Incidence of and Risk Factors for Histologically Confirmed Solid Benign Tumors among Long-term Survivors of Childhood Cancer

Judith L. Kok, Jop C. Teepen, Helena J. van der Pal, Flora E. van Leeuwen, Wim J. E. Tissing, Sebastian J. C. M. M. Neggers, Jacqueline J. Loonen, Marloes Louwerens, Birgitta Versluys, Marry M. van den Heuvel-Eibrink, Eline van Dulmen-den Broeder, Monique M. W. Jaspers, Hanneke M. van Santen, Margriet van der Heiden-van der Loo, Geert O. Janssens, John H. Maduro, Annette H. Bruggink, Marjolijn C. Jongmans, Leontien C. M. Kremer, C. cile M. Ronckers

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11 Citations (Scopus)


Importance: Survivors of childhood cancer (CCSs) face risk of developing subsequent tumors. Solid benign tumors may be cancer precursors; benign tumors and cancers may share etiologic factors. However, comprehensive data on the risk for solid benign tumors are lacking. Objective: To quantify the incidence of and treatment-related risk factors for histologically confirmed solid nonskin benign tumors among CCSs. Design, Setting, and Participants: This record linkage study involves the Dutch Childhood Oncology Group-Long-Term Effects After Childhood Cancer (DCOG-LATER) cohort of 6165 individuals diagnosed with childhood cancer at younger than 18 years from January 1, 1963, through December 31, 2001, in 7 Dutch pediatric centers and who survived at least 5 years after the diagnosis. Study groups eligible for record linkage from 1990 onward included 5843 CCSs (94.8%) and 883 siblings. Benign tumors were identified from the population-based Dutch histopathology and cytopathology registry (PALGA). Follow-up was completed on May 1, 2015. Data were analyzed from January 1, 1990, through May 1, 2015. Main Outcomes and Measures: Cumulative incidence of any subsequent benign tumor for cohort strata and multivariable Cox proportional hazards regression models (hazard ratios [HRs]) were used to evaluate potential risk factors for 8 major benign tumor subtypes. Results: Of the 5843 eligible CCSs (55.9% male), 542 (9.3%) developed a histologically confirmed subsequent benign tumor after a median follow-up of 22.7 years (range, 5.0-52.2 years). Among women, abdominopelvic radiotherapy inferred dose-dependent increased risks for uterine leiomyoma (n = 43) for doses of less than 20 Gy (HR, 1.9; 95% CI, 0.5-7.0), 20 to less than 30 Gy (HR, 3.4; 95% CI, 1.1-10.4), and at least 30 Gy (HR, 5.4; 95% CI, 2.4-12.4) compared with no abdominopelvic radiotherapy (P =.002 for trend). High-dose radiotherapy to the trunk was not associated with breast fibroadenoma (n = 45). Of 23 osseous and/or chondromatous neoplasms, 16 occurred among leukemia survivors, including 11 after total body irradiation (HR, 37.4; 95% CI, 14.8-94.7). Nerve sheath tumors (n = 55) were associated with radiotherapy (HR at 31 years of age, 2.9; 95% CI, 1.5-5.5) and a crude indicator of neurofibromatosis type 1 or 2 status (HR, 5.6; 95% CI, 2.3-13.7). Subsequent risk for benign tumors was higher than the risks for subsequent nonskin solid malignant neoplasms and for benign tumors among siblings. Conclusions and Relevance: This record linkage study uses a unique resource for valid and complete outcome assessment and shows that CCSs have an approximately 2-fold risk of developing subsequent benign tumors compared with siblings. Site-specific new findings, including for uterine leiomyoma, osteochondroma, and nervous system tumors, are important to enable early diagnosis; this information will be the first step for future surveillance guidelines that include some benign tumors in CCSs and will provide leads for in-depth etiologic studies..
Original languageEnglish
Pages (from-to)671-680
JournalJAMA Oncology
Issue number5
Publication statusPublished - 1 May 2019

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