1 Running Title: Second Malignant Cancers Second Malignant Neoplasms in Survivors of Childhood Cancer Ray M. Merrill and Arielle A. Sloan Department of Health Science, College of Life Sciences, Brigham Young University, Provo, Utah Corresponding author: Ray M. Merrill, Professor, Department of Health Science, College of Life Sciences, Brigham Young University, Provo, UT 84602, USA. Telephone: 801-422-9788; Fax: 801-422-9713 RMM: [email protected] BCA: [email protected] AAS: [email protected] Abstract word count: 212 Text word count: 4,113 Figures and tables: 1 (figure), 3 (tables) 2 Abstract Introduction: Individuals who survive a first primary cancer in childhood are at increased risk of a second malignant neoplasm. Study design: This cohort study updates a previous long-term report with 10 additional years of data to verify and add to our existing knowledge about subsequent primary cancer risk. Materials and Methods: Analyses are based on a cohort of 40,337 children (age < 20 years) who survived cancer for at least two months from 1973 through 2010 in the Surveillance, Epidemiology, and End Results (SEER) program. Each member of this cohort was followed for an average of 17.6 years. Observed/expected ratios based on cancer rates in the general population were calculated based on primary and second primary cancer types and with/without radiation treatment. Results: Follow-up of the cohort identified 1,081 second malignant neoplasms, which represented a 4.2fold increase in incidence compared with the general population (O/E=4.2, 95% CI=4.0-4.5). O/E ratios for subsequent cancer were consistently lower than in the first study, with the exception of Hodgkin’s lymphoma. Our study also found a heightened risk of esophageal, cecum, corpus uteri, and kidney cancers among Hodgkin’s lymphoma survivors, increased risk for salivary gland tumors among CNS patients, and increased risk of the oral cavity and pharynx, respiratory system, and soft tissue second primaries among bone cancer survivors. O/E risk of subsequent neoplasm was higher among radiation-treated individuals in our sample than in the original study. Conclusion: The increased risk and latency periods for second malignant cancer among childhood cancer patients depends on the cancer type and treatment, but risk of subsequent cancer lowers over time. Keywords: Childhood cancer, radiotherapy, secondary neoplasms, subsequent malignancies, treatment 3 Background Childhood cancer represents a major public health issue in the United States, and it is responsible for more child deaths from age 1-14 than any other cause except for motor vehicle accidents [1]. While lymphoid leukemia, lymphoma, and central nervous system (CNS) tumors account for over half of all childhood cancers, over a dozen forms of cancer manifest themselves commonly in childhood [2, 5]. Regardless of type, the prevalence of childhood cancer is generally highest among males and whites [3, 4] and among who are either younger than five or between 15 and19 years of age [5]. Advances in cancer recognition, tracking, and treatment have improved child cancer survival rates in recent years [5, 6]. Since 1990, five-year survival for childhood cancers has increased in the United States from 75.1% to 83.3% and ten-year survival from 71.9% to 76.6% [5]. Now that children with cancer are surviving longer, it is essential to understand their risk for subsequent malignant neoplasms later in life. Previous research has assessed short- and long-term risks of subsequent primary cancer among survivors of childhood cancer [2, 7-12]. A comprehensive body of information assembled on childhood cancer and risk of subsequent primary malignancies began in January 1970 and is called the Childhood Cancer Survivor Study [13]. The British Childhood Cancer Survivor Study identified individuals diagnosed with childhood cancer in Britain during 1940 through 1991 who had survived at least 5 years to conduct a population-based study of late mortality and the risks of second primary cancers [11]. The Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute has also studied new malignancies following childhood cancers diagnosed from 1973 to 2000 [2]. Our study will update their report with ten additional 4 years of data with the intent to verify and add to our existing knowledge about subsequent primary cancer risk. Site-specific latency periods will also be presented and results will be compared with the existing literature, which will have implications for patient follow-up monitoring. Methods Childhood Cancer Definition The Childhood Cancer Survivor Study classifies childhood and adolescent cancers as those cases diagnosed before the age of 21 [13]. However, other organizations classify childhood cancers as those involving individuals younger than 20, including the SEER program of the National Cancer Institute, the Environmental Protection Agency, and the American Childhood Cancer Organization [1, 10-11]. In the United States, the definitive source of cancer incidence and survival data comes from the Surveillance Epidemiology and End Results (SEER) Program of the National Cancer Institute [5, 6]. SEER data are currently available from 1973 to 2010 [1]. The SEER program and the International Classification for Childhood Cancer (ICCC) have provided the following list of childhood cancers: leukemia, lymphomas, CNS tumors, neuroblastoma, retinoblastoma, renal tumors, hepatic tumors, malignant bone tumors, soft tissue sarcomas, germ cell tumors, and other and unspecified malignant neoplasms [5, 14, 15]. SEER*Stat SEER*Stat is a statistical software product that provides a mechanism for SEER data analysis [16]. We used this software to compute multiple primary standardized 5 incidence ratios, which represent the observed divided by the expected number of cancer cases subsequent to a first primary cancer diagnosis. The observed is the actual count of events resulting in the cohort. The expected number of events is what we expect to be experienced, based on the data in general population and accumulated person-time at risk for this cohort. Included with our ratios are 95% confidence intervals. For our analysis, we also obtained excess risk, mean age at diagnosis, and mean age when the subsequent cancer occurred. Excess absolute cancer risk is cancer incidence beyond what we normally expect. We express this as the number of excess cases of cancer per 10,000 at-risk individuals per year. Only malignant neoplasms are considered in the current study, and cases based only on death certificates or autopsies have been excluded. The data-use agreement for accessing the SEER 1973-2010 research data files was entered into April, 24, 2013. The SEER program subsequently provided the authors with internet access to the cancer data files. We accordingly use the suggested SEER*Stat citation [16]. The SEER Program was initiated in 1973, when it began gathering and publishing population-based cancer incidence and survival data from seven tumor registries (Connecticut, Detroit [Metropolitan], Hawaii, Iowa, New Mexico, San FranciscoOakland, and Utah). In 1975, two additional tumor registries joined the SEER Program (Seattle [Puget Sound] and Atlanta [Metropolitan]). The nine tumor registries routinely obtained cancer data in their catchment areas from the records of all cancer patients identified by hospitals, clinics, nursing homes, private pathology laboratories, radiotherapy units, death certificates, and other health service units that provide 6 diagnostic or treatment services. The current analysis is based on SEER data collected from 1973 through 2010. Literature Review Selection Criteria We performed an extensive literature review to compare our results with previous research. Peer-reviewed articles published in English on second and subsequent malignant neoplasms in childhood cancer survivors during 1993-2011 were identified from electronic databases – PubMed, Wiley Online Library, ScienceDirect, American Association for Cancer Research, and CA: A Cancer Journal for Clinicians. The search terms used to identify all relevant published data in the above mentioned databases were: childhood cancers, second primary cancers from childhood cancer, subsequent cancers from childhood cancer, retinoblastoma, leukemia, neuroblastoma, hepatic tumor, central nervous system (CNS) tumors, lymphoma, renal tumors, malignant bone tumor, soft tissue sarcoma, germ cell tumors, thyroid tumor, skin carcinoma. Results and Discussion Table 1 provides a general overview of the demographic characteristics of the sample population. This study extended the study period of the 1973-2000 original SEER report by 10 years, and, consequently, included almost twice the number of individuals as the first study (40,337 children, as opposed to 23,819) and followed them for twice as long, on average (17.6 years versus 8.3). Consequently, the results of this study generally reflected findings from the 1973-2000 SEER report, such as the fact that acute lymphocytic leukemia remained the most common type of first cancer (accounting for 7 19% of cases, similar to the originally reported 21%), while 17% were CNS cancers (as opposed to 18% in the first study) [2]. Mean age at first cancer diagnosis also remained similar to the first study, both overall and stratified by gender [2]. The shortest latency period involved first primary melanoma, and the longest latency period involved first primary Hodgkin lymphoma. However, a number of differences were noted between this study and the original, which will be described in detail in this section. Tables 2 and 3 show the risk of subsequent cancer based on first cancer diagnosis and use of radiation treatment. Subsequent cancer risk among childhood cancer survivors—especially among patients who underwent radiation treatment—was greater than cancer risk in the general population, as reported in the original study [2]. Still, in several cases, higher O/E ratios were not statistically significant, and in other cases, small counts influenced reported associations. In our study, there was a 4.2-fold higher subsequent cancer incidence among childhood cancer survivors compared with the general population (O/E = 4.2, 95% CI = 4.0-4.5), which is significantly lower than the 6-fold O/E ratio observed in the previous study [2]. Cancer-specific O/E ratios were generally lower for cancers in this analysis regardless of whether or not radiation treatment was used, although these differences were generally non-significant. Two exceptions included Hodgkin’s lymphoma, which had a 6.9 subsequent cancer O/E ratio if treated with radiation and 5.0 without, as opposed to 1.2 and 0.35, respectively; and non-Hodgkin’s lymphoma without radiation treatment, which had a 4.3 O/E ratio as opposed to 2.85 [2]. The general decrease in the O/E ratio would be expected not only because cancer treatments and early detection have improved but because the impact of childhood cancer on subsequent cancer risk tends to 8 lower with age [2]. More longitudinal analysis should be conducted to determine whether the O/E ratio among Hodgkin’s lymphoma survivors and among non-Hodgkin’s lymphoma survivors who did not undergo radiation treatment will continue to increase. Concerning gender disparities, the male:female ratio of first cancer cases remained 54:46, and females in our study were still overrepresented for melanoma and Wilms’ tumor [2]. However, rather than outnumbering males for fibrosarcoma and carcinoma, as was the case in the original study, females outnumbered males for renal and thyroid cancers. Mean age at diagnosis was similar between males and females (10.1 versus 10.2 for females), as found previously, but mean age at a subsequent event was lower for males than for females (25.6 vs. 28.8). Increased risk of subsequent cancer was influenced by follow-up time (O/E = 5.6 [3.8-8.0] for 2-11 months, 7.3 [6.2-8.5] for 1259 months, 6.9 [6.0-7.9] for 60-119 months, and 3.4 [3.2-3.7] for 120+ months). The original SEER study did not include O/E ratios for esophageal and cecal cancer among Hodgkin’s disease survivors, salivary gland tumors among CNS survivors, or oral cavity, pharynx, respiratory and soft tissue cancers among bone cancer patients. In addition, no studies from our literature review identified specific links between these primary and second primary cancers. In our study, however, there was a significant association observed for each. The fact that this study found these and other associations among cancers for the first time may be due in part to the 10 years of follow-up that have been added since the original SEER report. Both Hodgkin’s and bone cancer, for example, were diagnosed at later ages in our study (15.8 years and 13.8, respectively), with latency periods of 19.1 and 13.5 years before the subsequent primary cancer [Table 1]. In the original study, 9 patients were followed up on average for only 8.3 years [2]. Regardless, further research on each of these subjects would prove valuable, especially because the second primary cancers described above are all most commonly diagnosed after middle age [68]. Several studies have emphasized the importance of long-term follow-up when investigating second malignant neoplasms [10, 18, 19, 34, 42, 49, 56, 57]. In our study, typically 15.2 years separated the first and subsequent neoplasm. The previous SEERbased study of new malignancies following childhood cancer included 10 fewer years in its analysis and failed to observe some of the findings observed in the current study, especially among individuals who were diagnosed with cancers later in childhood. The latency periods presented in this study should guide further research on the length of follow-up needed, and continued follow-up on this population should determine how risk of subsequent cancer changes over time. Conclusion The current study verifies several previous studies showing that children who survive various types of cancer are at increased risk of developing certain second malignant neoplasms. With follow-up, these excess cancer rates remain higher than the general population but may either lower or increase during specific ages. In addition to confirming several of the previously shown results, children with a first primary Hodgkin lymphoma were at increased risk for cancers of the esophagus, cecum, corpus uteri, and kidney; children with a first primary CNS were at increased risk for salivary gland tumors; children with a first primary bone tumor were at increased risk for cancers of the oral cavity and pharynx, respiratory system, and soft tissue; children 10 with a first primary soft tissue tumor were at increased risk for kidney carcinoma and lymphatic and hematopoietic diseases; children with a first primary germ cell tumor were at increased risk for cancers of the CNS and lymphatic and hematopoietic diseases; and children with a first thyroid tumor were at increased risk for cancers of the salivary gland and kidney. Further research regarding connections among these cancer types as well as further follow-up in this population are warranted in order to understand subsequent cancer risk over the life span among childhood cancer survivors. Competing Interests The authors have no conflicts of interest. Authors’ Contributions RMM: Analyzed and described the data, assisted in the literature review, and wrote the paper. AAS: Assisted in the literature review and writing the paper. Authors’ Information 11 RMM: Professor of Cancer Epidemiology and Biostatistics at Brigham Young University. Former Visiting fellow at the International Agency for Research on Cancer in Lyon, France, and former fellow at the National Cancer Institute, Rockville, Maryland. AAS: Student of Public Health at Brigham Young University. Abbreviations O = observed number of subsequent (2nd, 3rd, etc.) primary cancers; E = expected number of cancers in the general population; O/E = ratio of observed to expected cancers; CI: confidence interval; SEER: Surveillance, Epidemiology and End Results; CNS = central nervous system, including brain; Excess absolute risk (excess cancers per 10,000 person years, calculated as [(O-E)/person-years at risk] × 10,000). Acknowledgements We would like to thank Elizabeth Brutsch for her comments on the manuscript and suggestion of additional references. References 1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer Statistics, 2008. CA Cancer J Clin. 2008,58:71–96. 2. Inskip PD, Ries LAG, Cohen RJ, Curtis RE. New malignancies following childhood cancer. In New Malignancies among Cancer Survivors: SEER Cancer Registries, 1973-2000. National Cancer Institute. Edited by Curtis RE, Freedman DM, Ron E, Ries LAG, Hacker DG, Edwards BK, Tucker MA, Fraumeni JF Jr. (eds). NIH Publ. No. 05-5302. Bethesda, MD. 2006:465-482. 12 3. Ries LG, Smith MA, Gurney JG, et al (eds). Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975-1995. NIH Pub. No. 99-4649. Bethesda, MD, National Cancer Institute; 1999. 4. Ries LG, Eisner MP, Kosary CL, et al (eds). SEER Cancer Statistics Review, 19752001. Bethesda, MD, National Cancer Institute, 2004. 5. SEER Cancer Statistics Review, 1975-2010 [http://seer.cancer.gov/csr/1975_2010/]. Bethesda: National Cancer Institute. 2010-13. 6. Kohler BA, Ward E, McCarthy BJ, Schymura MJ, Ries LA, Eheman C, Jemal A, Anderson RN, Ajani UA, Edwards BK. Annual report to the nation on the status of cancer, 1975-2007, featuring tumors of the brain and other nervous system. J Natl Cancer Inst. 2011;103(9):14-36. 7. Meadows AT, Friedman DL, Neglia JP, Mertens AC, Donaldson SS, Stovall M, Hammond S, Yasui Y, Inskip PD. Second neoplasms in survivors of childhood cancer: findings from the Childhood Cancer Survivor Study cohort. J Clin Oncol 2009;27:2356-2362. 8. Wendland MM, Tsodikov A, Glenn MJ, Gaffney DK. Time interval to the development of breast carcinoma after treatment for Hodgkin disease. Cancer 2004; 101(6):1275-1282. 9. Cohen RJ, Curtis RE, Inskip PD, Fraumeni JF Jr. The risk of developing second cancers among survivors of childhood soft tissue sarcoma. Cancer 2005; 103(11):2391-2396. 10. Reulen RC, Taylor AJ, Winter DL, Stiller CA, Frobisher C, Lancashire ER, McClanahan FM, Sugden EM, Hawkins MM. British Childhood Cancer Survivor 13 Study The British Childhood Cancer Survivor Study (BCCSS) Steering Group: Longterm population-based risks of breast cancer after childhood cancer. Int J Cancer 2008;123:2156-2163. 11. Hawkins MM, Lancashire ER, Winter DL, Frobisher C, Reulen RC, Taylor AJ, Stevens MC, Jenney M. The British Childhood Cancer Survivor Study: Objectives, methods, population structure, response rates and initial descriptive information. Pediatr Blood Cancer 2008;50(5):1018-1125. 12. Inskip PD, Curtis RE. New malignancies following childhood cancer in the United States, 1973-2002. Int J Cancer 2007:121(10):2233-2240. 13. Robison LL, Armstrong GT, Boice JD, Chow EJ, Davies SM, Donaldson SS, Green DM, Hammond S, Meadows AT, Mertens AC, Mulvihill JJ, Nathan PC, Neglia JP, Packer RJ, Rajaraman P, Sklar CA, Stovall M, Strong LC, Yasui Y, Zeltzer LK. The childhood cancer survivor study: a national cancer institute-supported resource for outcome and intervention research. J Clin Oncol. 2009;27(14):2308-2318. 14. Surveillance Epidemiology and End Results. Documentation and recodes: International classification of childhood cancer [http://seer.cancer.gov/iccc/]. Washington: National Cancer Institute. 2011-13 [updated 2011; cited 2013 May 9]. 15. Kramárová E, Stiller CA. The international classification of childhood cancer. Int J Cancer 1996;68(6):759-765. 16. SEER*Stat Database: Incidence [http://seer.cancer.gov]. SEER 9 Regs Research Data, Sub (1973-2010). 2010-13 [updated Nov 2012; cited 2013 May 14]. 17. Neglia JP, Friedman DL, Yasui Y, Mertens AC, Hammond S, Stovall M, Donaldson SS, Meadows AT, Robison LL: Second malignant neoplasms in five-year survivors 14 of childhood cancer: childhood cancer survivor study. J Natl Cancer Inst 2011;93(8):618-629. 18. Reulen RC, Frobisher C, Winter DL, Kelly J, Lancashire ER, Stiller CA, PritchardJones K, Jenkinson HC, Hawkins MM; British Childhood Cancer Survivor Study Steering Group: Long-term risks of subsequent primary neoplasms among survivors of childhood cancer. JAMA 2011;305(22):2311-2319. 19. Castellino SM, Geiger AM, Mertens AC, Leisenring WM, Tooze JA, Goodman P, Stovall M, Robison LL, Hudson MM. Morbidity and mortality in long-term survivors of Hodgkin lymphoma: a report from the childhood cancer survivor study. Blood 2011;117(6):1806-1816. 20. Maule M, Scélo G, Pastore G, Brennan P, Hemminki K, Olsen JH, Tracey E, Pukkala E, Weiderpass E, Brewster DH, Tamaro S, Chia KS, Pompe-Kirn V, Kliewer EV, Tonita JM, Martos C, Jonasson JG, Merletti F, Boffetta P. Second malignancies after childhood noncentral nervous system solid cancer: Results from 13 cancer registries. Intl J Cancer 2011;129(8):1940-1952. 21. Henderson TO, Whitton J, Stovall M, Mertens AC, Mitby P, Friedman D, Strong LC, Hammond S, Neglia JP, Meadows AT, Robison L, Diller LL. Secondary sarcomas in childhood cancer survivors: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2007;99:300-308. 22. Veiga LH, Bhatti P, Ronckers CM, Sigurdson AJ, Stovall M, Smith SA, Weathers R, Leisenring W, Mertens AC, Hammond S, Neglia JP, Meadows AT, Donaldson SS, Sklar CA, Friedman DL, Robison LL, Inskip PD. Chemotherapy and thyroid cancer risk: A report from the childhood cancer survivor study. Cancer Epidemiol Biomarkers Prev. 2012;21(1):92-101. 15 23. Henderson TO, Rajaraman P, Stovall M, Constine LS, Olive A, Smith SA, Mertens A, Meadows A, Neglia JP, Hammond S, Whitton J, Inskip PD, Robison LL, Diller L. Risk factors associated with secondary sarcomas in childhood cancer survivors: a report from the childhood cancer survivor study. Intl J Rad Oncol, Biology Physics 2012;84(1):224-230. 24. Boukheris H, Stovall M, Gilbert ES, Stratton KL, Smith SA, Weathers R, Hammond S, Mertens AC, Donaldson SS, Armstrong GT, Robison LL, Neglia JP, Inskip PD: Risk of salivary gland cancer after childhood cancer: a report from the Childhood Cancer Survivor Study. Int J Radiat Oncol Biol Phys. 2013;85(3):776-783. 25. Nottage K, McFarlane J, Krasin MJ, Li C, Srivastava D, Robison LL, Hudson MM: Secondary colorectal carcinoma after childhood cancer. J Clin Oncol. 2012;30(20):2552-2558. 26. Bowers DC, Nathan PC, Constine L, Woodman C, Bhatia S, Keller K, Bashore L: Subsequent neoplasms of the CNS among survivors of childhood cancer: A systematic review. Lancet Oncol. 2013;14(8):e321-328. 27. Bhatia S, Robison LL, Oberlin O, Greenberg M, Bunin G, Fossati-Bellani F, Meadows AT. Breast cancer and other second neoplasms after childhood Hodgkin’s disease. N Engl J Med 1996;334:745-751. 28. Paulino AC, Fowler BZ. Secondary neoplasms after radiotherapy for a childhood solid tumor. Pediatr Hematol Oncol 2005;22(2):89-101. 29. Carroll WL, Finlay J. Cancer in Children and Adolescents. Sudbury, MA: Jones and Bartlett; 2010. 16 30. Davies RP, Slavotinek JP, Dorney SFA. VIP secreting tumors in infancy. Pediatr Radiol 1990;20(7):504-508. 31. Friedman DL, Whitton J, Leisenring W, Mertens AC, Hammond S, Stovall M, Donaldson SS, Meadows AT, Robison LL, Neglia JP. Subsequent neoplasms in 5year survivors of childhood cancer: The childhood cancer survivor study. J Natl Cancer Inst 2010;102(14):1083-1095. 32. Gold DG, Neglia JP, Dusenbery KE. Second neoplasms after megavoltage radiation for pediatric tumors. Cancer 2003;97(10):2588-2596. 33. Haddy TB, Mosher RB, Dinndorf PA, Reaman GH: Second neoplasms in survivors of childhood and adolescent cancer are often treatable. J Adolesc Health 2004;34(4):324-329. 34. Cardous-Ubbink MC, Heinen RC, Bakker PJM, van den Berg H, Oldenburger F, Caron HN, et al. Risk of second malignancies in long-term survivors of childhood cancer. Eur J Cancer. 2007;43:351-362. 35. Sklar CA, Mertens AC, Mitby P, Occhiogrosso G, Qin J, Heller G, Yasui Y, Robison LL: Risk of disease recurrence and second neoplasms in survivors of childhood cancer treated with growth hormone: a report from the childhood cancer survivor study. J Clin Endocrinol Metab. 2002;87(7):3136-3141. 36. Van der Waal RIF, Veerman AJP, Snow GB, van der Waal I: Oral squamous cell carcinoma following treatment of acute lymphoblastic leukaemia. J Oral Pathol Med. 1997;26:8-9. 37. Chow EJ, Friedman DL, Stovall M, Yasui Y, Whitton JA, Robison LL, Sklar CA. Risk of thyroid dysfuncton and subsequent thyroid cancer among survivors of acute 17 lymphoblastic leukemia: A report from the childhood cancer survivor study. Pediatr Blood Cancer 2009;53:432-437. 38. Brunetti D, Tamaro P, Fanin R, Cavallieri F, Stanta G. Family history of cancer and risk of second malignancies in young cancer patients in Trieste Italy. Int J Cancer 2005;115:814-821. 39. Landmann E, Ochlies I, Zimmermann M, Moser O, Graf N, Suttorp M, Greiner J, Reiter A; Berlin-Frankfurt-Münster group. Secondary non-Hodgkin lymphoma (NHL) in children and adolescents after childhood cancer other than NHL. Br J Haematol. 2008;143:387-394. 40. Pappo AS, Armstrong GT, Liu W, Srivastava DK, McDonald A, Leisenring WM, Hammond S, Stovall M, Neglia JP, Robison LL. Melanoma as a subsequent neoplasm in adult survivors of childhood cancer: A report from the childhood cancer survivor study. Pedr Blood & Cancer 2013;60:461-466. 41. Neglia JP, Robison LL, Stovall M, Liu Y, Packer RJ, Hammond S, Yasui Y, Kasper CE, Mertens AC, Donaldson SS, Meadows AT, Inskip PD. New primary neoplasms of the central nervous system in survivors of childhood cancer. J Natl Cancer Inst 2006;98(21):1528-1537. 42. Yasui Y, Liu Y, Neglia JP, Friedman DL, Bhatia S, Meadows AT, Diller LR, Mertens AC, Whitton J, Robison LL. A methodological issue in the analysis of secondprimary cancer incidence in long-term survivors of childhood cancers. Am J Epidemiol 2003;158(11):1108-1113. 18 43. Davies SM. Subsequent malignant neoplasms in survivors of childhood cancer: Childhood Cancer Survivor Study (CCSS) studies. Pediatr Blood Cancer 2007;48:727-730. 44. Kenney LB, Yasui Y, Inskip PD, Hammond S, Neglia JP, Mertens AC, Meadows AT, Friedman D, Robison LL, Diller L. Breast cancer in women who survived childhood cancer. Ann Intern Med. 2004;141:590-597. 45. Travis LB, Hill D, Dores GM, Gospodarowicz M, van Leeuwen FE, Holowaty E, Glimelius B, Andersson M, Pukkala E, Lynch CF, Pee D, Smith SA, Van't Veer MB, Joensuu T, Storm H, Stovall M, Boice JD Jr, Gilbert E, Gail MH. Cumulative absolute breast cancer risk for young women treated for Hodgkin lymphoma. J Natl Cancer Inst. 2005;97(19):1428-1437. 46. Hancock SL, Tucker MA, Hoppe, RT. Breast cancer after treatment of Hodgkin’s disease. J Natl Cancer Inst. 1993;85(1):25-31. 47. Nathan PC, Ness KK, Mahoney MC, Li Z, Hudson MM, Ford JS, Landier W, Stovall M, Armstrong GT, Henderson TO, Robison LL, Oeffinger KC. Screening and surveillance for second malignant neoplasms in adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. Ann Intern Med 2011;153(7):442-451. 48. Jazbec J, Ecimovic P, Jereb B. Second neoplasms after treatment of childhood cancer in Slovenia. Pediatr Blood Cancer 2004;42:574-581. 49. Tukenova M, Diallo I, Hawkins M, Guibout C, Quiniou E, Pacquement H, Dhermain F, Shamsaldin A, Oberlin O, de Vathaire F. Long-term mortality from second 19 malignant neoplasms in 5-year survivors of solid childhood tumors: temporal pattern risk according to type of treatment. Cancer Epidemiol Biomarkers 2010;19:707-715. 50. Guérin S, Dupuy A, Anderson H, Shamsaldin A, Svahn-Tapper G, Moller T, Quiniou E, Garwicz S, Hawkins M, Avril MF, Oberlin O, Chavaudra J, de Vathaire F. Radiation dose as a risk factor for malignant melanoma following childhood cancer. Eur J Cancer 2003, 39:2379-2386. 51. de Vathaire F, Hawkins M, Campbell S, Oberlin O, Raquin MA, Schlienger JY, Shamsaldin A, Diallo I, Bell J, Grimaud E, Hardiman C, Lagrange JL, DalySchveitzer N, Panis X, Zucker JM, Sancho-Garnier H, Eschwège F, Chavaudra J, Lemerle J. Second malignant neoplasms after a first cancer in childhood: temporal pattern of risk according to type of treatment. Br J Cancer 1999;79:1884-1893. 52. MacArthur AC, Spinelli JJ, Rogers PC, Goddard KJ, Phillips N, McBride ML. Risk of a second malignant neoplasm among 5-year survivors of cancer in childhood and adolescence in British Columbia, Canada. Pediatr Blood Cancer 2007;48:453-459. 53. Maule M, Scélo G, Pastore G, Brennan P, Hemminki K, Pukkala E, Weiderpass E, Olsen JH, Tracey E, McBride ML, Brewster DH, Pompe-Kirn V, Tonita JM, Kliewer EV, Chia KS, Jonasson JG, Martos C, Magnani C, Boffetta P. Risk of second malignant neoplasms after childhood central nervous system malignant tumours: An international study. Eur J Cancer 2008;44:830-839. 54. Garwicz S, Anderson H, Olsen JH, Døllner H, Hertz H, Jonmundsson G, Langmark F, Lanning M, Möller T, Sankila R, Tulinius H. Second malignant neoplasms after cancer in childhood and adolescence: a population-based case-control study in the 5 Nordic countries. Int J Cancer 2000;88:672-678. 20 55. Haddy N, Le Deley MC, Samand A, Diallo I, Guérin S, Guibout C, Oberlin O, Hawkins M, Zucker JM, de Vathaire F. Role of radiotherapy and chemotherapy in the risk of secondary leukemia after a solid tumour in childhood. Eur J Cancer 2006;42:2757-2764. 56. Laverdière C, Liu Q, Yasui Y, Nathan PC, Gurney JG, Stovall M, Diller LR, Cheung NK, Wolden S, Robison LL, Sklar CA. Long-term outcomes in survivors of neuroblastoma. J Natl Cancer Inst 2009;101:1131-1140. 57. Rubino C, Adjadj E, Guérin S, Guibout C, Shamsaldin A, Dondon MG, ValteauCouanet D, Hartmann O, Hawkins M, de Vathaire F. Long-term risk of second malignant neoplasms after neuroblastoma in childhood: role of treatment. Int J Cancer 2003;107:791-796. 58. Bluhm EC, Ronckers C, Hayashi RJ, Neglia JP, Mertens AC, Stovall M, Meadows AT, Mitby PA, Whitton JA, Hammond S, Barker JD, Donaldson SS, Robison LL, Inskip PD: Cause-specific mortality and second cancer incidence after non-Hodgkin lymphoma: A report from the Childhood Cancer Survivor Study. Blood J 2008;111:4014-4021. 59. Leung W, Sandlund JT, Hudson MM, Zhou Y, Hancock ML, Zhu Y, Ribeiro RC, Rubnitz JE, Kun LE, Razzouk B, Evans WE, Pui CH. Second malignancy after treatment of childhood non-Hodgkin lymphoma. Cancer 2001;92(7):1959-1966. 60. The Childhood Brain Tumor Foundation. Brain stem gliomas in childhood [http://www.childhoodbraintumor.org/index.php?view=article&catid=34%3Abraintumor-types-and-imaging&id=57%3Abrain-stem-gliomas-in- 21 childhood&format=pdf&option=com_content&Itemid=53]. 2010-2013 [updated 2010; retrieved 2012 October 1]. 61. Ceha HM, Balm AJ, de Jong D, van 't Veer LJ. Multiple malignancies in a patient with bilateral retinoblastoma. J Laryngol Otol. 1998;112(2):189-192. 62. Bhagia P, Colanta AB, Abramson DH, Carlson DL, Kleinerman RA, Kraus D, Dunkel IJ. Sinonasal adenocarcinoma: A rare second malignancy in long term retinoblastoma survivors. Pediatr Blood Cancer 2011;57(4):693-695. 63. Bataille V, Hiles R, Bishop JA. Retinoblastoma, melanoma and the atypical mole syndrome. Br J Dermatol. 1995;132(1):134-138. 64. Wong FL, Boice JD Jr, Abramson DH, Tarone RE, Kleinerman RA, Stovall M, Goldman MB, Seddon JM, Tarbell N, Fraumeni JF Jr, Li FP. Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk. JAMA 1997;278(15):1262-1267. 65. NCI [http://www.cancer.gov/cancertopics/pdq/treatment/thyroid/Patient/page4]. Treatment option overview. Washington: National Cancer Institute; 2013 [updated 2013 January 11; cited 2013 May 11]. 66. MD Anderson Cancer Center. Childhood melanoma [http://www.mdanderson.org/patient-and-cancer-information/cancerinformation/cancer-types/childhood-melanoma/index.html]. 67. Vezzadini C, Cremonini N, Sforza A, Presutti L, Chiarini V. Treated Wilm's tumor in childhood as potential risk factor for second thyroid cancer. Panminerva Med 2002;44(3):275-277. 68. NCI [http://seer.cancer.gov/archive/csr/1975_2003/results_single/sect_01_table.11_2 pgs.pdf]. Median age of cancer patients at diagnosis. [n.d.]. 22 23 Table 1: Descriptive characteristics of persons diagnosed with different histopathologic types of malignant childhood cancer (ages 019 years), both sexes, 1973-2010 Histopathology type* Total Number (%) Male Female Rate per 100,000 Male/Female (Ratio) Mean Mean Age at First Primary Diagnosis 7.0 9.5 15.8 12.8 8.9 2.9 1.8 4.5 5.5 13.8 11.0 14.3 16.5 16.3 3.9 Age at Latency Subsequent Period Primary Diagnosis 22.1 15.1 25.1 15.6 34.9 19.1 25.9 13.1 22.9 14.0 19.9 17.0 13.0 11.2 21.3 16.8 23.4 17.9 27.3 13.5 24.3 13.3 29.7 15.4 34.6 18.1 26.7 10.4 22.1 18.2 Acute lymphocytic leukemia 7,578 4,328 (57) 3,250 (43) 3.1/2.5 (1.3) Acute Myeloid leukemia 1,705 888 (52) 817 (48) 0.6/0.6 (1.0) Hodgkin lymphoma 3,535 1,821 (52) 1,714 (48) 1.3/1.3 (1.0) Non-Hodgkin lymphoma 2,752 1,863 (68) 889 (32) 1.3/0.7 (1.9) Brain, CNS tumors 7,036 3,876 (55) 3,160 (45) 2.8/2.4 (1.2) Neuroblastoma 2,154 1,136 (53) 1,018 (47) 0.8/0.8 (1.0) Retinoblastoma 824 414 (50) 410 (50) 0.3/0.3 (1.0) Renal tumors 1,754 838 (48) 916 (52) 0.6/0.7 (0.9) Hepatic tumors 515 299 (58) 216 (42) 0.2/0.2 (1.0) Bone tumors 2,277 1,330 (58) 947 (42) 1.0/0.7 (1.4) Soft tissue sarcoma 3,008 1,621 (54) 1,387 (46) 1.2/1.0 (1.2) Germ cell tumors 2,759 1,640 (59) 1,119 (41) 1.2/0.8 (1.5) Thyroid carcinoma 1,546 307 (20) 1,239 (80) 0.2/0.9 (0.2) Melanoma 1,329 533 (40) 796 (60) 0.4/0.6 (0.7) Wilms’ tumor 1,565 741 (47) 824 (53) 0.5/0.6 (0.8) Data source: Surveillance, Epidemiology, and End Results (SEER). Note: Includes children surviving 2 months or more after diagnosis. CNS: Central Nervous System. * Categories and ordering based on International Classification of Childhood Cancer [15]. Mean 24 Table 2: Childhood malignant cancer (ages 0-19 years) according to subsequent cancer risk (all sites) according to radiation treatment, 1973-2010 Age at Latency Bone Brain, Thyroid Leukemia First Period CNS Primary Diagnosis Histopathology type* 95% 95% Mean Mean O/E O/E O/E O/E O/E CI CI No. % Lower Upper Acute lymphocytic leukemia No 71 68 4.0 3.1 5.1 6.6 14.2 6.8 8.1 7.4 4.8 Yes 33 32 3.1 2.1 4.3 8.2 16.8 13.0 12.5 7.9 Acute myeloid leukemia No 12 50 3.2 1.6 5.6 9.5 26.8 7.4 Yes 12 50 10.2 3.8 22.3 10.0 12.7 26.5 27.6 Hodgkin lymphoma No 78 26 5.0 3.9 6.2 15.7 16.7 10.8 7.7 9.2 18.1 Yes 217 74 6.9 6.1 7.9 15.8 20.0 12.9 8.0 7.5 Non-Hodgkin lymphoma No 29 50 4.3 2.9 6.2 12.6 11.5 8.3 12.1 Yes 29 50 5.9 3.9 8.4 13.1 14.7 23.6 19.4 8.2 Brain, CNS tumors No 58 33 3.7 2.8 4.7 8.4 12.0 18.1 6.5 Yes 116 67 6.5 5.4 7.8 9.3 14.8 20.4 47.7 8.5 11.9 Neuroblastoma No 14 45 3.5 1.9 5.8 2.5 14.0 25 Yes 17 55 8.6 5.0 13.8 3.8 18.9 Retinoblastoma No 13 39 5.1 2.7 8.8 1.8 7.9 51.3 Yes 20 61 29.6 18.1 45.7 1.4 13.7 311.6 Renal tumors No 13 42 3.3 1.7 5.6 4.4 15.4 Yes 18 58 4.5 2.7 7.1 4.7 17.8 Hepatic tumors No 3 100 3.7 0.8 10.8 5.4 18 Yes 0 0 Bone tumors No 48 67 4.3 3.1 5.7 13.9 14.5 11.7 Yes 24 33 8.4 5.4 12.5 13.5 11.7 102.0 Soft tissue sarcoma No 22 33 1.6 1.0 2.4 11.4 12.8 15.1 Yes 45 67 7.3 5.4 9.8 10.6 13.7 48.7 Germ cell tumors No 60 80 2.5 1.9 3.2 14.2 13.8 Yes 15 20 2.8 1.6 4.6 14.6 22.2 Thyroid carcinoma No 26 67 1.5 1.0 2.2 16.5 19.7 Yes 13 33 1.8 1.0 3.1 16.5 14.9 Melanoma No 48 100 2.9 2.1 3.8 16.3 10.4 Yes 0 0 Wilms’ tumor No 10 37 3.0 1.5 5.8 3.3 16.9 Yes 17 63 4.4 2.5 7.0 4.6 18.7 Data source: Surveillance, Epidemiology, and End Results (SEER). Note: Includes children surviving 2 months or more after diagnosis. CNS: Central Nervous System. 21.8 29.4 7.1 5.0 6.0 5.2 19.5 35.5 15.3 5.9 18.6 7.1 26 * Categories and ordering based on International Classification of Childhood Cancer [15]. Table 3: Childhood malignant cancer (ages 0-19 years) according to subsequent cancer risk based on multiple primary standardized incidence ratios, 1973-2010 Histopathology type* Subsequent Cancer Site Observe Observed d /Expected 95% 95% CI CI Lower Upper Excess Cancers Per 10,000 Mean Latency Period Supporting References Acute Lymphocytic Leukemia Oral Cavity and Pharynx 9 16.0 7.3 30.4 1.0 15.7 2, 36 Salivary Gland 8 45.6 19.7 89.9 0.9 16.2 2, 32, 36 Bones and Joints 7 8.5 3.4 17.6 0.7 8.4 2, 31, 34 Soft Tissue including Heart 7 7.6 3 15.6 0.7 8.4 31, 37 24 9.3 6.0 13.9 2.5 14.2 2, 31, 33, 34, Brain, CNS 35 Thyroid 21 7.6 4.7 11.6 2.1 20.0 2, 31, 33, 34 27 Leukemia 13 4.6 2.4 7.8 1.2 9.0 Non-Lymphocytic Leukemia 13 12.1 6.4 20.6 1.4 9.0 Acute Non-Lymphocytic Leukemia 11 13.8 6.9 24.7 1.2 9.9 Myeloid and Monocytic Leukemia 13 13.2 7.0 22.6 1.4 9.0 Acute Myeloid Leukemia 11 16.3 8.1 29.1 1.2 9.9 31, 32, 38 Brain, CNS 3 9.7 2.0 28.4 2.5 17.7 31 Thyroid 3 6.8 1.4 19.9 2.4 17.4 31 Salivary Gland 7 32.1 12.9 66 1.2 21.1 2 Esophagus 4 27.3 7.4 69.9 0.7 26.9 Colon excluding Rectum 9 6.3 2.9 12 1.4 29.6 (ANLL) 34 Acute Myeloid Leukemia Hodgkin Lymphoma 2, 7, 27, 47, 49 Stomach 7 18.5 7.4 38.2 1.2 19.1 2, 7, 49 Cecum 3 13.2 2.7 38.6 0.5 30.2 Soft Tissue including Heart 19 23.7 14.3 37 3.3 15.7 2, 31, 51 Melanoma of the Skin 12 2.2 1.1 3.8 1.2 17.3 2, 7, 17, 43, 47, 50 Female Breast 96 11.4 9.2 13.9 15.9 20.9 2, 7, 8, 10, 17, 27, 31, 32, 28 38, 42-48 Pancreas Lung and Bronchus Bones and Joints 4 11.1 3 28.4 0.7 18.8 2 12 8.2 4.2 14.3 1.9 24.3 2, 49, 51 6 12.1 4.4 26.4 1.0 9.5 2, 7, 17, 27, 31, 49, 51 Corpus Uteri 4 3.9 1.1 10 0.5 19.4 Kidney 7 6.6 2.7 13.7 1.1 30.9 Brain, CNS 6 3.3 1.1 7.2 0.8 16.7 2, 7, 17, 27, 31, 49, 51 Thyroid 37 8.4 5.9 11.6 5.9 16.4 2, 7, 17, 27, 31, 32, 43 Non-Hodgkin Lymphoma 18 6.7 3.9 10.5 2.8 18.2 2, 7, 17, 27, 31, 32, 39 Leukemia 19 11.3 6.8 17.7 3.1 5.6 2, 7, 17, 27, 31, 48 Non-Lymphocytic Leukemia 18 17.2 10.2 27.3 3.1 5.6 Acute Non-Lymphocytic Leukemia 17 25.1 14.6 40.2 3.0 5.5 Myeloid and Monocytic Leukemia 16 16.5 9.5 26.9 2.7 5.4 Acute Myeloid Leukemia 15 25.4 14.2 41.8 2.6 5.1 2 (ANLL) Non-Hodgkin Lymphoma (except Burkitt Lymphoma) 31 29 Female Breast 7 5.8 2.3 12 2.7 25.3 2, 7, 13, 17, 31, 35, 47, 51, 58, 59 Brain 3 4.9 1 14.3 1.1 2.1 17, 41, 51, 58, 59 Thyroid 13 12.8 6.8 21.8 5.6 16.4 2, 7, 13, 17, 31, 32, 47,51, 52 Lymphoma 11 6.8 3.4 12.2 4.4 8.3 7, 17, 31, 53, Non-Hodgkin Lymphoma 6 7.3 2.7 15.8 2.4 9.4 31, 48, 58 Leukemia 7 10.7 4.3 22 3.0 1.7 2, 7, 59 Non-Lymphocytic Leukemia 7 20.0 8.0 41.2 3.1 1.7 Acute Non-Lymphocytic Leukemia (ANLL) 6 25.5 9.4 55.6 2.7 0.6 Myeloid and Monocytic Leukemia 7 21.6 8.7 44.5 3.1 1.7 Acute Myeloid Leukemia 4 19.6 5.3 50.1 1.8 1.5 Salivary Gland 4 21.3 5.8 54.6 0.5 17 Rectum and Rectosigmoid Junction 3 5.7 1.2 16.7 0.3 13.8 58, 59 2 59 Brain, CNS tumors 2, 47, 49, 53, 54 Liver 3 13.7 2.8 39.9 0.4 18.1 53 30 Pancreas 2 10.1 1.2 36.5 0.2 12 2 Bones and Joints 9 12.7 5.8 24.1 1.1 9.1 2, 7, 17, 31, 34, 51, 54 Soft Tissue including Heart 13 14.8 7.9 25.3 1.7 11.1 2, 31, 51, 53 Brain, CNS 72 32.3 25.3 40.7 9.5 15.4 2, 7, 13, 17, 31, 34, 40, 41, 48, 51, 52, 54 Thyroid 17 5.4 3.1 8.6 1.9 18.2 7, 13, 17, 31, 34, 48, 49, 51, 52, 53 Leukemia 21 9.1 5.6 13.8 2.6 4.8 7, 17, 31, 34, 51, 54 Lymphocytic Leukemia 7 5.5 2.2 11.3 0.8 6.5 Acute Lymphocytic Leukemia 6 5.1 1.9 11.1 0.7 2.9 Non-Lymphocytic Leukemia 14 13.4 5.6 13.8 2.6 2.9 Acute Non-Lymphocytic Leukemia (ANLL) 12 16.3 8.4 28.4 9.8 4.1 Myeloid and Monocytic Leukemia 14 14.6 8.0 24.4 1.8 3.9 Acute Myeloid Leukemia 12 18.9 9.8 33.1 1.6 4.1 53, 54 6 18.9 6.9 41.2 2.5 16.9 2 2, 33 Neuroblastoma and Other Peripheral Nervous Cell Tumors Digestive System 31 Kidney 7 35.5 14.3 73.1 3.0 16.3 2, 56 Thyroid 4 8.2 2.2 21.1 1.6 16.3 2, 7, 13, 31, 33, 48, 49, 51, 56, 57 Retinoblastoma Nose, Nasal Cavity and Middle Ear Bones and Joints 3 325.5 67.1 951.1 2.4 11 49, 61, 62 11 109.5 54.7 196 8.7 9 2, 15, 16, 49, 51, 54 Eye and Orbit - Non-Melanoma 4 107.2 29.2 274.5 3.2 9.6 2 Soft Tissue including Heart 3 22.4 4.6 65.6 2.3 16.2 2, 49, 51, 62 Leukemia 4 8.6 2.4 22.1 2.8 9 Acute Lymphocytic Leukemia 4 12.8 3.5 32.8 2.9 9 Kidney 5 25.0 8.1 58.4 1.9 12.3 Soft Tissue including Heart 5 18.2 5.9 42.5 1.9 12.7 31 Thyroid 4 4.9 1.3 12.5 1.3 20.4 31, 54 Leukemia 4 4.8 1.3 12.3 1.1 7.4 52 Non-Lymphocytic Leukemia 3 9.8 2 28.7 1.1 6.2 Acute Non-Lymphocytic Leukemia (ANLL) 3 13.2 2.7 38.5 1.1 6.2 Myeloid and Monocytic Leukemia 3 10.8 2.2 31.7 1.1 6.2 Acute Myeloid Leukemia 3 15.6 3.2 45.7 1.1 6.2 2 Renal Tumors 32 Bone Tumors Oral Cavity and Pharynx 3 8.9 1.8 26.0 1.2 31.8 Colon excluding Rectum 3 7.1 1.5 20.8 1.2 19.5 Respiratory System 3 5.7 1.2 16.8 1.1 17.2 Bones and Joints 7 31.8 12.8 65.6 3.1 4.1 7, 13, 52 7, 34, 48, 52, 54, 60 Soft Tissue including Heart 8 27.2 11.7 53.6 3.5 10.7 Kidney 3 9.5 2 27.7 1.2 18.7 Thyroid 5 3.9 1.3 9.1 1.7 14.1 13, 17, 34, 51, 52, 54 Female Breast 14 6.6 3.6 11.1 5.4 19 7, 10, 13, 17, 31, 34, 47, 52, 60 Leukemia 15 23 12.9 37.9 6.5 4.5 7, 34, 48, 52, 54, 55 Non-Lymphocytic Leukemia 14 37.5 20.5 62.9 6.2 3.9 Acute Non-Lymphocytic Leukemia (ANLL) 14 55.9 30.6 93.8 6.3 3.9 Myeloid and Monocytic Leukemia 14 40.4 22.1 67.8 6.2 3.9 Acute Myeloid Leukemia 11 50.2 25.1 89.9 4.9 4.9 3 178.9 36.9 522.9 1.4 0.3 Acute Monocytic Leukemia Soft Tissue Sarcomas 33 Oral Cavity and Pharynx 5 10.7 3.5 25.1 1.3 17.7 2 Tongue 3 25.8 5.3 75.4 0.8 12.6 9, 49 Lung and Bronchus 3 5.4 1.1 15.8 0.7 22 9, 49 Bones and Joints 9 28 12.8 53.2 2.5 9.4 2, 7, 17, 31, 34, 49, 51, 52, 54 Soft Tissue including Heart 9 20.2 9.2 38.4 2.5 11.6 Kidney 3 6.3 1.3 18.4 0.7 12.9 Brain, CNS 6 5.7 2.1 12.5 1.4 17.6 Lymphatic and Hematopoietic Diseases 9 2.5 1.2 4.8 1.6 5.7 Leukemia 8 7.4 3.2 14.6 2.0 6.3 9, 31, 34, 51 7, 13, 17, 34, 31, 41, 54 7, 9, 17, 31, 34, 48, 49, 54 Non-Lymphocytic Leukemia 8 14.6 6.3 28.9 2.2 6.3 Acute Non-Lymphocytic Leukemia (ANLL) 7 18.8 7.6 38.8 1.9 6.6 Myeloid and Monocytic Leukemia 8 15.9 6.9 31.3 2.2 6.6 Acute Myeloid Leukemia 7 21.8 8.7 44.8 1.9 6.6 9 28 13.1 8.7 19 6.9 12 2, 52 6 4.8 1.8 10.5 1.3 5.5 11 2.4 1.2 4.3 1.7 18.9 Germ Cell Tumors Testis Brain, CNS Lymphatic and Hematopoietic Diseases 34 Leukemia 7 5.7 2.3 11.7 1.5 12.5 54 Non-Lymphocytic Leukemia 6 8.6 3.1 18.6 1.4 12.6 Acute Non-Lymphocytic Leukemia (ANLL) 5 10.9 3.5 25.4 1.2 11.5 Myeloid and Monocytic Leukemia 6 9.2 3.4 20.1 1.4 12.6 Acute Myeloid Leukemia 4 10 2.7 25.5 1.0 13.2 Salivary Gland 4 35.6 9.7 91.1 1.6 8.0 Kidney 3 6.6 1.4 19.2 1.1 25.7 38 18.3 13.0 25.1 19.7 9.6 5 19.7 6.4 45.9 2.0 13.3 34, 51 1.4 21.0 7, 13, 34, 51 Thyroid Carcinomas Malignant Melanomas Melanoma of the Skin Wilms’ Tumor Soft Tissue including Heart Thyroid 4 5.4 1.5 13.8 Data source: Surveillance, Epidemiology, and End Results (SEER). Note: Includes children surviving 2 months or more after diagnosis. CNS: Central Nervous System. * Categories and ordering based on International Classification of Childhood Cancer [15].
© Copyright 2024