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Figure.  Cumulative Incidence of Benign Tumors for 5-Year Survivors of Childhood Cancer by Attained Age
Cumulative Incidence of Benign Tumors for 5-Year Survivors of Childhood Cancer by Attained Age

Participants are stratified by treatment (A) (including siblings) and period of diagnosis (B). Both analyses account for death as a competing risk. CT indicates chemotherapy; RT, radiotherapy.

Table 1.  Multivariable Cox Regression Models for Risk of Any Benign Tumor Among 5-Year Survivors of Childhood Cancer in the DCOG-LATER Cohorta
Multivariable Cox Regression Models for Risk of Any Benign Tumor Among 5-Year Survivors of Childhood Cancer in the DCOG-LATER Cohorta
Table 2.  Multivariable Cox Regression Analyses for Risk of Selected Benign Tumor Types Among 5-Year Survivors of Childhood Cancer in the DCOG-LATER Cohorta
Multivariable Cox Regression Analyses for Risk of Selected Benign Tumor Types Among 5-Year Survivors of Childhood Cancer in the DCOG-LATER Cohorta
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Original Investigation
March 28, 2019

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

Author Affiliations
  • 1Department of Pediatric Oncology, Emma Children’s Hospital, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, the Netherlands
  • 2Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
  • 3Department of Epidemiology and Biostatistics, the Netherlands Cancer Institute, Amsterdam, the Netherlands
  • 4Department of Pediatric Oncology/Hematology, University of Groningen/Beatrix Children’s Hospital, University Medical Center Groningen, Groningen, the Netherlands
  • 5Department of Pediatric Oncology/Hematology and Medicine section Endocrinology, Sophia Children’s Hospital/Erasmus Medical Center, Rotterdam, the Netherlands
  • 6Department of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands
  • 7Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
  • 8Department of Pediatric Oncology and Hematology, Wilhelmina Children’s Hospital/ University Medical Center Utrecht, the Netherlands
  • 9Department of Pediatric Oncology/Hematology, Sophia Children’s Hospital/Erasmus Medical Center, Rotterdam, the Netherlands
  • 10Department of Pediatric Oncology/Hematology, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
  • 11Department of Medical Informatics, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands
  • 12Department of Pediatric Endocrinology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, the Netherlands
  • 13Dutch Childhood Oncology Group, Utrecht, the Netherlands
  • 14Department of Radiation Oncology, University of Groningen/ University Medical Center Groningen, Groningen, the Netherlands
  • 15Foundation PALGA (Nationwide Network and Registry of Histopathology and Cytopathology), Houten, the Netherlands
  • 16Department of Human Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
  • 17Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
JAMA Oncol. 2019;5(5):671-680. doi:10.1001/jamaoncol.2018.6862
Key Points

Question  What are the incidence of and treatment-related risk factors for histologically confirmed solid benign tumors in long-term survivors of childhood cancer?

Findings  In this record linkage study of 5843 Dutch 5-year survivors of childhood cancer, 9.3% developed a benign tumor after a median follow-up of 22.7 years and at a median age of 30.0 years; the highest cumulative incidence of benign tumors was found in survivors treated with radiotherapy only (16.7%). Unlike breast fibroadenoma, nervous system tumors, uterine leiomyoma, and osteochondroma appeared to be associated with prior local radiotherapy.

Meaning  These findings in survivors of childhood cancer are important to enable early diagnosis, to develop organ-specific guidelines that include some benign tumors, and to guide in-depth etiologic studies.

Abstract

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.

Introduction

Survivors of childhood cancer (CCSs) are at high risk for late morbidities, including new tumors. Current research predominantly focuses on the burden of subsequent malignant neoplasms.1-4 Benign tumors are of importance too; benign tumors and subsequent malignant neoplasms may share etiologic factors and clinical manifestations that may affect quality of life or life expectancy.5 In addition, benign tumors may be cancer precursors, including for example colorectal adenoma6 and thyroid nodules,7 offering potential opportunities for early detection of precancerous growths.8-10

For some organs, elevated risks in CCSs were shown after radiotherapy, including benign tumors of the central nervous system,11,12 salivary and/or thyroid gland,13-15 and colorectal tract,16,17 mostly based on self-reports or retrospective medical record review. Benign tumors can occur as part of specific familial cancer predisposition syndromes, such as neurofibromatosis type 1 or 2 (NF1/NF2).18-20

We provide a comprehensive examination of the incidence of histologically confirmed subsequent benign tumors in long-term CCSs vs siblings. Furthermore, we evaluated treatment-related risk factors for benign tumors among CCSs. Our study used a record linkage approach combining the strengths of the Dutch Childhood Oncology Group–Long-Term Effects After Childhood Cancer (DCOG-LATER) cohort study and the population-based nationwide network and registry of histopathology and cytopathology in the Netherlands (PALGA).21

Methods

The DCOG-LATER cohort included 6165 individuals diagnosed with any type of childhood cancer at younger than 18 years from January 1, 1963, through December 31, 2001, in 7 Dutch pediatric centers who survived at least 5 years after the diagnosis. Data on prior diagnosis and treatment of primary tumors and recurrences are available in the DCOG-LATER registry. All cohort members were traced for vital status and address using national and municipal registries. The CCSs who participated in the 2013-2014 questionnaire survey (n = 3172) invited their respective siblings. In all, 883 of 1663 approached siblings (53.1%) were eligible for record linkage studies. The study protocol was declared exempt from review of medical intervention research by the institutional review boards of participating centers. More details were reported elsewhere.1

Definition and Ascertainment of Subsequent Benign Tumors

Histologically confirmed solid benign tumors (hereinafter referred to as benign tumors) were identified by linkage with PALGA, a database containing results of all pathology examinations performed in the Netherlands, which reached nationwide coverage during 1990.21 PALGA pathology reports contain short digital summary excerpts using thesaurus codes (based on Systematized Nomenclature of Medicine codes) to classify the pathologists’ review. The linkage was based on pseudonymized family name, sex, and date of birth. Potentially eligible excerpts were defined as those with benign tumor morphology codes (M8.XXX/0-M9.XXX/0), excluding skin, until May 2015. Resulting excerpts were manually reviewed by 2 of us (J.L.K. and C.M.R.) to identify eligible cases. Where necessary, an experienced late-effects specialist was consulted (H.J.vdP.). Benign tumors were classified according to morphology codes from the International Classification of Diseases for Oncology, Third Edition.22 We used data for subsequent malignant neoplasms to December 31, 2012 (ascertainment previously reported1) to compare the magnitude of the cumulative incidences of benign tumors and subsequent malignant neoplasms in our cohort and to identify groups of CCSs who developed both.

Statistical Analyses

Data were analyzed from January 1, 1990, through May 1, 2015. Survivors who declined approval for use of health care data (152 [2.5%]) and those who died, emigrated, or were lost to follow-up before 1990 (170 [2.8%]) were excluded. Follow-up started 5 years after the diagnosis of childhood cancer or January 1, 1990, whichever came last, and ended on the date of diagnosis of the first benign tumor, death, last known vital status (emigration, loss to follow-up), or end of the study (May 1, 2015), whichever came first. In analyses of any benign tumor, follow-up ended on the date of first occurring benign tumor; in analyses on specific benign tumor types, follow-up ended on the first occurring benign tumor of that particular type.

Multivariable Cox proportional hazards regression models were used to estimate risks of benign tumors associated with treatment and demographic factors (hazard ratios [HRs]). Cumulative incidences of benign tumors for survivors and siblings were calculated, accounting for death as a competing risk. To estimate risks in CCSs for 4 primary and 4 secondary outcome types, we used multivariable Cox proportional hazards regression models, including more detailed treatment variables (prescribed radiotherapy dose and 6 main chemotherapeutic groups) (eMethods in the Supplement). Risk models for meningioma23 and colorectal adenoma17 were reported previously. Attained age was used as the time scale to account for age-related increasing rates of benign tumors.24 The proportional hazards assumption was tested. If violated, risk estimates were presented at the median attained age of all CCSs. P < .05 was considered statistically significant, and all statistical tests were 2 sided. Analyses were performed using Stata software (version 13; StataCorp).

Results
Cohort Characteristics

This analysis included 5843 five-year CCSs (3269 male [55.9%] and 2574 female [44.1%]) who contributed 99 123 person-years at risk from January 1, 1990, through May 1, 2015, and 883 siblings contributing 19 177 person-years. Leukemia (1962 [33.6%]), lymphoma (950 [16.3%]), and central nervous system tumors (781 [13.4%]) were the most frequent childhood cancers (Table 1). For CCSs, median time since childhood cancer diagnosis was 22.7 years (range, 5.0-52.2 years) and median attained age at end of follow-up was 30.0 years (range, 5.8-67.5 years). For siblings, median attained age was 31.7 years (range, 9.5-73.3 years). In total, 542 CCSs and 56 siblings developed 1 or more benign tumors. Among CCSs with a benign tumor, 63 (11.6%) also developed a solid subsequent malignant neoplasm, including 35 with a benign tumor after a solid subsequent malignant neoplasm, 24 with a benign tumor before a solid subsequent malignant neoplasm, and 4 with synchronous benign tumor and subsequent malignant neoplasm diagnoses. In all, 484 cohort members died during follow-up, including 46 with benign tumors; 2 meningioma were listed as confirmed cause of death. After adjustment for attained age and sex, the incidence of benign tumors in CCSs vs siblings was significantly elevated (HR, 1.9; 95% CI, 1.5-2.6).

Demographic and Treatment-Related Risk Factors for Any Benign Tumor

Risk factors for the first benign tumor of any histologic type or location per individual (further referred to as any benign tumor) were evaluated in multivariable Cox proportional hazards regression models (Table 1) (model 1). Female CCSs had a significantly higher risk than male CCSs to develop any benign tumor (HR, 1.5; 95% CI, 1.3-1.8). No sex difference was observed when benign tumors of sex-specific organs were excluded. Children diagnosed with cancer before 5 years of age had a significantly increased risk of any benign tumor compared with children diagnosed at 10 to 17 years of age (HR, 1.5; 95% CI, 1.2-1.8). Of note, younger age at diagnosis equals longer follow-up time in models with attained age as time scale. Furthermore, a diagnosis of childhood cancer after 1985 inferred a 1.4-fold risk for benign tumors compared with those diagnosed before 1985 (HR for 1985-1994, 1.4 [95% CI, 1.1-1.8]; HR for 1995-2001, 1.4 [95% CI, 1.0-1.9]). A history of radiotherapy only (HR for 30 years of age, 2.3; 95% CI, 1.5-3.5 [proportional hazards assumption violated]) and combined radiotherapy and chemotherapy (HR, 2.5; 95% CI, 1.7-3.5) significantly increased the risk for benign tumor compared with surgery only or no recorded treatment. Relative to survivors of pediatric Hodgkin lymphoma (reference group), only survivors of medulloblastoma (HR, 2.0; 95% CI, 1.2-3.3) were at statistically significantly increased risk for benign tumors (Table 1) (model 2).

Cumulative Incidence

The cumulative incidence of BTs by age 30 years was highest after radiotherapy only (16.7%; 95% CI, 9.0%-26.3%) and after radiotherapy plus chemotherapy (11.2%; 95% CI, 8.1%-14.7%) with values of 4% to 6% for those treated otherwise and for siblings (Figure, A). By childhood cancer type, the highest cumulative incidences at 30 years of age were seen after medulloblastoma (11.5%; 95% CI, 6.5%-17.9%), neuroblastoma (10.5%; 95% CI, 7.0%-14.7%), and renal tumors (7.6%; 95% CI, 5.2%-10.5%) (eFigure 1 in the Supplement). Cumulative incidences at 30 years of age varied slightly by period of childhood cancer diagnosis, but did not seem to decrease for most recently treated patients, with cumulative incidences of 7.3% (95% CI, 5.8%-9.1%) for a childhood cancer diagnosis from 1963 to 1984; 8.4% (95% CI, 6.8%-10.2%), 1985 to 1994; and 7.5% (95% CI, 5.7%-9.5%), 1995 to 2001 (Figure, B). eFigure 2 in the Supplement also provides results using time since diagnosis as time scale. The cumulative incidences at 45 years of age for benign tumors (female CCSs, 24.7% [95% CI, 21.6%-27.9%]; male CCSs, 15.1% [95% CI, 13.1%-17.3%]) (eFigure 3 in the Supplement) were much higher than those for nonskin solid subsequent malignant neoplasms in the comparable subsample of a previous DCOG-LATER study of subsequent malignant neoplasms1 (females, 10.7% [95% CI, 8.4%-13.2%]; males, 5.7% [95% CI, 4.3%-5.7%]).

The most common benign tumors in CCSs were meningiomas (89 [16.4%]), and among siblings, fibroepithelial neoplasms (12 [21.4%]) (eTable 1 in the Supplement). In addition, nerve sheath tumors (50 [9.2%]) and osseous and/or chondromatous neoplasms (23 [4.2%]) were more frequently diagnosed in CCSs compared with siblings (1 [1.8%] for each tumor type).

Multivariable Risk Factor Analyses for Primary Outcome Groups

Among female CCSs, 50 myomatous neoplasms were diagnosed, including 43 uterine leiomyomas (eTable 2 in the Supplement). The most important risk factor for leiomyomas was abdominopelvic radiotherapy (including total body irradiation [TBI]), with a significant dose-dependent increase compared with female CCSs without such radiotherapy (HR for dose <20 Gy, 1.9 [95% CI, 0.5-7.0]; HR for dose of 20 to <30 Gy, 3.4 [95% CI, 1.1-10.4]; and HR for dose ≥30 Gy, 5.4 [95% CI, 2.4-12.4]) (Table 2); the test for trend reached significance (P = .002), however, not among exposed-only participants (P = .78). None of the chemotherapy groups was associated with uterine leiomyoma risk.

In the subgroup of fibroepithelial neoplasms (eTable 2 in the Supplement), 46 fibroadenomas of the breast were diagnosed (1 male and 45 female CCSs; age <50 years). Women treated with a radiotherapy dose of less than 20 Gy to the trunk (12 cases) had a significantly increased risk of breast fibroadenoma compared with women without such exposure (26 cases; HR, 3.8; 95% CI, 1.8-8.1), whereas those treated with a cumulative dose of 20 to less than 30 Gy (4 cases; HR, 2.7; 95% CI, 0.9-7.9) and at least 30 Gy (2 cases; HR, 1.0; 95% CI, 0.2-4.5) did not (P = .07 for trend among all survivors and P = .28 for trend among those with exposure only) (Table 2). In addition, female survivors who had received alkylating agents (29 cases of 1224 female cohort members) had a statistically significantly increased risk (HR, 2.1; 95% CI, 1.0-4.6; P = .048).

Nerve sheath tumors (n = 55) occurred across the body, including 29 schwannomas and 24 neurofibromas (eTable 2 in the Supplement). Six schwannomas concerned acoustic neuromas, 3 of which occurred after cranial radiotherapy for astrocytoma. In multivariable analyses, risk of nerve sheath tumors was elevated for the following 3 factors: (1) radiotherapy, the effect of which slightly decreased with increasing attained age (HR at 31 years of age, 2.9; 95% CI, 1.5-5.5 [proportional hazards assumption violated]); (2) an indicator variable for NF1/NF2–associated childhood cancer types (a definition is found in eTable 3 in the Supplement), with HRs of 5.6 (95% CI, 2.3-13.7) for central nervous system tumors and 2.4 (95% CI, 0.9-6.2) for other childhood cancer types among subgroups at increased NF1/NF2 probability vs all other CCSs; and (3) epipodophyllotoxins (HR, 3.8; 95% CI, 1.5-9.2) (Table 2). A significant effect of epipodophyllotoxins remained after adjustment for cranial radiotherapy and TBI. Because NF1/NF2 status may affect the association of prior radiotherapy on nerve sheath tumor, we also conducted analyses of interaction. No evidence in our data suggested that the effect of radiotherapy was stronger according to our crude surrogate indicator for NF1/NF2 status (Table 2).

Twenty-three subsequent osseous and/or chondromatous neoplasms occurred, including 21 osteochondromas (eTable 2 in the Supplement). These tumors occurred most often (16 of 23) among leukemia survivors, many of whom (11 of 16) had received hematopoietic cell transplant, all including TBI (HR, 37.4; 95% CI, 14.8-94.7) (Table 2). We did not find an effect of other radiotherapy or for 6 chemotherapy groups.

Multivariable Risk Factor Analyses for Secondary Outcome Groups

Multivariable Cox proportional hazards regression models for secondary outcomes are provided in eTable 4 in the Supplement. Patients treated with chemotherapy and radiotherapy had elevated risk for adenomas (HR, 2.8; 95% CI, 1.1-7.1) and for fibromatous neoplasms (HR, 4.4; 95% CI, 1.7-11.0), compared with those who had surgery only or no recorded treatment.

Discussion

In our record linkage study with high-quality treatment and outcome assessments, we observed the highest cumulative incidence of benign tumors by 30 years of age for CCSs treated with radiotherapy only (16.7%; 95% CI, 9.0%-26.3%). Notable findings of our exploratory risk factor analyses include the role of abdominopelvic radiotherapy in uterine leiomyoma, elevated risk for osteochondromas among survivors of leukemia, and strong effects of radiotherapy and a crude indicator of NF1/NF2 status for the risk of nerve sheath tumors. Moreover, we provide a comparison of risk for benign tumors in CCSs and a sibling group to provide some insight into background risk, because age-specific reference rates are not available for any of the reported outcomes. We observed that CCSs have an approximately 2-fold risk to develop subsequent benign tumors compared with siblings.

Our study shows that female survivors have a higher risk than male survivors, a difference attributable to sex-specific benign breast and uterine tumors. Moreover, the cumulative incidence at 45 years of age was more than twice as high for solid benign tumors than for nonskin solid malignant neoplasms, possibly reflecting differences in background risks of benign and malignant tumors. Although biopsies for suspected subsequent malignant neoplasms can contribute to excess risk for benign tumors, and 11.6% of patients with benign tumors also experienced a subsequent malignant neoplasm, only 0.7% of all benign tumors concerned synchronous benign tumor and subsequent malignant neoplasm diagnoses in a single organ. In all, survivors experienced higher rates of benign tumors than the sibling group.

We found evidence of a radiotherapy-related increased risk of uterine leiomyomas among women who had abdominopelvic radiotherapy (minimal dose, 2 Gy). Although the strongest dose-response test to support causality, the P value for trend among exposed patients was not significant, and this finding is consistent with a significant dose-response effect (odds ratio at 1 Gy, 1.61; 95% CI, 1.12-2.31) among 1190 female atomic bomb survivors who underwent ultrasonographic examination (238 cases).25 This exploratory finding warrants confirmation in other study populations, including studies using more specific measures of uterine radiation exposure (volume-based reconstructed doses).

Of all fibroadenomas, more than 50% were diagnosed among women without chest-directed radiotherapy, that is, in the large group of women not undergoing survivorship mammography or magnetic resonance imaging screening; all were diagnosed before the starting age of population-based screening eligibility (50 years).26,27 Two cases were synchronous with a diagnosis of breast cancer; 2 other fibroadenomas occurred after a breast cancer diagnosis, likely detected on routine imaging in breast cancer aftercare. There was no monotonic association of fibroadenoma risk with increasing dose of radiotherapy to the trunk. In summary, we did not find evidence of an increased risk of breast fibroadenoma nor of a strong role of prior childhood cancer therapy.

Adenomas are among the most prevalent benign tumors in our cohort and are of interest as potential cancer precursors. Teepen et al17 previously reported a positive association between abdominopelvic radiotherapy and colorectal adenoma. Other site-specific analyses13-15 were hampered by small numbers of cases; several known radiosensitive tissues were represented (eg, salivary, thyroid, and parathyroid glands). In line with a recent US report among 1296 CCSs (6 cases [0.5%]),28 we identified 4 (0.1%) liver adenomas.

Nerve sheath tumors are known to be associated with predisposition syndromes and prior radiation exposure.20,29 Although we confirmed strong effects of radiotherapy and a crude indicator of NF1/NF2 status, exploratory analyses showed no evidence that the effect of radiotherapy was stronger among NF1/NF2–associated childhood cancer types. As reported previously,23 meningioma represented the most common benign tumor (16.4%) primarily after cranial radiotherapy for leukemia and central nervous system tumors. Medulloblastoma survivors had high-dose, full-volume cranial radiotherapy, which offers a likely explanation for the elevated overall risk for benign tumors among CCSs with medulloblastoma vs Hodgkin lymphoma. In all, nervous system tumors accounted for a quarter of benign tumors.

Osteochondromas have been reported in other studies, in particular after treatment involving radiotherapy for leukemia and neuroblastoma.30-33 Herein we report on 21 cases, of whom 11 had received hematopoietic cell transplant, all including TBI. There appeared to be no association with other radiotherapy. Although the relevance of the TBI finding is unclear, it may be an indicator of other hematopoietic cell transplant–related exposures.

Strengths and Limitations

To our knowledge, this study is the first comprehensive evaluation of risk for benign tumors among long-term CCSs. Strengths include the availability of cohort-based detailed individual treatment information and objective and uniform data on histologically confirmed benign tumors from PALGA21; we collected data on benign tumors for more than 95% of the study population. Most benign tumors are not covered in cancer registries, so existing studies rely on patient self-report with medical verification or on medical record review. Another strength of this record linkage study is the comparison with a sibling group of CCSs. We hypothesize that siblings represent appropriate controls because general health awareness among siblings and CCSs may be more alike than for population-based comparison groups vs CCSs. There is some potential for survival bias and selection bias of the sibling sample; unlike the survivor cohort, siblings were recruited in 2013 to 2014, and inclusion depended on questionnaire participation (ie, siblings had to be alive). We expect small levels of bias because of low age-specific mortality rates and in view of prior work from the DCOG-LATER-VEVO (Fertility in Female Childhood Cancer Survivors) study group.34

A possible limitation of research on indolent benign tumors in CCSs is that survivors receive medical attention in survivorship care programs, and physicians may exert a lower threshold to order imaging for suspect lesions.26,33,35 However, most benign tumors identified in this study were not detected in screening programs, but rather, by symptoms. Cohort members receive guideline-based care without imaging-based screening, except for women at elevated risk of breast cancer who received mammography (and sometimes magnetic resonance imaging) from 2010 onwards (<10% of cohort).26 Also, we had no information on individual genetic predisposition. Finally, benign tumors diagnosed before 1990 were not captured by PALGA; by including only follow-up time from 1990, we have limited the underestimation of benign tumors owing to left truncation. Also, a slight chance of false-positive findings exists with the PALGA linkage on family name, sex, and birth date due to administrative twins. In addition, PALGA excerpts contain information on consecutive biopsies; sometimes the excerpt texts were not sufficiently specific to distinguish specimens from one lesion from specimens taken from different lesions or new lesions in the same organ. We therefore focused in the analyses on the first diagnosed benign tumor per outcome group. We had no information on benign tumors detected on imaging without histologic confirmation.

For follow-up of survivors of childhood cancer, it will be relevant to be aware of clinical symptoms related to uterine leiomyoma among women with a history of abdominopelvic radiotherapy, of osteochondroma among leukemia survivors, and of meningioma and nerve sheath tumors after (cranial) radiotherapy. Timely attention for these symptoms is relevant for early diagnosis and can help to diminish burden for survivors. In addition, early detection of benign tumors as precursors of subsequent malignant neoplasms (eg, colorectal adenoma, thyroid nodules) might decrease morbidity and mortality.8,36,37 Of interest are efforts of the International Guideline Harmonization Group to define or update surveillance recommendations for late effects (http://www.ighg.org).8,27 In this group, the benefits and harms of active surveillance of benign tumors should be discussed. For future research, investigation of the roles of prior therapy and genetic susceptibility among CCSs should be evaluated combining organ-specific volume-based reconstructed doses and results of genotyping.

Conclusions

In conclusion, our record linkage study shows a considerable cumulative incidence of solid benign tumors in CCSs, which is higher than for subsequent solid malignant neoplasms, and higher compared with siblings. We also identified risk factors for benign tumors. These findings are important to enable early diagnosis and to serve as the first step for future surveillance guidelines, including some benign tumors in CCSs. Also, they provide leads for further in-depth etiologic studies.

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Article Information

Accepted for Publication: November 30, 2018.

Corresponding Author: Judith L. Kok, MSc, Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, the Netherlands (j.l.kok-5@prinsesmaximacentrum.nl).

Published Online: March 28, 2019. doi:10.1001/jamaoncol.2018.6862

Author Contributions: Drs Kremer and Ronckers contributed equally. Ms Kok and Mr Teepen had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Kok, Teepen, van der Pal, Van Leeuwen, Bruggink, Kremer, Ronckers.

Acquisition, analysis, or interpretation of data: Kok, Teepen, van der Pal, Van Leeuwen, Tissing, Neggers, van den Heuvel-Eibrink, Loonen, Louwerens, van Dulmen-den Broeder, Jaspers, van Santen, van der Heiden-van der Loo, Versluys, Janssens, Maduro, Jongmans, Kremer, Ronckers.

Drafting of the manuscript: Kok, Teepen, Kremer, Ronckers.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Kok, Teepen, Kremer, Ronckers.

Obtained funding: van Leeuwen, Tissing, Kremer, Ronckers.

Administrative, technical, or material support: Tissing, van Dulmen-den Broeder, van den Heuvel-Eibrink, Loonen, Versluys, van der Heiden-van der Loo, Bruggink, Kremer.

Supervision: Kremer, Ronckers.

Conflict of Interest Disclosures: Dr Ronckers reported receiving grants from the Dutch Cancer Society and AMC Research Council during the conduct of the study. Dr van Santen reports personal fees from Ferring BV outside the submitted work. No other disclosures were reported.

Funding/Support: This work was supported by grants DCOG2011-5027 and UVA2012-5517 from the Dutch Cancer Society and a PhD grant awarded by the Academic Medical Center Executive Board to Drs Kremer and Ronckers (Dr Kok).

Role of the Funder/Sponsor: The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The Dutch Childhood Oncology Group–Long-Term Effects After Childhood Cancer (DCOG-LATER) Study Group for benign tumors includes the listed authors and the following collaborators: B. M. P Aleman (the Netherlands Cancer Institute, Amsterdam); M. H. van den Berg (Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam); D. Bresters (Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands); H. N. Caron (Emma Children’s Hospital/Amsterdam UMC, University of Amsterdam); S. C. Clement (Amsterdam UMC, Vrije Universiteit Amsterdam); L. A. Daniels (Leiden University Medical Center, Leiden, the Netherlands); W. V. Dolsma (University of Groningen/University Medical Center Groningen, Groningen, the Netherlands); M. A. Grootenhuis (Princess Máxima Center for Pediatric Oncology, Utrecht); C. J. A. Haasbeek (Amsterdam UMC, Vrije Universiteit Amsterdam); B. A. W. Hoeben (Radboud University Medical Center, Nijmegen, the Netherlands); J. G. den Hartogh (Dutch Childhood Cancer Parent Organisation, Nieuwegein, the Netherlands); N. Hollema (Dutch Childhood Oncology Group, Utrecht); F. Oldenburger (Amsterdam UMC, University of Amsterdam); A. Postma (Dutch Childhood Oncology Group, Utrecht); C. M. van Rij (Erasmus Medical Center, Rotterdam, the Netherlands); R. J. H. A. Tersteeg (University Medical Center Utrecht, Utrecht)

Meeting Presentations: This study was presented in part at the 15th International Conference on Long-Term Complications of Treatment of Children and Adolescents for Cancer; June 16, 2017; Atlanta, Georgia; and the European Society for Radiotherapy and Oncology (ESTRO 35) Conference; May 2, 2016; Turin, Italy.

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