Abstract
Background
The diagnosis of B-cell lymphoma, one of the commonest cancers seen in childhood and adolescence, is challenging. There is a crucial need to identify and delineate the prevalence of associated symptoms in order to improve early diagnosis.
Aims
To identify clinical presentations associated with childhood and adolescent B-cell lymphomas and estimate symptom prevalence.
Methods
A systematic review of observational studies and meta-analysis of proportions was carried out. Medline and EMBASE were systematically searched, with no language restrictions, from inception to 1st August 2022. Observational studies with at least 10 participants, exploring clinical presentations of any childhood and adolescent lymphoma, were selected. Proportions from each study were inputted to determine the weighted average (pooled) proportion, through random-effects meta-analysis.
Results
Studies reported on symptoms, signs and presentation sites at diagnosis of 12,207 children and adolescents up to the age of 20. Hodgkin’s lymphoma most frequently presented with adenopathy in the head-and-neck region (79% [95% CI 58%-91%]), whilst non-Hodgkin’s lymphoma presented abdominally (55% [95% CI 43%-68%]). Symptoms associated with lymphoma included cervical lymphadenopathy (48% [95% CI 20%-77%]), peripheral lymphadenopathy (51% [95% CI 37%-66%]), B-symptoms (40% [95% CI 34%-44%]), fever (43% [95% CI 34%-54%]), abdominal mass (46% [95% CI 29%-64%]), weight loss (53% [95% CI 39%-66%]), head-and-neck mass (21% [95% CI 6%-47%]), organomegaly (29% [95% CI 23%-37%]), night sweats (19% [95% CI 10%-32%]), abdominal pain (28% [95% CI 15%-47%]), bone pain (17% [95% CI 10%-28%]) and abnormal neurology (11% [95% CI 3%-28%]).
Conclusion
This systematic review and meta-analysis of proportions provides insight into the heterogeneous clinical presentations of B-cell lymphoma in childhood and adolescence and provides estimates of symptom prevalence. This information is likely to increase public and clinical awareness of lymphoma presentations and aid earlier diagnosis. This review further highlights the lack of studies exploring childhood and adolescent lymphoma presentations in primary care, where patients are likely to present at the earliest stages of their disease.
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Introduction
Childhood and adolescent cancers are uncommon, with an estimated global incidence rate of 156 per million [1]. Despite this low incidence, cancer is the commonest cause of death and disability in children and adolescents across the world, carrying vast human, socioeconomic and healthcare costs [2]. Early recognition of cancer plays an important role in reducing this long-term burden [3]. One of the biggest challenges to early recognition is the non-specific presentation of cancers in this age group, mimicking symptoms and signs associated with self-limiting diseases in childhood and adolescence.
Childhood and adolescent B-cell lymphomas are one of the commonest cancers in this age group and can be broadly categorised into Hodgkin’s lymphoma and B-cell non-Hodgkin’s lymphoma (e.g., mature B-cell neoplasms) [4]. Hodgkin’s lymphoma is frequently encountered in adolescence [5] whilst B-cell non-Hodgkin’s lymphoma across childhood and adolescence [6]. Lymphomas present heterogeneously across a range of sites on the body and are associated with a varied number of non-specific symptoms and signs [7]. Examples include Burkitt’s lymphoma which presents more commonly with facial or abdominal swelling and Hodgkin’s lymphoma with painless lymphadenopathy [7] and non-specific symptoms such as fever, weight loss and night sweats (i.e. B-symptoms). Such non-specific symptoms, coupled with the relative rarity of lymphoma, make prompt recognition by healthcare professionals particularly challenging. Lymphomas have one of the most protracted diagnostic intervals within cancers in this age group and are more frequently associated with advanced stages at diagnosis [8].
Several observational studies to date have explored clinical presentations of childhood and adolescent cancers to advance clinical knowledge and awareness in this area [9,10,11,12]. However, these studies are limited by sample size, with the majority based on single-centre data of a few hundred patients [13]. Additionally, as cancer in this age group is rare, conducting large observational, multi-centre cohorts have been limited by high costs. To overcome this challenge, the clinical presentations of other childhood cancers, such as leukaemias and central nervous system tumours, have been summarised in comprehensive literature reviews, providing the most up-to-date evidence for associated symptoms and signs [14, 15]. These reviews have highlighted the wide range of symptoms associated with childhood cancers, increased public and clinical awareness, and informed clinical guidance. Despite significant challenges in early diagnosis, there have been no literature reviews summarising clinical presentations or the relative importance of an individual symptom in a lymphoma diagnosis in children and adolescents to date. Accordingly, we have systematically reviewed all existing evidence and carried out a meta-analysis of proportions to advance knowledge of clinical presentations of B-cell lymphomas in this age group.
Methods
Search strategy
Medline and EMBASE were systematically searched, with no language restrictions, from inception to 1st August 2022 for the following search terms within the full text of the publication; “paediatric/pediatric”, “childhood”, “adolescent”, “diagnosis”, “clinical presentation”, “symptom”, “signs”, “lymphoma”, “Hodgkin’s”, “non-Hodgkin’s”. Reference lists of publications were further hand-searched. The full search strategies are available in the supplementary appendix (Supplementary Table 1).
Identification of studies
Title and abstracts were screened by two researchers (DS & CZ). Any observational studies (cohort, case-control, cross-sectional) with at least 10 participants less than 20 years of age, exploring clinical presentations of any childhood and adolescent B-cell lymphoma, were eligible for full-text review. Any T-cell non-Hodgkin’s lymphomas were excluded. Due to overlap with acute lymphoblastic leukaemia, B-cell lymphoblastic lymphoma diagnoses were also excluded. All non-English studies were translated.
Data extraction and analysis
Data was extracted using a standardised form (Supplementary Appendix Table 2). Information on publication details, number of participants and participant characteristics were included, as well as outcomes including disease site and clinical presentation.
There was variation in the description of clinical presentations across studies, with some studies reporting a cluster of symptoms (e.g. “B-symptoms”) and others reporting individual symptoms (e.g. “fever, weight loss”). B-symptoms were defined as the cluster of the following symptoms: fever, night sweats, and unintentional weight loss. We extracted the data as presented within individual studies. Different descriptions of symptoms and signs, which overall implied the same clinical presentation (e.g. difficulty breathing vs. dyspnoea) were combined for the meta-analysis. Additionally, swellings reported in narrow anatomical locations (e.g. jaw swelling and cheek swelling grouped as “head and neck swelling”) were combined for the meta-analysis. However, if a study uniquely reported a combination of symptoms or signs not present in other studies (e.g. sore throat and tonsillar mass were reported together only in one study), these were excluded from the meta-analysis.
For each study, participants with a symptom or sign, alongside site of the disease and the total number of participants in the study were recorded. Any missing data were addressed by contacting authors. For any overlapping data across studies, only the most recent and relevant publication was included. Two separate meta-analyses were carried out; the first providing pooled estimates for the prevalence of symptoms/signs reported, and the second providing pooled estimates for disease site reported. For studies reporting on symptoms and signs, proportions of study participants with symptoms in a specific disease site (e.g. abdominal pathology) were included in the systematic review but not included in the first meta-analysis as they were likely to skew results. However, if these studies reported the disease site for each study participant, they were included in the second meta-analysis.
In order to strike a balance between the need to clinically consider lymphoma as a differential diagnosis and symptoms that occur frequently in children and adolescents, only symptoms and signs occurring in more than 5% of the study population were included in the analysis. In studies reporting symptoms and signs for both Hodgkin’s and non-Hodgkin’s lymphoma, symptoms and signs were separately recorded for each type of lymphoma.
Quality assessment
Risk of bias tool for prevalence studies based on Hoy et al. 2012 [16] was used by one researcher (DS) to assess the quality of studies. This tool contains 10 domains, of which 4 assess external validity and 6 assess internal validity. Within external validity, the tool assesses the study population’s representativeness and within internal validity, the tool assesses case definitions, data collection methodology and length of follow up. Each domain is given a high-risk or low-risk grading and subsequently each study is given an overall assessment (either high, moderate or low risk).
Statistical analysis
Proportions from each study were inputted to determine the weighted average (pooled) proportion, through random-effects meta-analysis [17]. Briefly, we carried this out in two steps. Firstly, the proportion of each symptom or sign in an individual study was calculated and weighted by the inverse of its variance, to provide a weighted proportion. Subsequently, weighted proportions were summed and divided by the sum of the weights, to generate the pooled proportion.
Of note, as proportional data are often skewed, weighted proportions from each study were log transformed to fit a normal distribution and untransformed to provide interpretable results.
Furthermore, as between-study variation is expected across included observational studies, the pooled proportion was calculated using the restricted maximum likelihood (REML) random-effects model [17].
Heterogeneity was measured using I [2]. This measure assesses the percentage of the total observed variance, which can be accounted for by between-study variation. Small-study effect of studies was assessed using the Egger’s test [18].
An a priori decision was made to carry out the following subgroup analyses to assess heterogeneity: (1) geographical region, (2) study period, and (3) lymphoma type (Hodgkin’s vs. non-Hodgkin’s).
Our meta-analysis follows the Meta-analysis of Observational Studies in Epidemiology (MOOSE) criteria [19] and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [20]. All analyses were carried out using the “meta” package in R. This study was registered on PROSPERO (CRD42023304949).
Results
Our search strategy yielded 8923 articles, of which 263 were retrieved for full text review. 48 were eligible for meta-analysis (Fig. 1). Details of excluded studies can be found in the Supplementary Appendix (Supplementary Appendix Table 3).
Single and multi-centre studies reported on symptoms, signs and presentation sites at diagnosis of a total of 12,207 children and adolescents up to the age of 20 (Table 1, Supplementary Appendix Table 4 for quality assessment of each study). A diagnosis of lymphoma was more common in males.
General symptoms and signs
31 studies [9, 12, 21,13,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48] (n = 9488, range per study n = 10 to 2326) reported on symptoms and signs for either type of B-cell lymphoma. These included cervical lymphadenopathy (48% [95% CI 20%-77%]), peripheral lymphadenopathy (51% [95% CI 37%-66%]), B-symptoms (40% [95% CI 34%-44%]), fever (43% [95% CI 34%-54%]), abdominal mass (46% [95% CI 29%-64%]), weight loss (53% [95% CI 39%-66%]), head-and-neck mass (23% [95% CI 10%-45%]), organomegaly (29% [95% CI 23%-37%]), night sweats (19% [95% CI 10%-32%]), abdominal pain (28% [95% CI 15%-47%]), bone pain (17% [95% CI 10%-28%]) and abnormal neurology (11% [95% CI 3%-28%]).
12 studies [12, 22,23,13, 30, 31, 33, 35, 36, 40, 43, 45] (n = 4678, range per study n = 18 to 2200) reported on the symptoms and signs for Hodgkin’s lymphoma. These included any lymphadenopathy (80% [95% CI 74%-85%]), cervical lymphadenopathy (74% [95% CI 43%-91%]), B-symptoms (40% [95% CI 33%-47%]), fever (37% [95% CI 23%-53%]) and organomegaly (22% [95% CI 15%-29%]).
15 studies [9, 21, 24,25,26,27, 32, 34, 39,40,41, 44, 49,50,51,52] (n = 4258, range per study n = 18 to 2326) reported on the symptoms and signs for non-Hodgkin’s lymphoma. These included organomegaly (34% [95% CI 22%-48%]), B-symptoms (38% [95% CI 31%-44%]), cervical lymphadenopathy (28% [95% CI 17%-42%]), peripheral lymphadenopathy (45% [95% CI 31%-61%]), fever (47% [95% CI 35%-61%]), weight loss (58% [95% CI 41%-72%]), abdominal pain (29% [95% CI 12%-54%]) (Fig. 2).
Presentation sites
2 studies [33, 35] (n = 206, range per study n = 102 to 106) reported on the presentation sites for Hodgkin’s lymphoma. Hodgkin’s lymphoma commonly presented with a head and neck (adenopathy) presentation (79% [95% CI 58%-91%]) and subsequently most frequently as mediastinal presentation (34% [95% CI 26%-42%]) any peripheral (adenopathy) presentation (15% [95% CI 2%-24%]), and abdominal presentation (4% [95% CI 2%-8%]).
15 studies [10, 11, 53,54,55,56,57,58,59,60,61,62,63,64,65] (n = 4161, range per study n = 22 to 1217) reported on the presentation sites for non-Hodgkin’s lymphoma. These were abdominal presentation (55% [95% CI 43%-68%]), head and neck presentation (16% [95% CI 8%-34%]), any peripheral lymph node presentation (4% [95% CI 1%-9%]), neurological presentation (2% [95% CI 1%-4%]), mediastinal presentation (2% [95% CI 1%-6%]), bone presentation (1% [95% CI 0.06%-3%]) and skin presentation (1% [95% CI 0.04-2%]).
It was possible to further characterise presentation sites according to non-Hodgkin’s lymphoma subtypes. Accordingly, 11 studies [10, 11, 24, 41, 42, 53, 58, 59, 63, 64, 66] (n = 3123, range per study n = 31 to 1217) reported on Burkitt’s lymphoma. 61% [95% CI 45%-75%] of Burkitt’s lymphoma presented with abdominal pathology, 16% [95% CI 8%-29%]) with head and neck, 4% [95% CI 1%-10%]) with peripheral lymph node pathology, and 2% [95% CI 0.07%-6%] with central nervous system (CNS) pathology. In contrast, other non-Hodgkin’s lymphomas (2 studies [67, 68], n = 51) were less likely to present with abdominal pathology (19% [95% CI 1%-32%]) (Fig. 3).
Symptoms by presentation site
Four studies [21, 37, 38, 62] reported on both disease sites, the mediastinum/head-neck region, and associated symptomology, with one study focusing specifically on intensive care admissions [37]. Presentation in the head/neck or mediastinum was associated with lymphadenopathy (37% [95% CI 21%-57%]), dyspnoea (46% [95% CI 11%-86%]), fever (26% [95% CI 14%-41%]), stridor (9% [95% CI 35 − 28%]) and superior vena cava obstruction (14% [95% CI 4%-37%]).
Heterogeneity and small study effect assessment
Heterogeneity was high across all pooled estimates of an individual clinical presentation, with I2 above at least 60% for each (Supplementary Appendix Table 5). Subgroup analyses were carried out for lymphoma subtype, geographical region of study and time period of publication. Region of study accounted for the majority of heterogeneity observed in the clinical features “abdominal pain”, “peripheral lymphadenopathy” and “bone pain”, whilst lymphoma subtype accounted for heterogeneity observed in “weight loss” as well as “abnormal neurology” and time period accounted for heterogeneity observed in “B-symptoms” and “abdominal mass”. We were unable to account for the heterogeneity observed in any of the other clinical presentations. (Supplementary Appendix Table 5). Small study effects were detected for the symptoms/signs “peripheral lymph node” (p = 0.0002) and “B-symptoms” (p = 0.006) (Supplementary Appendix Table 6).
Discussion
To our knowledge this is the first systematic review and meta-analysis exploring the presenting features of B-cell lymphomas in children and adolescents. With symptoms and signs reported by 12,207 children and adolescents, this review provides a comprehensive summary of presentation patterns, highlighting the wide range of differences in presentation according to B-cell lymphoma type and location of cancer.
We found that Hodgkin’s lymphomas in this age group most commonly present in the head & neck region with lymphadenopathy, whilst non-Hodgkin’s lymphomas have much more varied presentations, with more frequent links to abdominal pathology. As B-cell non-Hodgkin’s lymphomas are most likely to have rapid progression and fast-growing masses [7], it is important to raise awareness of their varied presentation patterns within the general medical community. This may aid more prompt recognition by clinicians, faster referral to oncological services, and subsequent earlier diagnosis of these lymphomas.
We identified that B-symptoms (fever, weight loss and night sweats) were only reported in approximately 40% of presentations, which is in keeping with previous studies [7] but is often not reflected by clinical guidelines, such as the National Institute for Clinical Excellence (NICE) Suspected Cancer in the United Kingdom [69], where presence of B-symptoms are weighted significantly in suspected lymphoma diagnoses. This emphasises that although the presence of B-symptoms should be sought after when a child/adolescent presents with lymphadenopathy, other symptom combinations should also be considered. Seeking out the presence of other symptoms including abdominal pain, abdominal mass, bone pain and breathlessness, which we identified through this systematic review, may provide important information to clinicians and aid their decisions to further investigate or refer to a haemato-oncologist.
It is crucial to highlight that all studies included in this systematic review were based on secondary care/hospital data and thus, these symptoms and signs may not be fully reflective of earlier presentations to other healthcare settings, such as primary care. This is particularly important as patients are most likely to present to their primary care physician at the earliest stages of disease onset.
Furthermore, as our systematic review and meta-analysis included studies with > 10 participants, we may have not captured rarer relevant and important clinical presentations. These include gastrointestinal presentations such as intussusception [70] and bowel obstruction [71], upper respiratory tract symptoms such as asymmetrical tonsillar enlargement [72], sleep apnoea [73], wheeze and stridor [74], as well as rheumatic symptoms such as arthritis [75].
There were several limitations to this study. Firstly, there was high heterogeneity when the proportions of symptoms/signs were pooled in the meta-analysis. This is in line with reports from other meta-analysis of proportion studies [76], nevertheless, we further explored this heterogeneity through subgroup analyses in lymphoma type, geographical region, and study period, but we were unable to fully account for the observed heterogeneity in all clinical presentations. Secondly, assessment of study quality in this systematic review identified possible moderate risk of bias introduced from studies of varying quality. Finally, we detected small study effects in two symptoms, “peripheral lymph node” and “B-symptoms”, indicating that small studies estimate higher proportions for these symptoms compared to the larger studies in the meta-analysis. This implies that the estimate of prevalence for these two symptoms should be interpreted with caution.
Overall, through this systematic review and meta-analysis of proportions, we provide a summary of the prevalence of symptoms and signs associated with childhood and adolescent lymphoma. We demonstrate that well-known clinical features (lymphadenopathy and B-symptoms) are frequently observed at diagnosis but that other symptoms and signs such as abdominal pain, abdominal mass and bone pain may also play a central role in the earlier detection of lymphoma. We believe that this knowledge will increase public and clinical awareness of lymphoma presentations in children and adolescents. We also highlight that our understanding of B-cell lymphoma presentations at diagnosis in this age group is largely based on secondary care data and more primary care-based studies are needed to further characterise clinical features of lymphoma at the earlier stages of disease onset.
Data availability
No datasets were generated or analysed during the current study.
References
Steliarova-Foucher E, Colombet M, Ries LAG, et al. International incidence of childhood cancer, 2001-10: a population-based registry study. Lancet Oncol. 2017;18(6):719–31.
Collaborators GBDCC. The global burden of childhood and adolescent cancer in 2017: an analysis of the global burden of Disease Study 2017. Lancet Oncol. 2019;20(9):1211–25.
Youlden DR, Frazier AL, Gupta S, et al. Stage at diagnosis for childhood solid cancers in Australia: a population-based study. Cancer Epidemiol. 2019;59:208–14.
Pfister SM, Reyes-Mugica M, Chan JKC, et al. A Summary of the Inaugural WHO classification of Pediatric tumors: transitioning from the Optical into the Molecular Era. Cancer Discov. 2022;12(2):331–55.
Aben KK, van Gaal C, van Gils NA, van der Graaf WT, Zielhuis GA. Cancer in adolescents and young adults (15–29 years): a population-based study in the Netherlands 1989–2009. Acta Oncol. 2012;51(7):922–33.
Minard-Colin V, Brugieres L, Reiter A, et al. Non-hodgkin Lymphoma in Children and adolescents: Progress through effective collaboration, current knowledge, and challenges ahead. J Clin Oncol. 2015;33(27):2963–74.
Allen CE, Kelly KM, Bollard CM. Pediatric lymphomas and histiocytic disorders of childhood. Pediatr Clin North Am. 2015;62(1):139–65.
Herbert A, Lyratzopoulos G, Whelan J, et al. Diagnostic timeliness in adolescents and young adults with cancer: a cross-sectional analysis of the BRIGHTLIGHT cohort. Lancet Child Adolesc Health. 2018;2(3):180–90.
Burkhardt B, Oschlies I, Klapper W, et al. Non-hodgkin’s lymphoma in adolescents: experiences in 378 adolescent NHL patients treated according to pediatric NHL-BFM protocols. Leukemia. 2011;25(1):153–60.
Sandlund JT, Fonseca T, Leimig T, et al. Predominance and characteristics of Burkitt lymphoma among children with non-hodgkin lymphoma in northeastern Brazil. Leukemia. 1997;11(5):743–6.
Uccini S, Al-Jadiry MF, Cippitelli C, et al. Burkitt lymphoma in Iraqi children: a distinctive form of sporadic disease with high incidence of EBV(+) cases and more frequent expression of MUM1/IRF4 protein in cases with head and neck presentation. Pediatr Blood Cancer. 2018;65(12):e27399.
Sherief LM, Elsafy UR, Abdelkhalek ER, et al. Hodgkin lymphoma in childhood: clinicopathological features and therapy outcome at 2 centers from a developing country. Med (Baltim). 2015;94(15):e670.
Belgaumi A, Al-Kofide A, Joseph N, Jamil-Malik R, Khafaga Y, Sabbah R. Hodgkin lymphoma in very young children: clinical characteristics and outcome of treatment. Leuk Lymphoma. 2008;49(5):910–6.
Clarke RT, Van den Bruel A, Bankhead C, Mitchell CD, Phillips B, Thompson MJ. Clinical presentation of childhood leukaemia: a systematic review and meta-analysis. Arch Dis Child. 2016;101(10):894–901.
Wilne S, Collier J, Kennedy C, Koller K, Grundy R, Walker D. Presentation of childhood CNS tumours: a systematic review and meta-analysis. Lancet Oncol. 2007;8(8):685–95.
Hoy D, Brooks P, Woolf A, et al. Assessing risk of bias in prevalence studies: modification of an existing tool and evidence of interrater agreement. J Clin Epidemiol. 2012;65(9):934–9.
Barendregt JJ, Doi SA, Lee YY, Norman RE, Vos T. Meta-analysis of prevalence. J Epidemiol Community Health. 2013;67(11):974–8.
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–34.
Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of Observational studies in Epidemiology (MOOSE) group. JAMA. 2000;283(15):2008–12.
Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Rev Esp Cardiol (Engl Ed). 2021;74(9):790–9.
Anavi Y, Kaplinsky C, Calderon S, Zaizov R. Head, neck, and maxillofacial childhood Burkitt’s lymphoma: a retrospective analysis of 31 patients. J Oral Maxillofac Surg. 1990;48(7):708–13.
Ashraf MS, Naz F, Yakoob MY. Characteristics and survival outcomes of children with Hodgkin Lymphoma treated primarily with chemotherapy. J Pediatr Hematol Oncol. 2019;41(6):452–6.
Bazzeh F, Rihani R, Howard S, Sultan I. Comparing adult and pediatric Hodgkin lymphoma in the Surveillance, Epidemiology and End results Program, 1988–2005: an analysis of 21 734 cases. Leuk Lymphoma. 2010;51(12):2198–207.
Boerma EG, van Imhoff GW, Appel IM, Veeger NJ, Kluin PM, Kluin-Nelemans JC. Gender and age-related differences in Burkitt lymphoma–epidemiological and clinical data from the Netherlands. Eur J Cancer. 2004;40(18):2781–7.
Budiongo AN, Ngiyulu RM, Lebwaze BM, et al. Pediatric non-hodgkin lymphomas: first report from Central Africa. Pediatr Hematol Oncol. 2015;32(4):239–49.
Chen ZS, Zheng YZ, Chen YQ, Gao QL, Li J, Shen JZ. Clinical features and prognosis of children with mature B-cell non-hodgkin’s lymphoma: an analysis of 28 cases. [Chinese]. Chin J Contemp Pediatr. 2018;20(6):470–4.
Choeyprasert W, Anurathapan U, Pakakasama S, et al. Pediatric non-hodgkin lymphoma: characteristics, stratification, and treatment at a single institute in Thailand. Pediatr Int. 2019;61(1):49–57.
Dho YS, Kim H, Wang KC, et al. Pediatric spinal epidural lymphoma presenting with compressive myelopathy: a distinct pattern of Disease Presentation. World Neurosurg. 2018;114:e689–97.
Dommett RM, Redaniel MT, Stevens MCG, Hamilton W, Martin RM. Features of childhood cancer in primary care: a population-based nested case-control study. Br J Cancer. 2012;106(5):982–7.
Duan YL, Jin L, Yang J, et al. Clinical study of 83 cases of pediatric Hodgkin lymphoma. [Chinese]. J Leuk Lymphoma. 2016;25(5):275–80.
Englund A, Glimelius I, Rostgaard K, et al. Hodgkin lymphoma in children, adolescents and young adults - a comparative study of clinical presentation and treatment outcome. Acta Oncol. 2018;57(2):276–82.
Faizan M, Anwar S, Khan S. Demographics and outcome in paediatric non-hodgkin lymphoma: single centre experience at the Children Hospital, Lahore, Pakistan. J Coll Physicians Surg Pakistan. 2018;28(1):48–51.
Ghafoor T. Prognostic factors in pediatric Hodgkin lymphoma: experience from a developing country. Leuk Lymphoma. 2020;61(2):344–50.
Huang S, Yang J, Jin L, et al. [Clinical characteristics of 46 pediatric diffuse large B-cell lymphoma and treatment outcome]. Zhonghua Er Ke Za Zhi. 2019;57(10):774–9.
Karhan AN, Varan A, Akyüz C, et al. Outcome of 102 patients under 5 years of age with Hodgkin lymphoma. Arch Argent Pediatr. 2019;117(5):e459–65.
Karimi M, Mehrabani D, Yarmohammadi H, Jahromi FS. The prevalence of signs and symptoms of childhood leukemia and lymphoma in Fars Province, Southern Iran. Cancer Detect Prev. 2008;32(2):178–83.
Lee SH, Oh BL, Kimpo M, Quah TC. Epidemiology of childhood malignant mediastinal masses and clinical factors associated with intensive care unit admission: a Singapore experience. J Paediatr Child Health 2020.
Lilja-Fischer JK, Schroder H, Nielsen VE. Pediatric malignancies presenting in the head and neck. Int J Pediatr Otorhinolaryngol. 2019;118:36–41.
Meena JP, Gupta AK, Parihar M, Seth R. Clinical profile and outcomes of Non-hodgkin’s lymphoma in children: a report from a tertiary care hospital from India. Indian J Med Pediatr Oncol. 2019;40(1):41–7.
Mehreen A, Wali RM, Sindhu II, Asad M, Ria S. Retrospective analysis of clinical features and treatment outcomes of children with Hodgkin’s lymphoma treated with different chemotherapy protocols at a tertiary care center in Pakistan. J Pak Med Assoc. 2019;69(9):1266–72.
Orem J, Mulumba Y, Algeri S, et al. Clinical characteristics, treatment and outcome of childhood Burkitt’s lymphoma at the Uganda Cancer Institute. Trans Royal Soc Trop Med Hygiene. 2011;105(12):717–26.
Otmani N, Khattab M. Oral Burkitt’s lymphoma in children: the Moroccan experience. Int J Oral Maxillofac Surg. 2008;37(1):36–40.
Seth R, Das RR, Puri K, Singh P. Clinical Profile and Chemotherapy Response in Children with Hodgkin Lymphoma at a Tertiary Care Centre. J Clin Diagn Res. 2015;9(11):Sc25–30.
Sevinir B, Demirkaya M. The diagnostic characteristics of pediatric non-hodgkin lymphoma patients. [Turkish]. Guncel Pediatri. 2009;7(3):111–6.
Trehan A, Singla S, Marwaha RK, Bansal D, Srinivasan R. Hodgkin lymphoma in children: experience in a tertiary care centre in India. J Pediatr Hematol Oncol. 2013;35(3):174–9.
Yakubu M, Ahmadu BU, Yerima TS, Simon P, Hezekiah IA, Pwavimbo AJ. Prevalence and clinical manifestation of lymphomas in North Eastern Nigeria. Indian J Cancer. 2015;52(4):551–5.
Zheng YZ, Chen ZS, Hua XL, et al. Clinical characteristics and prognostic factors of children with Non-hodgkin’s lymphoma of different pathological subtypes. [Chinese]. Zhongguo Shi Yan xue ye xue Za Zhi. 2020;28(2):500–6.
Katz J, Polliack A, Harushouski I, Ben Oliel R, Marmary Y. Bell’s palsy as a sign of Burkitt’s lymphoma in children. Blood. 1995;86(5):2052.
Chen C, Zheng YZ, Hua XL, et al. [Clinical features and prognostic factors of 18 children with anaplastic large cell Lymphoma]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2019;27(3):809–915.
Han JY, Suh JK, Lee SW, Koh KN, Im HJ, Seo JJ. Clinical characteristics and treatment outcomes of children with anaplastic large cell lymphoma: a single center experience. Blood Res. 2014;49(4):246–52.
Williams D, Mori T, Reiter A, et al. Central nervous system involvement in anaplastic large cell lymphoma in childhood: results from a multicentre European and Japanese study. Pediatr Blood Cancer. 2013;60(10):E118–21.
Yang J, Jin L, Zheng HY, et al. [Clinical features and therapeutic effect of 38 children with anaplastic large cell lymphoma]. Zhonghua Er Ke Za Zhi. 2012;50(3):223–6.
Cunha KC, Oliveira MC, Gomes AC, de Castro LP, Viana MB. Clinical course and prognostic factors of children with Burkitt’s lymphoma in a developing country: the experience of a single centre in Brazil. Rev Bras Hematol Hemoter. 2012;34(5):361–6.
Guo J, Zhu YP, Gao J, et al. Clinical and prognostic analysis of 43 children with mature B-cell Non-hodgkin’s Lymphoma/Acute lymphoblastic leukemia. [Chinese]. Zhongguo Shi Yan xue ye xue Za Zhi / Zhongguo Bing Li Sheng Li Xue Hui = Journal of experimental hematology /. Chinese Association of Pathophysiology. 2016;24(1):72–9.
Karadeniz C, Oguz A, Citak EC, et al. Clinical characteristics and treatment results of pediatric B-cell non-hodgkin lymphoma patients in a single center. Pediatr Hematol Oncol. 2007;24(6):417–30.
Kobayashi R, Tanaka F, Nakazawa A, et al. Pediatric follicular lymphoma in Japan. Int J Hematol. 2017;105(6):849–53.
Lervat C, Auperin A, Patte C, et al. Head and neck presentations of B-NHL and B-AL in children/adolescents: experience of the LMB89 study. Pediatr Blood Cancer. 2014;61(3):473–8.
Mlotha J, Naidoo S. Oro-facial manifestations of Burkitt’s lymphoma: an analysis of 680 cases from Malawi. SADJ. 2011;66(2):77–9.
Muwakkit SA, Razzouk BI, Shabb NS, et al. Clinical presentation and treatment outcome of children with Burkitt lymphoma in Lebanon: a single institution’s experience. J Pediatr Hematol Oncol. 2004;26(11):749–53.
Oliveira MCL, Sampaio KC, Brito AC, et al. 30 years of experience with Non-hodgkin Lymphoma in Children and adolescents: a retrospective cohort study. Rev Assoc Med Bras (1992). 2020;66(1):25–30.
Owusu L, Yeboah FA, Osei-Akoto A, Rettig T, Arthur FKN. Clinical and epidemiological characterisation of Burkitt’s lymphoma: an eight-year case study at Komfo Anokye Teaching Hospital, Ghana. Br J Biomed Sci. 2010;67(1):9–14.
Roh JL, Huh J, Moon HN. Lymphomas of the head and neck in the pediatric population. Int J Pediatr Otorhinolaryngol. 2007;71(9):1471–7.
Stefan DC, Lutchman R. Burkitt lymphoma: epidemiological features and survival in a South African centre. Infect Agent Cancer. 2014;9:19.
Zhang M, Jin L, Yang J, et al. [Clinical and prognostic analysis of 186 children with Burkitt’s lymphoma]. Zhonghua Er Ke Za Zhi. 2018;56(8):605–10.
Sherief LM, Elsafy UR, Abdelkhalek ER, Kamal NM, Youssef DM, Elbehedy R. Disease patterns of pediatric non-hodgkin lymphoma: a study from a developing area in Egypt. Mol Clin Oncol. 2015;3(1):139–44.
Cavdar AO, Yavuz G, Babacan E et al. Burkitt’s lymphoma in Turkish children: clinical, viral [EBV] and molecular studies. Leukemia & Lymphoma 1994; 14(3–4): 323 – 30.
Ataş E, Kutluk MT, Akyüz C, et al. Clinical features and treatment results of children with diffuse large B-cell lymphoma. Pediatr Hematol Oncol. 2014;31(6):509–17.
Kontny U, Oschlies I, Woessmann W, et al. Non-anaplastic peripheral T-cell lymphoma in children and adolescents–a retrospective analysis of the NHL-BFM study group. Br J Haematol. 2015;168(6):835–44.
National Institute for Health and Care Excellence. Suspected cancer: recognition and referral [NG12]. 2015.
Bussell HR, Kroiss S, Tharakan SJ, Meuli M, Moehrlen U. Intussusception in children: lessons learned from intestinal lymphoma as a rare lead-point. Pediatr Surg Int. 2019;35(8):879–85.
Bandyopadhyay R, Sinha SK, Chatterjee U, et al. Primary pediatric gastrointestinal lymphoma. Indian J Med Pediatr Oncol. 2011;32(2):92–5.
Ridgway D, Wolff LJ, Neerhout RC, Tilford DL. Unsuspected non-hodgkin’s lymphoma of the tonsils and adenoids in children. Pediatrics. 1987;79(3):399–402.
Toader C, Toader M, Stoica A, et al. Tonsillar lymphoma masquerading as obstructive sleep apnea - pediatric case report. Rom J Morphol Embryol. 2016;57(2 Suppl):885–91.
Saraswatula A, McShane D, Tideswell D, et al. Mediastinal masses masquerading as common respiratory conditions of childhood: a case series. Eur J Pediatrics. 2009;168(11):1395–9.
Falcini F, Bardare M, Cimaz R, Lippi A, Corona F. Arthritis as a presenting feature of non-hodgkin’s lymphoma. Arch Dis Child. 1998;78(4):367–70.
Barker TH, Migliavaca CB, Stein C, et al. Conducting proportional meta-analysis in different types of systematic reviews: a guide for synthesisers of evidence. BMC Med Res Methodol. 2021;21(1):189.
Karayalcin G, Behm FG, Gieser PW, et al. Lymphocyte predominant Hodgkin disease: clinico-pathologic features and results of treatment–the Pediatric Oncology Group experience. Med Pediatr Oncol. 1997;29(6):519–25.
Acknowledgements
DS was funded by Children with Cancer UK.
Funding
CRUK EDDCPJT\100016. The funding body 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.
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Concept and design: DS, AH, JHC, Acquisition, analysis, or interpretation of data: DS, CZ, AH, JHC, Drafting of the manuscript: DS, Critical revision of the manuscript for important intellectual content: DS, CZ, AH, JHC, Statistical analysis: DS. DS had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. AH and JHC provided supervision to DS through the study. All information and materials in the manuscript are original.
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All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: JHC reports grants from National Institute for Health Research Biomedical Research Centre, Oxford, grants from John Fell Oxford University Press Research Fund, grants from Cancer Research UK (CR-UK) grant number C5255/A18085, through the Cancer Research UK Oxford Centre, grants from the Oxford Wellcome Institutional Strategic Support Fund (204826/Z/16/Z), during the conduct of the study. Julia Hippisley-Cox is the Chief Investigator for QResearch and Professor in Clinical Epidemiology and General Practice at the University of Oxford. She is a Professorial Fellow and a Trustee of St Anne’s College Oxford and an NHS GP, an Honorary Consultant with NHS England and Oxford Health NHS Foundation Trust. JHC has a 50% shareholding in ClinRisk Ltd, co-owning it with her husband, who is a director. As a shareholder and spouse of a director she has a financial and family interest in the ongoing and future success of the company (outside the scope of this study). The company licences software both to the private sector and to NHS bodies or bodies that provide services to the NHS (through GP electronic health record providers, pharmacies, hospital providers and other NHS providers). This software implements algorithms developed from access to the QResearch database during her time at the University of Nottingham. DS, CZ, AH declare no conflicts of interest.
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Saatci, D., Zhu, C., Harnden, A. et al. Presentation of B-cell lymphoma in childhood and adolescence: a systematic review and meta-analysis. BMC Cancer 24, 718 (2024). https://doi.org/10.1186/s12885-024-12372-w
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DOI: https://doi.org/10.1186/s12885-024-12372-w