# Risk of subsequent primary lymphoma in a cohort of 69,460 five-year survivors of childhood and adolescent cancer in Europe: The PanCareSurFup study

Isabelle M. Dudley, Ceren Sunguc, Emma J. Heymer, David L. Winter, Jop C. Teepen, Fabiën Naomi Belle, Edit Bárdi, Francesca Bagnasco, Thorgerdur Gudmundsdottir, Roderick Skinner, et al.

► To cite this version:

Isabelle M. Dudley, Ceren Sunguc, Emma J. Heymer, David L. Winter, Jop C. Teepen, et al. Risk of subsequent primary lymphoma in a cohort of 69,460 five-year survivors of childhood and adolescent cancer in Europe: The PanCareSurFup study. Cancer, 2023, 129 (3), pp.426-440. 10.1002/cncr.34561. hal-04122464

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DOI: 10.1002/cncr.34561

ORIGINAL ARTICLE

# Risk of subsequent primary lymphoma in a cohort of 69,460 five-year survivors of childhood and adolescent cancer in Europe: The PanCareSurFup study

Isabelle M. Dudley MD<fnref n="1" />

Ceren Sunguc MSc<fnref n="1" />

Emma J. Heymer MSc<fnref n="1" />

David L. Winter HNC<fnref n="1" />

Jop C. Teepen PhD<fnref n="2" />

Fabiën N. Belle PhD<fnref n="3" />,<fnref n="4" />

Edit Bárdi MD, PhD<fnref n="5" />,<fnref n="6" />

Francesca Bagnasco PhD<fnref n="7" />

Thorgerdur Gudmundsdottir MD<fnref n="8" />,<fnref n="9" />

Roderick Skinner MD, PhD<fnref n="10" />,<fnref n="11" />

Gisela Michel PhD<fnref n="12" />

Julianne Byrne PhD¹³

Hilde Øfstaas PhD¹⁴

Momcilo Jankovic MD¹⁵

Maja Česen Mazić MD, PhD¹⁶

Luzius Mader PhD<fnref n="3" />

Jaqueline Loonen MD, PhD¹⁷

Stanislaw Garwicz MD¹⁸

Thomas Wiebe MD¹⁸

Daniela Alessi PhD¹⁹,²⁰

Rodrigue S. Allodji PhD²¹

Nadia Haddy PhD²¹

Desiree Grabow PhD²²

Peter Kaatsch PhD²²

Melanie Kaiser PhD²²

Milena M. Maule PhD¹⁹,²⁰

Zsuzsanna Jakab MD, PhD²³

Maria Winther Gunnes MD, PhD¹⁴,²⁴

Monica Terenziani MD²⁵

Lorna Zadravec Zaletel MD, PhD²⁶

Claudia E. Kuehni MD<fnref n="3" />,²⁷

Riccardo Haupt MD²⁸

Florent de Vathaire PhD²¹

Leontien C. Kremer MD, PhD<fnref n="2" />,<fnref n="9" />

Päivi M. Lähteenmäki MD, PhD³⁰

Jeanette F. Winther MD, PhD<fnref n="8" />,³¹

Lars Hjorth MD, PhD¹⁸

Michael M. Hawkins DPhil<fnref n="1" />

Raoul C. Reulen PhD<fnref n="1" />

<footnote n="1">¹Center for Childhood Cancer Survivor Studies, Institute of Applied Health Research, University of Birmingham, Birmingham, UK</footnote>

<footnote n="2">²Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands</footnote>

<footnote n="3">³Childhood Cancer Research Group, Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland</footnote>

<footnote n="4">⁴Center for Primary Care and Public Health (Unisante), University of Lausanne, Lausanne, Switzerland</footnote>

<footnote n="5">⁵St Anna Children's Hospital, Vienna, Austria</footnote>

<footnote n="6">⁶Department of Pediatrics and Adolescent Medicine, Johannes Kepler University Linz, Kepler University Hospital, Linz, Austria</footnote>

<footnote n="7">⁷Scientific Directorate, IRCCS Istituto Giannina Gaslini, Genova, Italy</footnote>

<footnote n="8">⁸Danish Cancer Society Research Center, Childhood Cancer Research Group, Copenhagen, Denmark</footnote>

<footnote n="9">⁹Children's Hospital, Landspitali University Hospital, Reykjavik, Iceland</footnote>

<footnote n="10">¹⁰Great North Children's Hospital, Newcastle upon Tyne Hospitals National Health Service Foundation Trust, Newcastle upon Tyne, UK</footnote>

<footnote n="11">¹¹Newcastle University Center for Cancer, Newcastle University, Newcastle upon Tyne, UK</footnote>

<footnote n="12">¹²Department of Health Sciences and Medicine, University of Lucerne, Lucerne, Switzerland</footnote>

<footnote>Coauthor Stanislaw Garwicz MD died November 27, 2018. This work is dedicated to him.</footnote>

<footnote>This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.</footnote>

<footnote>© 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.</footnote>
¹³Boyne Research Institute, Bettystown, Co Meath, Ireland

¹⁴Division of Pediatric and Adolescent Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway

¹⁵Pediatric Clinic, University of Milano-Bicocca, Hospital San Gerardo, Monza, Italy

¹⁶University Children's Hospital Ljubljana, University Medical Center Ljubljana, Ljubljana, Slovenia

¹⁷Department of Hematology, Radboud University Medical Center, Nijmegen, Netherlands

¹⁸Department of Clinical Sciences Lund, Pediatrics, Lund University, Skane University Hospital, Lund, Sweden

¹⁹Childhood Cancer Registry of Piedmont, Cancer Epidemiology Unit, Department of Medical Sciences, University of Turin, Turin, Italy

²⁰Reference Center for Epidemiology and Cancer Prevention-Piemonte, University Hospital Città della Salute e della Scienza di Torino, Turin, Italy

²¹Radiation Epidemiology Team, Center for Research in Epidemiology and Population Health, National Institute of Health and Medical Research Unit 1018, University Paris Saclay, Gustave Roussy, Villejuif, France

²²German Childhood Cancer Registry, Division of Childhood Cancer Epidemiology, Institute of Medical Biostatistics, Epidemiology, and Informatics, Johannes-Gutenberg University Mainz, Mainz, Germany

²³Hungarian Childhood Cancer Registry, Second Department of Pediatrics, Semmelweis University, Budapest, Hungary

²⁴Department of Registration, Cancer Registry of Norway, Oslo, Norway

²⁵Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

²⁶Division of Radiotherapy, Institute of Oncology, Ljubljana, Slovenia

²⁷Division of Pediatric Hematology/Oncology, Department of Pediatrics, University Children's Hospital of Bern, University of Bern, Bern, Switzerland

²⁸Diagnosis, Observation, Prevention After Oncologic Treatment (DOPO) Clinic, Division of Hematology/Oncology, IRCCS Istituto Giannina Gaslini, Genova, Italy

²⁹Emma Children's Hospital, Amsterdam, Netherlands

³⁰Department of Pediatrics and Adolescent Medicine, Turku University and Turku University Hospital, Turku, Finland

³¹Department of Clinical Medicine, Faculty of Health, Aarhus University and University Hospital, Aarhus, Denmark

## Correspondence

Raoul C. Reulen, Centre for Childhood Cancer Survivor Studies, Institute of Applied Health Research, Robert Aitken Building, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.

Email: r.c.reulen@bham.ac.uk

## Funding information

European Union's Seventh Framework Programme for research, technological development and demonstration, Grant/ Award Number: 257505; The Foundation Force de recherche sur le cancer de l'enfant (FORCE), The Italian Association for Cancer Research and the Compagnia; San Paolo; The Fondo Chiara Rama ONLUS; The Swedish Childhood Cancer Fund; The French Association for Cancer Research (ARC); The French National Agency for Research (ANR) (Hope-Epi project); The French National Cancer Institute (INCA); Pfizer Foundation for Children and Adolescent Health; Slovenian Research Agency; The Swiss Paediatric Oncology Group; The Swiss Cancer League, Grant/Award Numbers: KLS-3412-02-2014, KLS-3886-02-2016, KLS-5432-08-2021; The Swiss Cancer Research foundation, Grant/ Award Numbers: KFS-02783-02-2011, KFS- 4157-02-2017, KLA/KFS-4825-01-2019, KFS-4722-02-2019, KFS-5302-02-2021; The Swiss National Science Foundation, Grant/ Award Number: PDFMP3_141775; The Dutch Cancer Society, Grant/Award Numbers: DCOG2011-5027, UVA2012-5517; The Norwegian Childhood Cancer Foundation, and

## Abstract

**Background:** Survivors of Hodgkin lymphoma (HL) are at risk of developing non-Hodgkin lymphoma (NHL) after treatment; however, the risks of developing subsequent primary lymphomas (SPLs), including HL and NHL, after different types of childhood cancer are unknown. The authors quantified the risk of SPLs using the largest cohort of childhood cancer survivors worldwide.

**Methods:** The Pan-European Network for Care of Survivors After Childhood and Adolescent Cancer (PanCare) Survivor Care and Follow-Up Studies (PanCare-SurFup) cohort includes 69,460 five-year survivors of childhood cancer, diagnosed during 1940 through 2008, from 12 European countries. Risks of SPLs were quantified by standardized incidence ratios (SIRs) and relative risks (RRs) using multivariable Poisson regression.

**Results:** Overall, 140 SPLs, including 104 NHLs and 36 HLs, were identified. Survivors were at 60% increased risk of an SPL compared with the general population (SIR, 1.6; 95% confidence interval [CI], 1.4–1.9). Survivors were twice as likely to develop NHL (SIR, 2.3; 95% CI, 1.9–2.8), with the greatest risks among survivors of HL (SIR, 7.1; 95% CI, 5.1–10.0), Wilms tumor (SIR, 3.1; 95% CI, 1.7–5.7), leukemia (SIR, 2.8; 95% CI, 1.8–4.4), and bone sarcoma (SIR, 2.7; 95% CI, 1.4–5.4). Treatment with chemotherapy for any cancer doubled the RR of NHL (RR, 2.1; 95% CI, 1.2–3.9), but treatment with radiotherapy did not (RR, 1.2; 95% CI, 0.7–2.0). Survivors were at similar risk of developing a subsequent HL as the general population (SIR, 1.1; 95% CI, 0.8–1.5).

**Conclusions:** In addition to HL, the authors show here for the first time that survivors of Wilms tumor, leukemia, and bone sarcoma are at risk of NHL. Survivors
Children with Cancer UK, Grant/Award
Number: 20457

and health care professionals should be aware of the risk of NHL in these survivors
and in any survivors treated with chemotherapy.

KEYWORDS

childhood cancer survivors, Hodgkin lymphoma, late effects, non-Hodgkin lymphoma, second
cancers, subsequent primary lymphoma

INTRODUCTION

Approximately 35,000 children and adolescents are diagnosed with
cancer in Europe each year.¹ Since the 1970s, 5-year survival rates
have improved dramatically and now reach 80% in most European
countries, mostly because of combined chemotherapy modalities and
improvements in the delivery of radiotherapy.¹⁻³ There are currently
over 500,000 childhood cancer survivors in Europe, and this number
continues to increase.¹ The risk of premature morbidity and mortality
for childhood cancer survivors compared with the general population
is well documented, with many health risks arising 20–30 years after
a childhood cancer diagnosis. Approximately 60% of childhood cancer
survivors develop at least one chronic health condition during their
lifetime, and more than one in four develop severe or life-threatening
diseases.⁴,⁵

A serious long-term consequence of treatment of childhood
cancer is the increased risk of developing subsequent primary neo-
plasms, which is in the range of three to five times greater that of the
general population.⁶⁻⁹ Existing evidence suggests that survivors are
at increased risk of several types of subsequent primary neoplasms,
particularly central nervous system tumors; nonmelanoma skin can-
cer; and digestive, breast, bone, and genitourinary cancers. Limited
numbers of studies have shown that the overall risk of subsequent
primary lymphoma (SPL) is also increased⁷,⁹⁻¹¹; however, to our
knowledge, few previous large-scale studies have comprehensively
investigated the risk of developing SPLs among childhood cancer
survivors—with the largest previous study to date including 45
SPLs.¹⁰ Studies of survivors of Hodgkin lymphoma (HL) have found an
increased risk of non-Hodgkin lymphoma (NHL) but mostly included
HL survivors who were diagnosed in adulthood.¹²⁻²¹ To date, no
large-scale study has characterized the risks of SPLs and of specific
SPLs by type of childhood cancer, sex, age at diagnosis, decade of
diagnosis, attained age, and treatment factors. Identification of those
survivors at highest risk of an SPL would be important for informing
survivors and health care professionals of who is at risk, potentially
detecting SPLs early, and may give clues about potential biologic
mechanisms.

The principal aim of this largest ever cohort study was to
quantify the risk of developing an SPL, further subdivided into HL and
NHL, among 69,460 survivors of childhood cancer within Europe and
compare this risk with that in the general population, including three
times the number of SPLs compared with the largest previous study
to date.¹⁰ Secondary aims included investigating variations in risk,
which may be associated with certain demographic and oncologic

factors, and assessing the level of risk sustained in the long term
(beyond age 40 years).

MATERIALS AND METHODS

PanCare Childhood and Adolescent Cancer Survivor
Care and Follow-Up Studies

The Pan-European Network for Care of Survivors after Childhood
and Adolescent Cancer (PanCare) is a network of health care pro-
fessionals, researchers, childhood cancer survivors, and their families
that aims to improve both the care and the quality of life for survi-
vors of childhood cancer.²² Funded by the seventh Framework Pro-
gram of the European Union, a consortium among several institutions
of PanCare members established the largest ever collaborative,
comprehensive study for childhood cancer survivors: *The PanCare
Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies*
(PanCareSurFup). The overall objectives of PanCareSurFup are to
investigate long-term health risks for childhood cancer survivors,
establish clinical guidelines for their follow-up care, and disseminate
research results.²³⁻²⁵ The PanCareSurFup cohort comprises data
from 5-year survivors of childhood cancer (diagnosed at ages birth to
20 years between 1940 and 2008) across 12 European countries:
France, Italy, Hungary, the Netherlands, Denmark, Sweden, Norway,
Finland, Iceland, Slovenia, Switzerland, and the United Kingdom (see
Table S1). Data were sourced from both population-based cancer
registries and major treatment centers. Ethical approval and consent
for data collection were obtained from the ethical and legal bodies in
each of the respective countries contributing to PanCareSurFup.
Ethical approval was not obtained specifically for this study because
it involved pooling of nonidentifiable data.

Childhood cancer classification

Because of various practices across different countries in terms of
childhood cancer registration, the cancer site and the type of child-
hood cancer were coded using a range of classification systems. To
standardize this across the pooled cohort, all childhood tumor classi-
fication codes were converted into codes from the third revision of the
*International Classification of Diseases for Oncology* using the Cancer
Registry Tools Program.²⁶,²⁷ These were then categorised into child-
hood cancers subgroups according to the *International Classification of*
*Childhood Cancer*, third edition.²⁸ Individuals were excluded from the pooled cohort if: (1) they had a primary diagnosis of myelodysplastic syndrome, Langerhans cell histiocytosis, or chronic myeloproliferative or lymphoproliferative disorders; (2) tumor coding was nonmalignant, except for intracranial and bladder tumors; and (3) tumor codes were not classifiable according to the third revision of the *International Classification of Childhood Cancer*.

## Identification of subsequent primary lymphomas

SPLs were ascertained using various methods, primarily through population-based cancer registries and follow-up clinics and validated through pathology reports or other means of clinical diagnosis. The SPLs were classified by site according to the *International Classification of Diseases* using the revision appropriate to the year of diagnosis (see Table S2). For inclusion as an SPL, the subsequent lymphoma had to have a different morphology classification than the original childhood cancer, as defined by the *International Classification of Diseases for Oncology*, third edition classification. In addition, we excluded subsequent NHLs diagnosed after a primary NHL in childhood (N = 8) and subsequent HLs after a primary HL (N = 1), regardless of any difference in morphology. Also, all NHL survivors were excluded from analyses relating to subsequent NHLs, and all HL survivors were excluded from analyses relating to subsequent HLs.

## Statistical analysis

Individuals entered the cohort at 5-year survival from childhood cancer diagnosis and remained at risk of an SPL until the first occurrence of loss to follow-up, death, or study exit date. Standardized incidence ratios (SIRs) were calculated as the ratio of the observed to expected numbers of lymphomas. Expected rates were calculated by accruing person-years at risk stratified by age, country, sex, and calendar year, and multiplying by the equivalent lymphoma incidence rates for the general population.²⁹ General population incidence rates (also stratified by age, country, sex, and calendar year) were obtained from the *Cancer Incidence in Five Continents* project.³⁰ Site-specific incidence rates do not exist for Hungary, hence these were estimated using Slovakian incidence rates because it is their neighboring country with similar demographic characteristics.³¹ Absolute excess risks (AERs) were calculated as the observed minus the expected number of lymphomas, divided by person-years at risk, and multiplied by 100,000. This can be interpreted as the number of excess lymphomas observed beyond those expected per 100,000 person-years. Multivariable Poisson regression models were fitted to estimate the relative risk (RR) of all SPLs and subsequent primary NHLs and HLs while adjusting for the effect of potentially confounding factors: sex, childhood cancer diagnosis, country, decade of childhood diagnosis, age at childhood diagnosis, and attained age. RRs can be interpreted as the ratio of SIRs, adjusted for potential confounders. Likelihood-ratio tests were applied to generate *p* values

for linear trend for ordinal factors of interest or heterogeneity for nominal variables. Because of a relatively small number of observations in subsequent primary HLs, AERs could not be calculated.

SIRs, AERs, and RRs were calculated for the treatment factors radiotherapy (*yes/no*) and chemotherapy (*yes/no*) for those countries where <30% of treatment data were missing. Therefore, the Nordic countries and an Italian population-based cohort were completely excluded from analyses involving treatment variables regardless of whether treatment data were available to avoid potential bias. By using this approach, for 10.5% of survivors, the radiotherapy data were missing; and, for 12.4% of survivors, the chemotherapy data were missing. In all, information on radiotherapy was available for 90 SPLs, and information on chemotherapy was available for 88 SPLs.

To assess the probability of developing an SPL with increasing attained age, the cumulative incidence accounting for the competing risk of death was estimated for types of childhood cancer with ≥20 observed SPLs. All statistical analyses were conducted in Stata software (Stata Corporation).³² All analyses were based on complete case analysis (i.e., list-wise deletion). A two-sided *p* value < .05 was considered statistically significant.

## RESULTS

### Cohort characteristics

Among 69,460 five-year survivors of childhood cancer, in total, 1,264,624 person-years were accrued, with loss to follow-up not exceeding 6% in any country (see Table S1). Over the follow-up period, 140 SPLs were observed in survivors across an age range from 5 to 88 years. From the 140 SPLs, 104 (74.2%) were classified as NHL, and 36 (25.7%) were classified as HL. Most of the SPLs occurred in males (66.4%) and in those surviving HL (n = 33) and leukemia (n = 31; Table 1).

### Overall risk of any subsequent primary lymphoma

Overall, childhood cancer survivors were 60% more likely to develop an SPL compared with the expected rates from the general population (SIR, 1.6; 95% CI, 1.4–1.9), with four additional cases of lymphoma observed per 100,000 person-years (AER, 4.3; 95% CI, 2.8–6.6; Table 2). In particular, HL survivors (SIR, 4.1; 95% CI, 2.9–5.8), but also Wilms tumor (SIR, 2.2; 95% CI, 1.3–3.8), leukemia (SIR, 2.1; 95% CI, 1.5–3.0), and bone sarcoma (SIR, 2.1; 95% CI, 1.1–3.9) survivors, were at increased risk of developing an SPL. Overall, the SIR decreased with increasing attained age (*p* for trend < .001), but the risk was no longer significantly increased beyond age 50 years (SIR, 1.3; 95% CI, 0.8–2.1). There was a significant increase in SPL risk among those who had received chemotherapy for any childhood cancer compared with those who had not (RR, 1.8; 95% CI, 1.1–2.9; Table 2), independent of whether or not survivors also had received
<table><caption>TABLE 1 Characteristics of 69,460 five-year survivors in the PanCareSurFup cohort and of the 140 individuals who developed a subsequent primary lymphoma (further subdivided into non-Hodgkin and Hodgkin lymphoma, respectively)</caption><thead><tr><th rowspan="2">Factor</th><th rowspan="2"></th><th colspan="4">No. of survivors (%)</th></tr><tr><th>PanCareSurFup cohort</th><th>All lymphoma</th><th>Non-Hodgkin lymphoma</th><th>Hodgkin lymphoma</th></tr></thead><tbody><tr><td>Overall</td><td>—</td><td>69,460 (100.0)</td><td>140 (100.0)</td><td>104 (100.0)</td><td>36 (100.0)</td></tr><tr><td rowspan="2">Sex</td><td>Male</td><td>37,738 (54.3)</td><td>93 (66.4)</td><td>67 (64.4)</td><td>26 (72.0)</td></tr><tr><td>Female</td><td>31,722 (45.7)</td><td>47 (33.6)</td><td>37 (35.6)</td><td>10 (28.0)</td></tr><tr><td rowspan="5">Childhood cancer diagnosis</td><td>Leukemia</td><td>16,646 (24.0)</td><td>31 (22.1)</td><td>19 (18.3)</td><td>12 (33.0)</td></tr><tr><td>Hodgkin lymphoma</td><td>6046 (8.7)</td><td>33 (23.6)</td><td>33 (31.7)</td><td>0 (0.0)</td></tr><tr><td>Non-Hodgkin lymphoma</td><td>4078 (5.9)</td><td>5 (3.6)</td><td>0 (0.0)</td><td>5 (14.0)</td></tr><tr><td>CNS tumors</td><td>14,592 (21.0)</td><td>14 (10.0)</td><td>9 (8.7)</td><td>5 (14.0)</td></tr><tr><td>Neuroblastoma</td><td>3178 (4.6)</td><td>4 (2.9)</td><td>3 (2.9)</td><td>1 (3.0)</td></tr><tr><td rowspan="10">Data provider country</td><td>Retinoblastoma</td><td>2590 (3.7)</td><td>3 (2.1)</td><td>2 (1.9)</td><td>1 (3.0)</td></tr><tr><td>Wilms tumor</td><td>4783 (6.9)</td><td>14 (10.0)</td><td>10 (9.6)</td><td>4 (11.0)</td></tr><tr><td>Bone sarcoma</td><td>3173 (4.6)</td><td>10 (7.1)</td><td>8 (7.7)</td><td>2 (6.0)</td></tr><tr><td>Soft tissue sarcoma</td><td>4531 (6.5)</td><td>4 (2.9)</td><td>2 (1.9)</td><td>2 (6.0)</td></tr><tr><td>Thyroid carcinoma</td><td>1295 (1.9)</td><td>4 (2.9)</td><td>3 (2.9)</td><td>1 (3.0)</td></tr><tr><td>Gonadal</td><td>2721 (3.9)</td><td>2 (1.4)</td><td>2 (1.9)</td><td>0 (0.0)</td></tr><tr><td>Malignant melanoma</td><td>1458 (2.1)</td><td>4 (2.9)</td><td>3 (2.9)</td><td>1 (3.0)</td></tr><tr><td>Other<sup>a</sup></td><td>4369 (6.3)</td><td>12 (8.6)</td><td>10 (9.6)</td><td>2 (6.0)</td></tr><tr><td>France</td><td>3138 (4.5)</td><td>8 (5.7)</td><td>7 (6.7)</td><td>1 (3.0)</td></tr><tr><td>Hungary</td><td>4885 (7.0)</td><td>8 (5.7)</td><td>7 (6.7)</td><td>1 (3.0)</td></tr><tr><td>Italy, population-based<sup>b</sup></td><td>7476 (10.8)</td><td>6 (4.3)</td><td>3 (2.9)</td><td>3 (8.0)</td></tr><tr><td rowspan="10">Decade of childhood cancer diagnosis</td><td>Italy, hospital-based<sup>c</sup></td><td>1490 (2.1)</td><td>3 (2.1)</td><td>3 (2.9)</td><td>0 (0.0)</td></tr><tr><td>Netherlands</td><td>6044 (8.7)</td><td>15 (10.7)</td><td>9 (8.7)</td><td>6 (17.0)</td></tr><tr><td>Denmark</td><td>4840 (7.0)</td><td>5 (3.6)</td><td>2 (1.9)</td><td>3 (8.0)</td></tr><tr><td>Sweden</td><td>7709 (11.1)</td><td>15 (10.7)</td><td>9 (8.7)</td><td>6 (17.0)</td></tr><tr><td>Norway</td><td>3783 (5.4)</td><td>0 (0.0)</td><td>0 (0.0)</td><td>0 (0.0)</td></tr><tr><td>Finland</td><td>6229 (9.0)</td><td>19 (13.6)</td><td>16 (15.4)</td><td>3 (8.0)</td></tr><tr><td>Iceland</td><td>275 (0.4)</td><td>0 (0.0)</td><td>0 (0.0)</td><td>0 (0.0)</td></tr><tr><td>Slovenia</td><td>1252 (1.8)</td><td>1 (0.7)</td><td>1 (1.0)</td><td>0 (0.0)</td></tr><tr><td>Switzerland</td><td>4379 (6.3)</td><td>7 (5.0)</td><td>5 (4.8)</td><td>2 (6.0)</td></tr><tr><td>United Kingdom</td><td>17,960 (25.9)</td><td>53 (37.9)</td><td>42 (40.4)</td><td>11 (31.0)</td></tr><tr><td rowspan="4">Age at childhood cancer diagnosis, years</td><td>&lt;1970</td><td>8993 (12.9)</td><td>39 (27.9)</td><td>28 (26.9)</td><td>11 (31.0)</td></tr><tr><td>1970-1979</td><td>13,479 (19.4)</td><td>39 (27.9)</td><td>30 (28.8)</td><td>9 (25.0)</td></tr><tr><td>1980-1989</td><td>20,900 (30.1)</td><td>44 (31.4)</td><td>33 (31.7)</td><td>11 (31.0)</td></tr><tr><td>1990-2008</td><td>26,088 (37.6)</td><td>18 (12.9)</td><td>13 (12.5)</td><td>5 (14.0)</td></tr><tr><td rowspan="4">Age at childhood cancer diagnosis, years</td><td>Birth to 4</td><td>26,696 (38.4)</td><td>40 (28.6)</td><td>27 (26.0)</td><td>13 (36.0)</td></tr><tr><td>5-9</td><td>15,743 (22.7)</td><td>31 (22.1)</td><td>21 (20.2)</td><td>10 (28.0)</td></tr><tr><td>10-14</td><td>15,491 (22.3)</td><td>45 (32.1)</td><td>37 (35.6)</td><td>8 (22.0)</td></tr><tr><td>15-20</td><td>11,530 (16.6)</td><td>24 (17.1)</td><td>19 (18.3)</td><td>5 (14.0)</td></tr></tbody></table>
<table><caption>TABLE 1 (Continued)</caption><thead><tr><th rowspan="2">Factor</th><th rowspan="2"></th><th colspan="4">No. of survivors (%)</th></tr><tr><th>PanCareSurFup cohort</th><th>All lymphoma</th><th>Non-Hodgkin lymphoma</th><th>Hodgkin lymphoma</th></tr></thead><tbody><tr><td rowspan="5">Attained age, years<sup>d</sup></td><td>&lt;20</td><td>15,405 (22.2)</td><td>35 (25.0)</td><td>23 (22.1)</td><td>12 (33.0)</td></tr><tr><td>20-29</td><td>18,877 (27.2)</td><td>39 (27.9)</td><td>27 (26.0)</td><td>12 (33.0)</td></tr><tr><td>30-39</td><td>17,144 (24.7)</td><td>24 (17.1)</td><td>16 (15.4)</td><td>8 (22.0)</td></tr><tr><td>40-49</td><td>10,970 (15.8)</td><td>24 (17.1)</td><td>20 (19.2)</td><td>4 (11.0)</td></tr><tr><td>≥50</td><td>7064 (10.2)</td><td>18 (12.9)</td><td>18 (17.3)</td><td>0 (0.0)</td></tr><tr><td rowspan="4">Follow-up time since 5-year survival, years<sup>d</sup></td><td>0-9</td><td>23,923 (34.4)</td><td>52 (37.1)</td><td>36 (34.6)</td><td>16 (44.0)</td></tr><tr><td>10-19</td><td>15,801 (22.7)</td><td>36 (25.7)</td><td>25 (24.0)</td><td>11 (31.0)</td></tr><tr><td>20-29</td><td>16,103 (23.2)</td><td>27 (19.3)</td><td>20 (19.2)</td><td>7 (19.0)</td></tr><tr><td>≥30</td><td>13,633 (19.6)</td><td>25 (17.9)</td><td>23 (22.1)</td><td>2 (6.0)</td></tr></tbody></table>

Abbreviations: 95% CI, 95% confidence interval; AER, absolute excess risk; CNS, central nervous system; PanCareSurFup, the Pan-European Network for Care of Survivors After Childhood and Adolescent Cancer (PanCare) Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies; RR, relative risk; SIR, standardized incidence ratio; SPL, subsequent primary lymphoma.

<sup>a</sup>The category other includes: other and unspecified carcinomas (n = 1181), other unspecified malignant tumors (n = 641), malignant extracranial/ extragonadal germ cell tumors (n = 433), skin carcinomas (n = 423), unspecified lymphomas (n = 402), hepatoblastoma (n = 319), miscellaneous lymphoreticular neoplasms (n = 279), nasopharyngeal carcinomas (n = 194), renal carcinomas (n = 124), other peripheral nervous cell tumors (n = 94), adrenocortical carcinomas (n = 86), hepatic carcinomas (n = 84), other specified, malignant tumors (n = 59), unspecified malignant renal tumors (n = 35), and unspecified malignant hepatic tumors (n = 15).

<sup>b</sup>Population-based cohort from the Italian Association of Cancer Registries (AIRTUM).

<sup>c</sup>Hospital-based registry from the Italian Registry of Off-Therapy Patients, Genoa.

<sup>d</sup>The number of survivors relates to the highest attained age/follow-up reached, e.g., at exit of cohort.

radiotherapy. The cumulative incidence of developing an SPL by age 65 years was highest after HL, with a probability of developing an SPL of 1.6% (95% CI, 0.7%-3.1%), whereas only 0.6% was expected based on general population rates (Figure 1).

survivors who had received radiotherapy for any childhood cancer (RR, 1.2; 95% CI, 0.7-2.0). The cumulative incidence of developing NHL after HL was 1.6% (95% CI, 0.7%-3.1%) by age 65 years (Figure 1; all SPLs after HL were NHLs).

## Risk of subsequent primary non-Hodgkin lymphoma

Overall, childhood cancer survivors were 2.3 times more likely to develop NHL than the general population (SIR, 2.3; 95% CI, 1.9-2.8), with five additional cases of NHL observed per 100,000 person-years (AER, 4.9; 95% CI, 3.5-6.9; Table 3). Male and female childhood cancer survivors were at similar risk when adjusted for confounding factors (p for heterogeneity = .91). Survivors of HL and Wilms tumor were at greatest risk of developing NHL (SIR, 7.1 [95% CI, 5.1-10.0] and 3.1 [95% CI, 1.7-5.7], respectively), but the risk also was great for survivors of leukemia (SIR, 2.8; 95% CI, 1.8-4.4) and bone sarcoma (SIR, 2.7; 95% CI, 1.4-5.4).

More recent decades of childhood cancer diagnosis showed an increase in the SIRs of developing NHL (p for trend < .001), but this effect was not apparent after adjustment for confounders (p for trend = .64), particularly attained age. Increasing attained age and follow-up time demonstrated a decreasing trend in the SIRs of developing NHL (Table 3; p for trend < .001). There was a significantly increased risk of developing NHL among survivors who had received chemotherapy for any childhood cancer (RR, 2.1; 95% CI, 1.2-3.9). However, the RR was not significantly increased for

## Risk of subsequent primary Hodgkin lymphoma

Overall, childhood cancer survivors were no more likely to develop HL compared with the general population (SIR, 1.1; 95% CI, 0.8-1.5; Table 4). A childhood cancer diagnosis of NHL conferred an increased risk of developing HL relative to the general population (SIR, 2.4; 95% CI, 1.0-5.9). This was not observed following other types of childhood cancer. The SIR for HL did not vary by decade of diagnosis (p for trend = .21), age at diagnosis (p = .97), or with attained age (p for trend = .24), although multivariable analyses suggested that the RRs were lower in those diagnosed in more recent decades (p for trend = .03).

## DISCUSSION

### Main findings

To our knowledge, this is by far the largest cohort study analyzing the risk of SPLs in childhood cancer survivors and, for the first time within a large-scale study, the risks of NHL and HL individually. Novel
<table><caption>TABLE 2 Standardized incidence ratios, relative risks, and absolute excess risks, with 95% confidence intervals, for developing a subsequent primary lymphoma among a cohort of childhood cancer survivors</caption><thead><tr><th>Factor</th><th></th><th>Person-years</th><th>Obs/Exp</th><th>SIR (95% CI)</th><th>RR (95% CI)<sup>b</sup></th><th>AER (95% CI)</th></tr></thead><tbody><tr><td>Overall</td><td>—</td><td>1,264,624</td><td>140/85.6</td><td>1.6 (1.4-1.9)</td><td>—</td><td>4.3 (2.8-6.6)</td></tr><tr><td rowspan="3">Sex<sup>a</sup></td><td>Male</td><td>676,132</td><td>93/51.5</td><td>1.8 (1.5-2.2)</td><td>1.0 (Ref)</td><td>6.1 (3.9-9.7)</td></tr><tr><td>Female</td><td>588,492</td><td>47/34.1</td><td>1.4 (1.0-1.8)</td><td>0.8 (0.5-1.1)</td><td>2.2 (0.8-6.2)</td></tr><tr><td>p for heterogeneity</td><td></td><td></td><td>.12</td><td>.14</td><td>.03</td></tr><tr><td rowspan="13">Childhood cancer type<sup>a</sup></td><td>Leukemia</td><td>259,372</td><td>31/14.8</td><td>2.1 (1.5-3.0)</td><td>1.0 (Ref)</td><td>6.3 (3.2,12.3)</td></tr><tr><td>Hodgkin lymphoma</td><td>98,744</td><td>33/8.0</td><td>4.1 (2.9-5.8)</td><td>1.9 (1.1-3.3)</td><td>25.3 (16.2-39.7)</td></tr><tr><td>Non-Hodgkin lymphoma</td><td>70,165</td><td>5/5.4</td><td>0.9 (0.4-2.2)</td><td>0.4 (0.2-1.1)</td><td>0.0 (0.0-0.0)</td></tr><tr><td>CNS tumors</td><td>263,500</td><td>14/18.6</td><td>0.8 (0.4-1.3)</td><td>0.4 (0.2-0.7)</td><td>0.0 (0.0-0.0)</td></tr><tr><td>Neuroblastoma</td><td>61,967</td><td>4/3.3</td><td>1.2 (0.5-3.3)</td><td>0.6 (0.2-1.8)</td><td>1.2 (0.0-231.2)</td></tr><tr><td>Retinoblastoma</td><td>70,625</td><td>3/4.4</td><td>0.7 (0.2-2.1)</td><td>0.4 (0.1-1.3)</td><td>0.0 (0.0-0.0)</td></tr><tr><td>Wilms tumor</td><td>109,314</td><td>14/6.2</td><td>2.2 (1.3-3.8)</td><td>1.2 (0.6-2.2)</td><td>7.1 (2.8-18.3)</td></tr><tr><td>Bone sarcoma</td><td>57,666</td><td>10/4.8</td><td>2.1 (1.1-3.9)</td><td>1.0 (0.4-2.1)</td><td>9.1 (2.8-29.7)</td></tr><tr><td>Soft tissue sarcoma</td><td>93,042</td><td>4/6.8</td><td>0.6 (0.2-1.6)</td><td>0.3 (0.1-0.8)</td><td>0.0 (0.0-0.0)</td></tr><tr><td>Thyroid carcinoma</td><td>23,535</td><td>4/1.8</td><td>2.2 (0.8-5.9)</td><td>1.1 (0.4-3.3)</td><td>9.3 (1.5-55.9)</td></tr><tr><td>Gonadal</td><td>48,850</td><td>2/3.6</td><td>0.6 (0.1-2.2)</td><td>0.3 (0.1-1.2)</td><td>0.0 (0.0-0.0)</td></tr><tr><td>Malignant melanoma</td><td>24,949</td><td>4/1.9</td><td>2.1 (0.8-5.5)</td><td>1.0 (0.3-3.0)</td><td>8.3 (1.2-55.2)</td></tr><tr><td>Other</td><td>82,894</td><td>12/6.0</td><td>2.0 (1.1-3.5)</td><td>0.9 (0.5-1.9)</td><td>7.2 (2.3-22.5)</td></tr><tr><td>p for heterogeneity</td><td></td><td></td><td>&lt;.001</td><td>&lt;.001</td><td>&lt;.001</td></tr><tr><td rowspan="5">Decade of childhood cancer diagnosis<sup>a</sup></td><td>&lt;1970</td><td>310,237</td><td>39/28.5</td><td>1.4 (1.0-1.9)</td><td>1.0 (Ref)</td><td>3.4 (1.1-10.9)</td></tr><tr><td>1970-1979</td><td>353,278</td><td>39/23.1</td><td>1.7 (1.2-2.3)</td><td>1.0 (0.6-1.6)</td><td>4.5 (2.1-9.7)</td></tr><tr><td>1980-1989</td><td>399,362</td><td>44/23.3</td><td>1.9 (1.4-2.5)</td><td>1.0 (0.6-1.8)</td><td>5.2 (2.8-9.7)</td></tr><tr><td>1990-2008</td><td>201,748</td><td>18/10.7</td><td>1.7 (1.1-2.7)</td><td>0.8 (0.4-1.5)</td><td>3.6 (1.2-11.3)</td></tr><tr><td>p for trend</td><td></td><td></td><td>.24</td><td>.58</td><td>.83</td></tr><tr><td rowspan="5">Age at childhood cancer diagnosis, years<sup>a</sup></td><td>Birth to 4</td><td>526,239</td><td>40/28.1</td><td>1.4 (1.0-1.9)</td><td>1.0 (Ref)</td><td>2.3 (0.8-6.4)</td></tr><tr><td>5-9</td><td>294,119</td><td>31/19.8</td><td>1.6 (1.1-2.2)</td><td>1.1 (0.7-1.9)</td><td>3.8 (1.4-10.1)</td></tr><tr><td>10-14</td><td>288,376</td><td>45/24.6</td><td>1.8 (1.4-2.5)</td><td>1.5 (0.8-2.5)</td><td>7.1 (3.7-13.5)</td></tr><tr><td>15-20</td><td>155,890</td><td>24/13.1</td><td>1.8 (1.2-2.7)</td><td>1.5 (0.8-3.0)</td><td>7.0 (2.9-16.9)</td></tr><tr><td>p for trend</td><td></td><td></td><td>.22</td><td>.15</td><td>.04</td></tr><tr><td rowspan="6">Attained age, years<sup>a</sup></td><td>&lt;20</td><td>410,373</td><td>35/13.3</td><td>2.6 (1.9-3.7)</td><td>1.0 (Ref)</td><td>5.3 (3.1-9.0)</td></tr><tr><td>20-29</td><td>419,216</td><td>39/26.1</td><td>1.5 (1.1-2.0)</td><td>0.5 (0.3-0.8)</td><td>3.1 (1.2-7.9)</td></tr><tr><td>30-39</td><td>262,126</td><td>24/19.3</td><td>1.2 (0.8-1.9)</td><td>0.4 (0.2-0.6)</td><td>1.8 (0.2-13.7)</td></tr><tr><td>40-49</td><td>120,676</td><td>24/13.4</td><td>1.8 (1.2-2.7)</td><td>0.5 (0.3-1.0)</td><td>8.7 (3.5-21.7)</td></tr><tr><td>≥50</td><td>52,243</td><td>18/13.4</td><td>1.3 (0.8-2.1)</td><td>0.4 (0.2-0.9)</td><td>8.7 (1.4-54.0)</td></tr><tr><td>p for trend</td><td></td><td></td><td>.02</td><td>.01</td><td>.59</td></tr><tr><td rowspan="5">Follow-up time since 5-year survival, years<sup>b</sup></td><td>0-9</td><td>565,883</td><td>52/23.5</td><td>2.2 (1.7-2.9)</td><td>0.7 (0.4-1.0)</td><td>5.0 (3.1-8.3)</td></tr><tr><td>10-19</td><td>370,881</td><td>36/23.6</td><td>1.5 (1.1-2.1)</td><td>0.6 (0.4-1.0)</td><td>3.3 (1.3-8.6)</td></tr><tr><td>20-29</td><td>212,289</td><td>27/18.2</td><td>1.5 (1.0-2.2)</td><td>0.6 (0.3-1.0)</td><td>4.1 (1.3-13.2)</td></tr><tr><td>≥30</td><td>115,571</td><td>25/20.2</td><td>1.2 (0.8-1.8)</td><td>0.7 (0.4-1.0)</td><td>4.1 (0.5-32.1)</td></tr><tr><td>p for trend</td><td></td><td></td><td>.01</td><td>.04</td><td>.59</td></tr></tbody></table>
<table><caption>TABLE 2 (Continued)</caption><thead><tr><th>Factor</th><th></th><th>Person-years</th><th>Obs/Exp</th><th>SIR (95% CI)</th><th>RR (95% CI)<sup>b</sup></th><th>AER (95% CI)</th></tr></thead><tbody><tr><td rowspan="4">Radiotherapy<sup>c,d</sup></td><td>No</td><td>272,789</td><td>31/18.2</td><td>1.7 (1.2-2.4)</td><td>1.0 (Ref)</td><td>4.7 (2.0-11.0)</td></tr><tr><td>Yes</td><td>478,392</td><td>59/33.9</td><td>1.7 (1.3-2.2)</td><td>1.1 (0.7-1.7)</td><td>5.3 (2.9-9.6)</td></tr><tr><td>Missing</td><td>86,824</td><td>5/5.3</td><td>—</td><td>—</td><td>—</td></tr><tr><td><i>p</i> for heterogeneity</td><td></td><td></td><td>.92</td><td>.63</td><td>.83</td></tr><tr><td rowspan="4">Chemotherapy<sup>c,d</sup></td><td>No</td><td>275,213</td><td>29/23.0</td><td>1.3 (0.9-1.8)</td><td>1.0 (Ref)</td><td>2.2 (0.4-12.6)</td></tr><tr><td>Yes</td><td>447,974</td><td>59/27.0</td><td>2.2 (1.7-2.8)</td><td>1.8 (1.1-2.9)</td><td>7.1 (4.5-11.4)</td></tr><tr><td>Missing</td><td>114,818</td><td>7/7.4</td><td>—</td><td>—</td><td>—</td></tr><tr><td><i>p</i> for heterogeneity</td><td></td><td></td><td>.01</td><td>.02</td><td>.07</td></tr></tbody></table>

Abbreviations: 95% CI, 95% confidence interval; AER, absolute excess risk; CNS, central nervous system; Exp, expected; Obs, observed; Ref, reference category; RR, relative risk; SIR, standardized incidence ratio.

<sup>a</sup>RRs were derived from a model including sex, childhood cancer diagnosis, country, decade of childhood diagnosis, age at childhood diagnosis, and attained age.

<sup>b</sup>RRs were derived from a model including sex, childhood cancer diagnosis, country, decade of childhood diagnosis, age at childhood diagnosis, and follow-up time.

<sup>c</sup>RRs were derived from a model including sex, country, age at childhood diagnosis, attained age and treatment.

<sup>d</sup>Analyses relating to treatment included data from data providers that had <30% of missing data (Nordic countries and Italian population-based cohort were excluded; treatment data were not available at all for Nordic countries).

<figure><img src="image_9.png" /><figcaption>FIGURE 1 Cumulative incidence of developing a subsequent primary lymphoma (all types) for types of childhood cancer with at least 20 observed lymphomas, as a function of attained age.</figcaption></figure>

findings include that childhood cancer survivors are 2.3 times more likely to develop NHL than the general population, with survivors of HL, Wilms tumor, leukemia, and bone sarcoma at greatest risk. Conversely, the risk of HL among childhood cancer survivors is not increased, except in survivors of NHL. This study has further found

that childhood cancer survivors who have received chemotherapy are almost twice as likely to develop a subsequent primary NHL than survivors treated without chemotherapy. This increase in risk, however, does not extend to survivors who received radiotherapy for any childhood cancer.
<table><caption>TABLE 3 Standardized incidence ratios, relative risks, and absolute excess risks, with 95% confidence intervals, for developing a subsequent primary non-Hodgkin lymphoma among a cohort of childhood cancer survivors (excluding non-Hodgkin lymphoma survivors)</caption><thead><tr><th>Factor</th><th></th><th>Obs/Exp</th><th>SIR (95% CI)</th><th>RR (95% CI)</th><th>AER (95% CI)</th></tr></thead><tbody><tr><td>Overall</td><td></td><td>104/45.0</td><td>2.3 (1.9-2.8)</td><td>—</td><td>4.9 (3.5-6.9)</td></tr><tr><td rowspan="3">Sex<sup>a</sup></td><td>Male</td><td>67/27.5</td><td>2.4 (1.9-3.1)</td><td>1.0 (Ref)</td><td>6.3 (4.2-9.5)</td></tr><tr><td>Female</td><td>37/17.6</td><td>2.1 (1.5-2.9)</td><td>1.0 (0.6-1.5)</td><td>3.4 (1.9-6.3)</td></tr><tr><td>p for heterogeneity</td><td></td><td>.47</td><td>.91</td><td>.09</td></tr><tr><td rowspan="12">Childhood cancer type<sup>a</sup></td><td>Leukemia</td><td>19/6.8</td><td>2.8 (1.8-4.4)</td><td>1.0 (Ref)</td><td>4.7 (2.3-9.5)</td></tr><tr><td>Hodgkin lymphoma</td><td>33/4.6</td><td>7.1 (5.1-10.0)</td><td>3.2 (1.7-6.0)</td><td>28.7 (19.3-42.7)</td></tr><tr><td>CNS tumors</td><td>9/10.8</td><td>0.8 (0.4-1.6)</td><td>0.4 (0.2-0.9)</td><td>0.0</td></tr><tr><td>Neuroblastoma</td><td>3/1.7</td><td>1.8 (0.6-5.6)</td><td>0.8 (0.2-2.7)</td><td>2.1 (0.2-27.6)</td></tr><tr><td>Retinoblastoma</td><td>2/2.6</td><td>0.8 (0.2-3.0)</td><td>0.5 (0.1-2.0)</td><td>0.0</td></tr><tr><td>Wilms tumor</td><td>10/3.2</td><td>3.1 (1.7-5.7)</td><td>1.4 (0.6-3.2)</td><td>6.2 (2.5-15.5)</td></tr><tr><td>Bone sarcoma</td><td>8/2.9</td><td>2.7 (1.4-5.4)</td><td>1.2 (0.5-3.1)</td><td>8.8 (2.9-26.2)</td></tr><tr><td>Soft tissue sarcoma</td><td>2/4.1</td><td>0.5 (0.1-2.0)</td><td>0.2 (0.1-1.0)</td><td>0.0</td></tr><tr><td>Thyroid carcinoma</td><td>3/1.2</td><td>2.6 (0.8-8.1)</td><td>1.3 (0.4-4.9)</td><td>7.9 (1.3-49.3)</td></tr><tr><td>Gonadal</td><td>2/2.2</td><td>0.9 (0.2-3.7)</td><td>0.4 (0.1-2.0)</td><td>0.0</td></tr><tr><td>Malignant melanoma</td><td>3/1.2</td><td>2.4 (0.8-7.5)</td><td>1.3 (0.4-4.7)</td><td>7.1 (1.0-48.4)</td></tr><tr><td>Other</td><td>10/3.7</td><td>2.7 (1.4-5.0)</td><td>1.3 (0.6-3.1)</td><td>7.6 (2.8-20.3)</td></tr><tr><td>p for heterogeneity</td><td></td><td>&lt;.001</td><td>&lt;.001</td><td>&lt;.001</td></tr><tr><td rowspan="5">Decade of childhood cancer diagnosis<sup>a</sup></td><td>&lt;1970</td><td>28/19.5</td><td>1.4 (1.0-2.1)</td><td>1.0 (Ref)</td><td>2.9 (0.8-9.7)</td></tr><tr><td>1970-1979</td><td>30/12.2</td><td>2.5 (1.7-3.5)</td><td>1.3 (0.7-2.3)</td><td>5.3 (2.9-9.7)</td></tr><tr><td>1980-1989</td><td>33/9.7</td><td>3.4 (2.4-4.8)</td><td>1.5 (0.7-2.9)</td><td>6.2 (3.9-10.1)</td></tr><tr><td>1990-2008</td><td>13/3.7</td><td>3.5 (2.1-6.1)</td><td>1.1 (0.5-2.7)</td><td>5.0 (2.3-10.7)</td></tr><tr><td>p for trend</td><td></td><td>&lt;.001</td><td>.64</td><td>.58</td></tr><tr><td rowspan="5">Age at childhood cancer diagnosis, years<sup>a</sup></td><td>0-3</td><td>27/13.9</td><td>1.9 (1.3-2.8)</td><td>1.0 (Ref)</td><td>2.6 (1.2-5.6)</td></tr><tr><td>4-7</td><td>21/9.7</td><td>2.2 (1.4-3.3)</td><td>1.1 (0.6-2.1)</td><td>4.2 (1.9-9.3)</td></tr><tr><td>8-11</td><td>37/13.6</td><td>2.7 (2.0-3.8)</td><td>1.5 (0.8-2.9)</td><td>8.8 (5.3-14.7)</td></tr><tr><td>12-21</td><td>19/7.9</td><td>2.4 (1.5-3.8)</td><td>1.4 (0.6-3.4)</td><td>7.5 (3.5-16.2)</td></tr><tr><td>p for trend</td><td></td><td>.59</td><td>.28</td><td>.03</td></tr><tr><td rowspan="6">Attained age, years<sup>a</sup></td><td>&lt;20</td><td>23/4.9</td><td>4.7 (3.1-7.1)</td><td>1.0 (Ref)</td><td>4.6 (2.8-7.8)</td></tr><tr><td>20-29</td><td>27/8.5</td><td>3.2 (2.2-4.6)</td><td>0.5 (0.3-1.0)</td><td>4.7 (2.7-8.2)</td></tr><tr><td>30-39</td><td>16/10.2</td><td>1.6 (1.0-2.6)</td><td>0.3 (0.1-0.5)</td><td>2.4 (0.6-9.1)</td></tr><tr><td>40-49</td><td>20/1</td><td>2.0 (1.3-3.1)</td><td>0.4 (0.2-0.8)</td><td>8.7 (3.6-21.1)</td></tr><tr><td>≥50</td><td>18/11.5</td><td>1.6 (1.0-2.5)</td><td>0.3 (0.1-0.8)</td><td>13.3 (3.7-47.6)</td></tr><tr><td>p for trend</td><td></td><td>&lt;.001</td><td>&lt;.001</td><td>.39</td></tr><tr><td rowspan="5">Follow-up time since 5-year survival, years<sup>b</sup></td><td>0-9</td><td>36/8.1</td><td>4.4 (3.2-6.1)</td><td>1.0 (Ref)</td><td>5.2 (3.4-8.0)</td></tr><tr><td>10-19</td><td>25/9.5</td><td>2.6 (1.8-3.9)</td><td>0.6 (0.3-1.0)</td><td>4.4 (2.4-8.3)</td></tr><tr><td>20-29</td><td>20/11.0</td><td>1.8 (1.2-2.8)</td><td>0.4 (0.2-0.8)</td><td>4.5 (1.7-11.8)</td></tr><tr><td>≥30</td><td>23/16.4</td><td>1.4 (0.9-2.1)</td><td>0.4 (0.2-0.8)</td><td>6.0 (1.4-25.0)</td></tr><tr><td>p for trend</td><td></td><td>&lt;.001</td><td>&lt;.001</td><td>.82</td></tr><tr><td rowspan="2">Radiotherapy<sup>c,d</sup></td><td>No</td><td>21/9.5</td><td>2.2 (1.4-3.4)</td><td>1.0 (Ref)</td><td>4.5 (2.1-9.8)</td></tr><tr><td>Yes</td><td>48/18.1</td><td>2.7 (2.0-3.5)</td><td>1.2 (0.7-2.0)</td><td>6.6 (4.2-10.4)</td></tr></tbody></table>
<table><caption>TABLE 3 (Continued)</caption><thead><tr><th>Factor</th><th></th><th>Obs/Exp</th><th>SIR (95% CI)</th><th>RR (95% CI)</th><th>AER (95% CI)</th></tr></thead><tbody><tr><td rowspan="6">Chemotherapy<sup>c,d</sup></td><td>Missing</td><td>5/2.3</td><td>—</td><td>—</td><td>—</td></tr><tr><td><i>p</i> for heterogeneity</td><td></td><td>.48</td><td>.32</td><td>.38</td></tr><tr><td>No</td><td>22/14.3</td><td>1.5 (1.0–2.3)</td><td>1.0 (Ref)</td><td>2.9 (0.9–9.5)</td></tr><tr><td>Yes</td><td>46/12.1</td><td>3.8 (2.8–5.1)</td><td>2.1 (1.2–3.9)</td><td>8.2 (5.5–12.1)</td></tr><tr><td>Missing</td><td>6/3.6</td><td>—</td><td>—</td><td>—</td></tr><tr><td><i>p</i> for heterogeneity</td><td></td><td>&lt; .001</td><td>.01</td><td>.04</td></tr></tbody></table>

Abbreviations: 95% CI, 95% confidence interval; AER, absolute excess risk; CNS, central nervous system; Exp, expected; Obs, observed; Ref, reference category; RR, relative risk; SIR, standardized incidence ratio.

<sup>a</sup>RRs were derived from a model including sex, childhood cancer diagnosis, country, decade of childhood diagnosis, age at childhood diagnosis, and attained age.

<sup>b</sup>RRs were derived from a model including sex, childhood cancer diagnosis, country, decade of childhood diagnosis, age at childhood diagnosis, and follow-up time.

<sup>c</sup>RRs were derived from a model including sex, country, age at childhood diagnosis, attained age, and treatment.

<sup>d</sup>Analyses relating to treatment included data from data providers that had <30% of missing data (Nordic countries and Italian population-based cohorts were excluded; treatment data were not available at all for Nordic countries).

Previous studies

When evaluating the overall risk of childhood cancer survivors developing SPLs, the SIR of 1.6 for total lymphoma found in this analysis was consistent with the results of the North American Childhood Cancer Survivor Study conducted in a cohort of 14,359 childhood cancer survivors (SIR, 1.6; 95% CI, 1.2–2.1).¹⁰ In that North American study, the SIR beyond age 40 years was still increased 2.6-fold (95% CI, 1.5–5.6); however, in our data, the risk was not increased beyond age 50 years (SIR, 1.3; 95% CI, 0.8–2.1),¹¹ although overlapping confidence intervals suggest that these SIRs are not necessarily inconsistent. There have been suggestions that, for the generality of survivors, historic treatment regimens across North America may have been more aggressive than across Europe, which may translate into a higher risk of long-term complications of treatment, including subsequent primary malignancies.³³ Other studies documenting the risk of developing SPLs derived their data from European cohorts (Nordic countries and the Netherlands, respectively), which also contributed to the current PanCareSurFup cohort. Consistent with our findings, the Nordic study reported a moderately increased risk for bone marrow and lymphatic system malignancies, although this includes a wider range of diagnoses and thus is less valid to interpret for SPL alone (SIR, 2.6; 95% CI, 2.2–3.2).⁷ A Dutch study among 6165 childhood cancer survivors quoted a slightly higher, but not inconsistent, risk of NHL (SIR, 3.9; 95% CI, 2.0–7.0).⁸ Furthermore, the Dutch study observed only six cases of HL and, as a result, reported a lower and insignificant risk of HL (SIR, 1.9; 95% CI, 0.7–4.1), which supports our finding that childhood cancer survivors are no more likely to develop HL than the general population.

Although very few studies have investigated the risk of NHL among the generality of childhood cancer survivors, several studies have reported increased risks of NHL after (mostly) adult HL, with

a wide range in SIRs from 3.0 to 32.0, which is not inconsistent with the SIR of 7.1 found in the current analysis.¹²⁻¹⁷,²⁰,²¹

Postulated risks factors include immunodeficiency, because Zarate-Osorno et al.³⁴ concluded that the types of NHL diagnosed among patients with HL were clinically, histologically, and immunophenotypically similar to that found in immunosuppressed patients. Here, we found that survivors who received chemotherapy were at the highest risk. Whether any specific chemotherapeutic agent or whether chemotherapy-induced immunosuppression may be implicated in the development of NHL, however, is not clear. Swerdlow et al¹⁶ found increased risks of NHL among HL survivors after various different chemotherapy regimens, suggesting that not one specific chemotherapy agent is implicated. We also found increased risks of NHL among survivors of Wilms tumor, leukemia, and bone sarcoma who likely have received different chemotherapy regimens. Exposure to prolonged chemotherapy has been shown to be immunosuppressive and thus may create an environment in which latent oncogenic viruses, such as Epstein-Barr virus, that have been associated with NHL development may be reactivated.³⁵,³⁶ Among (bilateral) Wilms tumor survivors, the increased risk may to some extent also be related to immunosuppressive therapy for a kidney transplant, which could cause posttransplantation lymphoproliferative disorders,³⁷ including NHL, although typically this occurs in the first few years after kidney transplantation, with a potential second peak 7–10 years later.³⁸ However, in our data, all Wilms tumor survivors who developed NHL had unilateral Wilms tumor; and, for 9 of 10 Wilms tumor survivors who developed NHL, this occurred at least 13 years after the original Wilms tumor diagnosis (range, 6–53 years), suggesting that this is probably an unlikely explanation. Similarly, stem cell transplantation among leukemia survivors may have increased the risk of post-transplantation lymphoproliferative disorders, including NHL; but, in our cohort, only one leukemia survivor with NHL had undergone stem cell transplantation. Further studies evaluating detailed
treatment factors and the role of specific chemotherapy exposures in relation to immunosuppression and Epstein-Barr virus infection status are warranted.

In the current study, there was no indication of any significant difference in the risk of SPL between those who received radiotherapy only during childhood and those who did not. This is

<table><caption>TABLE 4 Standardized incidence ratios, relative risks, and absolute excess risks, with 95% confidence intervals, for developing a subsequent primary Hodgkin lymphoma among a cohort of childhood cancer survivors (excluding Hodgkin lymphoma survivors)</caption><thead><tr><th>Factor</th><th></th><th>Obs/Exp</th><th>SIR (95% CI)</th><th>RR (95% CI)<sup>b</sup></th></tr></thead><tbody><tr><td>Overall</td><td></td><td>36/34.2</td><td>1.1 (0.8-1.5)</td><td>-</td></tr><tr><td rowspan="3">Sex</td><td>Males</td><td>26/19.4</td><td>1.3 (0.9-2.0)</td><td>1.0 (ref.)</td></tr><tr><td>Females</td><td>10/14.7</td><td>0.7 (0.4-1.3)</td><td>0.5 (0.3-1.1)</td></tr><tr><td>p for heterogeneity</td><td></td><td>.06</td><td>.09</td></tr><tr><td rowspan="5">Childhood cancer diagnosis</td><td>Leukemia</td><td>12/8.0</td><td>1.5 (0.9-2.6)</td><td>1.0 (Ref)</td></tr><tr><td>Non-Hodgkin lymphoma</td><td>5/2.0</td><td>2.4 (1.0-5.9)</td><td>1.2 (0.4-3.7)</td></tr><tr><td>CNS tumors</td><td>5/7.8</td><td>0.6 (0.3-1.5)</td><td>0.3 (0.1-0.9)</td></tr><tr><td>Other<sup>c</sup></td><td>14/16.3</td><td>0.9 (0.5-1.4)</td><td>0.3 (0.1-0.8)</td></tr><tr><td>p for heterogeneity</td><td></td><td>.19</td><td>.02</td></tr><tr><td rowspan="5">Decade of childhood cancer diagnosis</td><td>&lt;1970</td><td>11/7.3</td><td>1.5 (0.8-2.7)</td><td>1.0 (Ref)</td></tr><tr><td>1970-1979</td><td>9/9.2</td><td>1.0 (0.5-1.9)</td><td>0.4 (0.2-1.1)</td></tr><tr><td>1980-1989</td><td>11/11.8</td><td>0.9 (0.5-1.7)</td><td>0.4 (0.1-0.9)</td></tr><tr><td>1990-2008</td><td>5/5.9</td><td>0.8 (0.4--2.0)</td><td>0.3 (0.1-0.9)</td></tr><tr><td>p for trend</td><td></td><td>.23</td><td>.03</td></tr><tr><td rowspan="5">Age at childhood cancer diagnosis, years</td><td>Birth to 3</td><td>13/13.6</td><td>1.0 (0.6-1.6)</td><td>1.0 (Ref)</td></tr><tr><td>4-7</td><td>10/8.5</td><td>1.2 (0.6-2.2)</td><td>1.2 (0.5-2.9)</td></tr><tr><td>8-11</td><td>8/8.1</td><td>1.0 (0.5-2.0)</td><td>1.2 (0.5-3.2)</td></tr><tr><td>12-21</td><td>5/3.9</td><td>1.3 (0.5-3.1)</td><td>2.0 (0.7-6.3)</td></tr><tr><td>p for trend</td><td></td><td>.69</td><td>.29</td></tr><tr><td rowspan="5">Attained age, years</td><td>&lt;20</td><td>12/7.8</td><td>1.5 (0.9-2.7)</td><td>1.0 (Ref)</td></tr><tr><td>20-29</td><td>12/15.4</td><td>0.8 (0.4-1.4)</td><td>0.4 (0.2-1.0)</td></tr><tr><td>30-39</td><td>8/7.5</td><td>1.1 (0.5-2.1)</td><td>0.5 (0.2-1.3)</td></tr><tr><td>40-49</td><td>4/2.5</td><td>1.6 (0.6-4.3)</td><td>0.7 (0.2-2.3)</td></tr><tr><td>p for trend</td><td></td><td>—</td><td>0.0</td></tr><tr><td rowspan="5">Follow-up time since 5-year survival, years<sup>a</sup></td><td>0-9</td><td>16/13.1</td><td>1.2 (0.7-2.0)</td><td>1.0 (Ref)</td></tr><tr><td>10-19</td><td>11/12.5</td><td>0.9 (0.5-1.6)</td><td>0.4 (0.2-0.9)</td></tr><tr><td>20-29</td><td>7/6.1</td><td>1.2 (0.6-2.4)</td><td>0.5 (0.2-1.2)</td></tr><tr><td>≥30</td><td>2/2.6</td><td>0.8 (0.2-3.1)</td><td>0.6 (0.2-2.0)</td></tr><tr><td>p for trend</td><td></td><td>.58</td><td>.05</td></tr><tr><td rowspan="4">Radiotherapy<sup>c,d</sup></td><td>No</td><td>10/7.7</td><td>1.3 (0.7-2.4)</td><td>1.0 (Ref)</td></tr><tr><td>Yes</td><td>11/12.9</td><td>0.9 (0.5-1.5)</td><td>0.8 (0.3-2.0)</td></tr><tr><td>Missing</td><td>0/2.4</td><td>—</td><td>—</td></tr><tr><td>p for heterogeneity</td><td></td><td>.34</td><td>.71</td></tr><tr><td rowspan="2">Chemotherapy<sup>c,d</sup></td><td>No</td><td>7/7.3</td><td>1.0 (0.5-2.0)</td><td>1.0 (Ref)</td></tr><tr><td>Yes</td><td>13/12.6</td><td>1.0 (0.6-1.8)</td><td>1.1 (0.4-2.9)</td></tr></tbody></table>
<table><caption>TABLE 4 (Continued)</caption><thead><tr><th>Factor</th><th>Obs/Exp</th><th>SIR (95% CI)</th><th>RR (95% CI)<sup>b</sup></th></tr></thead><tbody><tr><td>Missing</td><td>1/3.2</td><td>—</td><td>—</td></tr><tr><td><i>p</i> for heterogeneity</td><td></td><td>.87</td><td>.79</td></tr></tbody></table>

Abbreviations: 95% CI, 95% confidence interval; CNS, central nervous system; Exp, expected; Obs, observed; Ref, reference category; RR, relative risk; SIR, standardized incidence ratio.

<sup>a</sup>RRs were derived from a model including sex, childhood cancer diagnosis, country, decade of childhood diagnosis, age at childhood diagnosis, and attained age.

<sup>b</sup>RRs were derived from a model including sex, childhood cancer diagnosis, country, decade of childhood diagnosis, age at childhood diagnosis, and follow-up time.

<sup>c</sup>RRs were derived from a model including sex, country, age at childhood diagnosis, attained age and treatment.

<sup>d</sup>Analyses relating to treatment included data from data providers that had <30% of missing data (Nordic countries and Italian population-based cohorts were excluded; treatment data were not available at all for Nordic countries).

consistent with research conducted in individuals who were exposed to radiation after the atomic bomb, in whom no increased risk was observed either.<sup>39</sup>

## Clinical implications

Current guidelines from the Children's Oncology Group for the long-term surveillance of childhood cancer survivors do not include details of an increased SPL risk.<sup>40</sup> Although we do not advocate surveillance of survivors because the absolute risks are small, survivors of HL, Wilms tumor, leukemia, and bone sarcoma should be encouraged to seek clinical advice from a medical professional if potentially relevant symptoms of NHL develop, including swellings, fever, and night sweats. Previous studies identified HL survivors to be at risk of NHL, but here we found that survivors of Wilms tumor, leukemia, and bone sarcoma are also at risk; it would be important for health care professionals responsible for the long-term follow-up of these survivors to be aware of the increased risk. Finally, it may be worth emphasizing to survivors that treatment with radiotherapy does not seem to suggest an increased risk of SPLs.

## Study limitations

One of the potential limitations of this study is the lack of detailed data concerning childhood treatment variables, such as cumulative doses of radiotherapy (including radiotherapy field) and chemotherapy. To fully assess the effect of treatment modalities on SPL risk, it would be beneficial to perform further analysis in the form of a nested case-control study in which detailed treatment information would be collected so that the risk of developing an SPL by cumulative doses of both radiation and chemotherapy agents can be calculated.

Another potential limitation of the study is the relatively small number of subsequent primary HLs observed, meaning that some components of the study may lack statistical power for further detailed analyses. That said, with more than three times the number

of SPLs compared with the next largest study, this study is the largest cohort of childhood cancer survivors with subsequent HLs to date and hence provides the most accurate estimates of these risks.<sup>10</sup>

Furthermore, it is feasible that, in some instances, the first primary lymphoma was misdiagnosed as HL instead of NHL.<sup>12</sup> In such cases, the subsequent primary NHL would not have been a true subsequent primary and thus resulted in an overestimate of the risk of developing NHL after HL. Although we cannot investigate the extent to which such misclassification has occurred, in a German study among adult patients with HL (aged 19-71 years), misclassification of the first primary lymphoma as HL instead of NHL occurred only for 2.1% of patients, suggesting that the extent to which potential misclassification might affect our results is likely minimal.<sup>19</sup> Also, we observed increased risks of NHL in survivors of Wilms tumor, leukemia, and bone sarcoma, suggesting that there is a critical role of treatment or immunodeficiency in the development of NHL after childhood cancer, and the increase cannot be caused only by misclassification of the first primary cancer.

Another potential limitation relates to heterogeneity in subtypes of subsequent primary NHL, with each subtype potentially having a different etiology. An investigation of treatment-related risk factors for subtypes of NHL is simply not feasible within this large-scale cohort study and would require a case-control study.

## CONCLUSION

In conclusion, in this largest cohort study to date, we demonstrate that the risk of developing NHL was increased particularly among those surviving HL, Wilms tumor, leukemia, and bone sarcoma and those who were treated with chemotherapy for any cancer. Only NHL survivors were at increased risk of HL. Although, for most childhood cancer survivors, the absolute risk of developing an SPL is low, health care professionals should be aware of the increased risk of developing NHL among survivors of HL, Wilms tumor, leukemia and bone sarcoma and in any survivors treated with chemotherapy. Survivors should be encouraged to seek clinical advice from a medical
professional if potentially relevant symptoms of NHL develop,
including swellings, fever, and night sweats.

AUTHOR CONTRIBUTIONS

Statistical analysis: Isabelle M. Dudley, Raoul C. Reulen, Michael M. Hawkins, David L. Winter, and Ceren Sunguc; initial drafting of the article: Isabelle M. Dudley, Raoul C. Reulen, and Michael M. Hawkins; study design and concept: Raoul C. Reulen, Michael M. Hawkins, Leontien C. Kremer, Florent de Vathaire, Lars Hjorth, Roderick Skinner, Riccardo Haupt, and Jop C. Teepen; data provider lead: Jeanette F. Winther, Lars Hjorth, Thorgerdur Gudmundsdottir, Maria Winther Gunnes, Päivi M. Lähteenmäki, Lorna Zadravec Zaletel, Riccardo Haupt, Monica Terenziani, Florent de Vathaire, Leontien C. Kremer, Claudia E. Kuehni, Zsuzsanna Jakab, and Stanislaw Garwicz; data curation: Raoul C. Reulen, David L. Winter, Desiree Grabow, Melanie Kaiser, and Peter Kaatsch; interpretation of data and critically revising of the article: all authors; all authors contributed to final review and editing.

ACKNOWLEDGMENTS

The authors are very grateful to the childhood cancer survivors
whose information was used in this data set. The authors thank the
following individuals from each country for their contribution to data
preparation: France: Angela Jackson, Florent Dayet, Amar Kahlouche,
Fara Diop, Sylvie Challeton, Martine Labbé, and Isao Kobayashi; Italy:
the Italian Association of Pediatric Hematology and Oncology-Off
Therapy Registry Group, Maura Massimino, Silvia Caruso, Monica
Muraca, Vera Morsellino, Claudia Casella, Lucia Miligi, Anita
Andreano, Andrea Biondi, and the Italian Association of Cancer
Registries Working Group; Netherlands: Dutch Childhood Oncology
Group LATER, Wim Tissing, Marry van den Heuvel-Eibrink, Eline van
Dulmen, Dorine Bresters, and Birgitta Versluys; Slovenia: Tina Žagar;
Sweden: Ingemar Andersson and Susanne Nordenfelt; Switzerland:
Elisabeth Kiraly, Vera Mitter, Shelagh Redmond, and the Swiss Pe-
diatric Oncology Group (www.spog.ch); United Kingdom: Julie Kelly.
Author Isabelle M. Dudley also thanks the Arthur Thomson Trust at
the University of Birmingham for their financial support and interest
in this project. The PanCareSurFup consortium and related work was
supported by the European Union's Seventh Framework Programme
for research, technological development, and demonstration under
grant agreement no. 257505. Additional financial support was
received from: the Foundation Force de Recherche sur le Cancer de
l'Enfant, The Italian Association for Cancer Research and the Com-
pagnia San Paolo, the Fondo Chiara Rama ONLUS, the Swedish
Childhood Cancer Fund, the French Association for Cancer Research,
the French National Agency for Research (Hope-Epi project), the
French National Cancer Institute, Pfizer Foundation for Children and
Adolescent Health, the Slovenian Research Agency, the Swiss Pae-
diatric Oncology Group, the Swiss Cancer League (KLS-3412-02-
2014, KLS-3886-02-2016, and KLS-5432-08-2021), the Swiss Can-
cer Research Foundation (KFS-02783-02-2011, KFS-4157-02-2017,
KLA/KFS-4825-01-2019, KFS-4722-02-2019, and KFS-5302-02-
2021), the Swiss National Science Foundation (PDFMP3_141775),

the Dutch Cancer Society (DCOG2011-5027 and UVA2012-5517),
the Norwegian Childhood Cancer Foundation, and Children with
Cancer UK (grant no: 20457).

CONFLICTS OF INTEREST

Zsuzsanna Jakab reports personal fees from Semmelweis Egyetem
outside the submitted work. Lars Hjorth reports personal fees from
Bayer and F. Hoffmann-La Roche outside the submitted work. The
remaining authors made no disclosures.

DATA AVAILABILITY STATEMENT

Access to anonymized data may be granted under conditions agreed
with the relevant (local) legal and research ethics committees and
with appropriate data sharing agreements and permissions from each
data provider in place. Any data sharing would have to comply with
the EU General Data Protection Regulation. The data that support
the findings of this study are not publicly available because of privacy
and ethical restrictions. Aggregated data in the form of tables may be
available on reasonable request.

ORCID

Ceren Sunguc https://orcid.org/0000-0001-7831-960X

Emma J. Heymer https://orcid.org/0000-0001-5115-0293

David L. Winter https://orcid.org/0000-0002-1597-4081

Jop C. Teepen https://orcid.org/0000-0002-2647-2677

Fabiën N. Belle https://orcid.org/0000-0002-0037-4817

Edit Bárdi https://orcid.org/0000-0001-7424-6255

Francesca Bagnasco https://orcid.org/0000-0003-1601-9518

Thorgerdur Gudmundsdottir https://orcid.org/0000-0001-6396-1018

Roderick Skinner https://orcid.org/0000-0002-1162-675X

Gisela Michel https://orcid.org/0000-0002-9589-0928

Julianne Byrne https://orcid.org/0000-0002-1070-3004

Momcilo Jankovic https://orcid.org/0000-0001-9773-0576

Maja Česen Mazić https://orcid.org/0000-0003-2434-8960

Luzius Mader https://orcid.org/0000-0001-5613-4356

Jaqueline Loonen https://orcid.org/0000-0002-9963-8367

Thomas Wiebe https://orcid.org/0000-0002-7567-9076

Daniela Alessi https://orcid.org/0000-0002-3746-3346

Rodrigue S. Allodji https://orcid.org/0000-0002-1895-8415

Nadia Haddy https://orcid.org/0000-0001-9316-8280

Desiree Grabow https://orcid.org/0000-0002-4853-3303

Peter Kaatsch https://orcid.org/0000-0002-8565-0832

Melanie Kaiser https://orcid.org/0000-0002-3362-2530

Milena M. Maule https://orcid.org/0000-0003-2142-1288

Zsuzsanna Jakab https://orcid.org/0000-0002-5410-1187

Maria Winther Gunnes https://orcid.org/0000-0003-2514-0547

Monica Terenziani https://orcid.org/0000-0002-7080-6718

Lorna Zadravec Zaletel https://orcid.org/0000-0002-4423-0276

Claudia E. Kuehni https://orcid.org/0000-0001-8957-2002

Riccardo Haupt https://orcid.org/0000-0003-0571-8460

Florent de Vathaire https://orcid.org/0000-0002-8374-9281

Leontien C. Kremer https://orcid.org/0000-0001-7422-3248
Päivi M. Lähteenmäki https://orcid.org/0000-0002-5500-9606

Jeanette F. Winther https://orcid.org/0000-0002-3440-5108

Lars Hjorth https://orcid.org/0000-0002-8302-7174

Michael M. Hawkins https://orcid.org/0000-0001-6496-4800

Raoul C. Reulen https://orcid.org/0000-0002-7328-0467

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SUPPORTING INFORMATION

Additional supporting information can be found online in the Sup-
porting Information section at the end of this article.

How to cite this article: Dudley IM, Sunguc C, Heymer EJ, et al. Risk of subsequent primary lymphoma in a cohort of 69,460 five-year survivors of childhood and adolescent cancer in Europe: the PanCareSurFup study. *Cancer*. 2023;129(3):426-440. doi:10.1002/cncr.34561