight into etiologic factors associated with both malignancies. In the present study, we describe the risk of second cancers among a large number of patients with CLL reported to the population-based cancer registries that comprise the Surveillance, Epidemiology and End Results (SEER) Program.     Study design Top Abstract Introduction Study design Results and discussion References Patients and methods Included in the present analysis are 16 367 patients with CLL registered in the SEER Program between 1973 and 1996. Data describing 9456 of these patients, diagnosed through 1988, were reported in a previous publication.3 Follow-up for this subgroup is now updated from 1989 to 1996. Person-years of observation began from 2 months after the date of CLL diagnosis to the date of last follow-up, death, diagnosis of a second cancer, or the end of the study (December 31, 1996), whichever occurred first. Expected numbers of cancers were estimated from the multiplication of the SEER incidence rates specific for 5-year age, sex, race, and 5-year calendar year intervals by the accumulated person-years at risk. Risk of second cancers was estimated as the ratio of observed to expected number of cases (O/E) with 95% confidence intervals (CI), assuming a Poisson distribution. Cancer sites were classified according to the World Health Organization's International Classification of Diseases for Oncology, Second Edition.4 For our analysis, we compared the 2 largest treatment groups, ie, those who received chemotherapy only as initial therapy and those who did not receive treatment. Neither information on subsequent courses of therapy nor information regarding the specific chemotherapeutic agents with which patients were initially treated was available in the SEER Program. As a surrogate, the study period was divided into 1973-1989 and 1990-1996; the former represents an era before the widespread use of nucleoside analogs for CLL, whereas in the latter period the greater availability of those cytotoxic agents made it more likely that patients with CLL may have received them.5,6 Diagnoses of secondary lymphopoietic malignancies that may represent transformation of CLL7 were excluded from the analyses.     Results and discussion Top Abstract Introduction Study design Results and discussion References Overall, 16 367 patients with CLL, including 5-year survivors (7024) and 10-year survivors (2479), were evaluated for second cancer risk, accumulating a total of 84 667 person-years of follow-up (Table 1). The mean age at diagnosis was 69.7 years, and the average follow-up was 5.2 years. Second cancers occurred in 1820 patients (O/E = 1.20; 95% CI, 1.15-1.26). Risks of subsequent neoplasms in the < 1 year, 1-4 year, 5-9 year, and  10 year intervals following CLL diagnosis were 1.25, 1.25, 1.14, and 1.16, respectively (P for trend = .14). Second cancer risks for patients who received chemotherapy only as the first course of treatment (O/E = 1.21) were similar to risks for those who received no treatment initially (O/E = 1.19). No significant difference in risk of all solid tumors combined was found for patients diagnosed with CLL between 1973-1989 (O/E = 1.19) and 1990-1996 (O/E = 1.29).                                View this table: [in this window] [in a new window]   Table 1. Observed numbers and observed/expected ratios of solid tumors among 16 367 of the 2-month survivors of chronic lymphocytic leukemia reported to the SEER Program between 1973 and 1996  Significantly increased risks were observed for Kaposi sarcoma (KS) (O/E = 5.09), malignant melanoma (O/E = 3.18), and cancers of the larynx (O/E = 1.72) and the lung (O/E = 1.66). Men with CLL, but not women, experienced significantly increased risks of brain cancer (O/E = 1.91). In addition, significant excesses of cancers of the stomach (O/E = 1.76) and bladder (O/E = 1.52) were restricted to women. Prior studies of patients with CLL have documented increased risks of various forms of skin cancer, including malignant melanoma,2,8-11 probably resulting from the immune perturbations.12 Risk of malignant melanoma is elevated in patients with therapeutic immune suppression associated with organ transplantation, and this risk is further enhanced by increases in sunlight exposure.13 However, the apparent excess of skin cancers in CLL may be partly due to the increased medical surveillance of these patients. Clinical features of patients with CLL with subsequent KS (6 women, 3 men) are presented in Table 2. To our knowledge, we are the first to report an increased risk of KS among patients with CLL. Two-fold to 7-fold increased risks of KS have been observed among patients with all types of lymphoid malignancies combined (Hodgkin disease, non-Hodgkin lymphoma, and all leukemia),14,15 but risk estimates for CLL were not provided separately. In one registry-based study that reported a 3-fold risk of sarcoma after CLL,16 KS-specific risks were not estimated.                                View this table: [in this window] [in a new window]   Table 2. Characteristics of 9 patients with chronic lymphocytic leukemia who subsequently developed Kaposi sarcoma reported to the SEER Program, 1973-1996  The increased risk of brain cancer among men with CLL is consistent with our earlier study,3 although the basis for this association remains unclear. The majority of brain cancers were glioblastomas that, in contrast to lymphomas of the central nervous system, have not been linked to compromised immune function. The excess risk of bladder cancer that we observed among women may be related to chemotherapy, particularly cyclophosphamide,17 although we did not have access to treatment information beyond the initial regimen. The increased risk of stomach cancer among women may be explained by an immune-related predisposition to Helicobacter pylori infection, an important risk factor for gastric carcinoma.18 However, these associations were limited to one sex, and they may have resulted from multiple statistical comparisons. Although increased medical surveillance may be involved also, the excess risks extended throughout the period of observation. The elevated risk of lung and laryngeal cancers in both sexes suggests the role of cigarette smoking, which may contribute to the increase of bladder19 and gastric cancers.20 Data on tobacco smoking were not available in our study, but it seems plausible that the carcinogenic effects of smoking are heightened by radiotherapy, chemotherapy, and/or immune deficiency.21,22 Our data indicate that the overall risk of developing a second cancer is modestly but significantly elevated, independent of initial treatment, in persons with CLL compared with those in the general population. In terms of absolute risk, an excess of 366 solid tumors, including approximately 9 KSs, might be observed among 100 000 patients with CLL during each year of follow-up. Although the role of shared etiologic factors remains unclear, the pattern of excess cancers in CLL survivors suggests an influence of immunodeficiency associated with CLL.23 Given the prolonged survival of patients with CLL, it is important for physicians to be alert to the occurrence of second cancers, particularly when new symptoms or physical findings arise. It would also seem prudent to urge patients with CLL to avoid exposures to carcinogens such as tobacco smoke and excessive sunlight. Further studies of second cancers in CLL should address the role of shared risk factors, immunologic impairment, and/or other determinants. Where feasible, molecular probes should be included to elucidate the mechanisms underlying the constellation of tumors associated with CLL.     Acknowledgments We thank Shannon Merkle for computing support, Rochelle Curtis and Lynn Ries for helpful discussions with regard to the SEER Program, and Dr James J. Goedert for critical review of the manuscript.     Footnotes Submitted March 26, 2001; accepted May 10, 2001. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734. Reprints: Michie Hisada, National Cancer Institute, 6120 Executive Blvd, EPS 8008, Rockville, MD 20852; e-mail: mh280i{at}nih.gov.     References Top Abstract Introduction Study design Results and discussion References 1. Bannerji R, Byrd JC. Update on the biology of chronic lymphocytic leukemia. Curr Opin Oncol. 2000;12:22-29[CrossRef][Medline] [Order article via Infotrieve]. 2. Greene MH, Hoover RN, Fraumeni JF Jr. Subsequent cancer in patients with chronic lymphocytic leukemiaa possible immunologic mechanism. J Natl Cancer Inst. 1978;61:337-340. 3. Travis LB, Curtis RE, Hankey BF, Fraumeni JF Jr. Second cancers in patients with chronic lymphocytic leukemia. J Natl Cancer Inst. 1992;84:1422-1427[Abstract/Free Full Text]. 4. World Health Organization. International Classification of Diseases for Oncology 2nd ed. Geneva, Switzerland: World Health Organization; 1990:1-144. 5. Carson DA, Piro LD, Wasson DB, et al. Activity of 2-chloro-2'-deoxyadenosine in chronic lymphocytic leukemia, hairy cell leukemia, and autoimmune hemolytic anemia. Adv Exp Med Biol. 1989;253A:427-431. 6. Cheson BD. Recent advances in the treatment of B-cell chronic lymphocytic leukemia. Oncology. 1990;4:71-84[Medline] [Order article via Infotrieve]. 7. Giles FJ, O'Brien SM, Keating MJ. Chronic lymphocytic leukemia in (Richter's) transformation. Semin Oncol. 1998;25:117-125[Medline] [Order article via Infotrieve]. 8. Berg JW. The incidence of multiple primary cancers: I. Development of further cancer in patients with lymphomas, leukemias, and myelomas. J Natl Cancer Inst. 1967;38:741-752. 9. Manusow D, Weinerman BH. Subsequent neoplasia in chronic lymphocytic leukemia. JAMA. 1975;232:267-269[Abstract]. 10. Gunz FM, Angus HB. Leukemia and cancer in the same patient. Cancer. 1985;18:145-152[CrossRef]. 11. Levi F, Randimbison L, Te VC, La Vecchia C. Non Hodgkin's lymphomas, chronic lymphocytic leukemias and skin cancers. Br J Cancer. 1996;74:1847-1850[Medline] [Order article via Infotrieve]. 12. Bartik MM, Welker D, Kay NE. Impairments in immune cell function in B cell chronic lymphocytic leukemia. Semin Oncol. 1998;25:27-33[Medline] [Order article via Infotrieve]. 13. Hoover R. Effects of drugs immunosuppression. In: Hiatt HH,Watson JD,Winsten JA, eds. Origins of Human Cancer. Book A. Incidence of Cancer in Humans. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory; 1977:369-379. 14. Iscovich J, Boffetta P, Winkelmann R, Brennan P. Classic Kaposi's sarcoma as a second primary neoplasm. Int J Cancer. 1999;80:178-182[CrossRef][Medline] [Order article via Infotrieve]. 15. Dictor M, Attewell R. Epidemiology of Kaposi's sarcoma in Sweden prior to the acquired immunodeficiency syndrome. Int J Cancer. 1988;42:346-351[Medline] [Order article via Infotrieve]. 16. Mellemgaard A, Geisler CH, Storm HH. Risk of kidney cancer and other second solid malignancies in patients with chronic lymphocytic leukemia. Eur J Haematol. 1994;53:218-222[Medline] [Order article via Infotrieve]. 17. Travis LB, Curtis RE, Glimelius B, et al. Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin's lymphoma. J Natl Cancer Inst. 1995;87:524-530[Abstract/Free Full Text]. 18. International Agency for Research on Cancer. Infection with Helicobacter pylori. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol 61. Schistosomes, Liver Flukes and Helicobacter pylori. Lyon, France: IARC; 1996:177-240. 19. Baron JA, Rohan TE. Tobacco. In: Schottenfeld D,Fraumeni JF Jr, eds. Cancer Epidemiology and Prevention 2nd ed. New York, NY: Oxford University Press; 1996:269-289. 20. Chow WH, Swanson CA, Lissowska J, et al. Risk of stomach cancer in relation to consumption of cigarettes, alcohol, tea and coffee in Warsaw, Poland. Int J Cancer. 1999;81:871-876[CrossRef][Medline] [Order article via Infotrieve]. 21. Van Leeuwen FE, Klokman WJ, Stovall M, et al. Roles of radiotherapy and smoking in lung cancer following Hodgkin's disease. J Natl Cancer Inst. 1995;87:1530-1537[Abstract/Free Full Text]. 22. Swerdlow AJ, Schoemaker MJ, Allerton R, et al. Lung cancer after Hodgkin's disease: a nested case-control study of the relation to treatment. J Clin Oncol. 2001;19:1610-1618[Abstract/Free Full Text]. 23. Linet MS, Cartwright RA. The leukemias. In: Schottenfeld D,Fraumeni JF Jr, eds. Cancer Epidemiology and Prevention 2nd ed. New York, NY: Oxford University Press; 1996:841-892. © 2001 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. D. Volkheimer, J. B. Weinberg, B. E. Beasley, J. F. Whitesides, J. P. Gockerman, J. O. Moore, G. Kelsoe, B. K. Goodman, and M. C. Levesque Progressive immunoglobulin gene mutations in chronic lymphocytic leukemia: evidence for antigen-driven intraclonal diversification Blood, February 15, 2007; 109(4): 1559 - 1567. [Abstract] [Full Text] [PDF] M. Hisada, B. E. Chen, E. S. Jaffe, and L. B. Travis Second Cancer Incidence and Cause-Specific Mortality Among 3104 Patients With Hairy Cell Leukemia: A Population-Based Study J Natl Cancer Inst, February 7, 2007; 99(3): 215 - 222. [Abstract] [Full Text] [PDF] N. Zanesi, R. Aqeilan, A. Drusco, M. Kaou, C. Sevignani, S. Costinean, L. Bortesi, G. La Rocca, P. Koldovsky, S. Volinia, et al. Effect of Rapamycin on Mouse Chronic Lymphocytic Leukemia and the Development of Nonhematopoietic Malignancies in E{micro}-TCL1 Transgenic Mice Cancer Res., January 15, 2006; 66(2): 915 - 920. [Abstract] [Full Text] [PDF] This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Hisada, M. Articles by Travis, L. B. Search for Related Content PubMed PubMed Citation Articles by Hisada, M. Articles by Travis, L. B. 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