Restaging Pediatric Patients Diagnosed with Burkitt Lymphoma using the International Pediatric Non-Hodgkin Lymphoma Staging System and Applying its new Response Criteria

Restaging Pediatric Patients Diagnosed with Burkitt Lymphoma using the International Pediatric Non-Hodgkin Lymphoma Staging System and Applying its new Response Criteria | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Restaging Pediatric Patients Diagnosed with Burkitt Lymphoma using the International Pediatric Non-Hodgkin Lymphoma Staging System and Applying its new Response Criteria Mai Adel, Asmaa Hamoda, Sherif Abou Elnaga, Naglaa Mostafa, Amal Refaat, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8586186/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background: Burkitt lymphoma is the most common mature B-cell lymphoma in children. Accurate staging is essential for risk stratification, treatment planning, and predicting outcomes. The International Pediatric Non-Hodgkin Lymphoma Staging System provides a more detailed assessment compared with the St. Jude/Murphy system.This retrospective study aimed to restage newly diagnosed pediatric BL patients using IPNHLSS and to assess its prognostic value in predicting survival outcomes in a single-institution cohort study. Methods: the study included 100 pediatric BL patients treated according to LMB 96 protocol between 2018 and 2023. All patients were staged using both the St. Jude/Murphy system and IPNHLSS. Clinical characteristics, treatment response, and outcomes were analyzed, and the prognostic impact of the staging systems was compared. Results: Using the St. Jude/Murphy system, patients were distributed as stage III (91%), and IV (6%). When restaged with IPNHLSS , stage III (74%), and stage IV (23%). At a median follow-up of 25months, the 3-year event-free survival (EFS) and overall survival (OS) were 79.7% and 85.8%, respectively. While EFS , according to staging system , 59.5 % stage IV by IPSS , VS 50 % by Murphy , in comparison to 85 % stage III by IPNHLSS , VS 81.1 % by Murphy , with significant p value (0.01). Conclusion: IPNHLSS provides a more precise evaluation of disease extent in pediatric BL, particularly regarding bone marrow involvement, and demonstrates prognostic relevance. Burkitt lymphoma Pediatric oncology International Pediatric Non-Hodgkin Lymphoma Staging System (IPNHLSS) St. Jude/Murphy staging Prognosis Survival outcomes Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Non-Hodgkin lymphomas (NHLs) represent the third most common childhood malignancy, accounting for approximately 7–10% of pediatric cancers worldwide [ 20 ]. Burkitt lymphoma (BL) is the most frequent subtype, characterized by its highly aggressive clinical course and rapid doubling time[34]. Although the disease is potentially curable with intensive, short-duration chemotherapy, accurate staging remains critical for treatment allocation and prognostic assessment. The St. Jude/Murphy staging system, developed in the 1980s, has been the standard approach for classification Murphy [32].While widely adopted, this system primarily reflects tumor bulk and distribution, but it has limitations in describing the complex anatomical and biological features of BL, particularly with regard to bone marrow and central nervous system (CNS) involvement. These limitations may contribute to variability in treatment response and survival outcomes among patients with the same stage. To address these shortcomings, the International Pediatric Non-Hodgkin Lymphoma Staging System (IPNHLSS) was proposed in 2015 to provide a more detailed and standardized framework [77] .Unlike the Murphy system, IPNHLSS incorporates comprehensive radiological, clinical, and pathological criteria, with particular emphasis on extra nodal disease and bone marrow. Early reports suggested that IPNHLSS improved the accuracy of disease stratification and may better reflect prognosis in children with BL and other NHL subtypes [59,77]. However, evidence regarding the practical application and prognostic utility of IPNHLSS in pediatric BL, especially in low- and middle-income countries, remains limited. Evaluating its impact on treatment outcomes compared with the Murphy system is therefore essential. This retrospective study aimed to restage newly diagnosed pediatric BL patients using IPNHLSS and to assess its prognostic value in predicting survival outcomes in a single-institution cohort treated according to the modified LMB 96 protocol. Methodology Study Design and Patients This retrospective study included 100 consecutive pediatric patients newly diagnosed with Burkitt lymphoma (BL) Children Cancer Hospital Egypt (CCHE-57357) ,between January 2019 to December 2023. Eligible patients were aged ≤18 years and had confirmed BL according to the World Health Organization (WHO) 2016 classification. Patients with prior chemotherapy or incomplete clinical records were excluded. Ethical Considerations The study was approved by the Institutional Review Board of Children Cancer Hospital Egypt (CCHE-5735). Written informed consent was obtained from parents or legal guardians, and Consent was obtained from patients when appropriate, in accordance with the Declaration of Helsinki. This research didn’t receive funding. Materials and methods: This retrospective study included 100 patients, with age less than18 years diagnosed with newly diagnosed mature B-Cell NHL (Burkitt lymphoma), treated at the Children’s Cancer Hospital Egypt (CCHE-5735) during the period from January 2019 to December 2023, with minimum one year follow-up from the end of treatment. The institutional review board approved the study, and informed consent was obtained before diagnostic assessment and therapy. Burkitt lymphoma proved by pathology and confirmed with immunophenotyping and Cmyc rearrangement by Fish technique. The following data were collected : 1- Serum Laboratory investigations: CBC, ESR, LDH, Kidney and liver function test and electrolytes. 2-Initial PET-CT whole body for staging. 3-Biopsy from primary site: morphology, immunophenotyping and C myc. 4-BMA and biopsy: with morphology, immunophenotyping , Cmyc rearrangement detection by FISH on BMA sample to asses disease extent and for proper staging. All patients were staged dually according to Murphy’s staging and IPNHLSS. Patients were classified into 3 risk groups as per FAB LMB 96 protocols. Grouping depends on: stage, resection status, percentage of blasts in bone marrow and CNS involvement. 1-Group A: resected stage I and abdominal stage II totally resected. Group B: Patients not eligible for inclusion in group B or C. Group C: Patients with CNS involvement and bone marrow infiltration, but more than 25 % blasts. Treatment and disease assessment All patients were treated according to FAB LMB 96 protocols, details of chemotherapy received are shown in ( Supplementary figure 2 ) . Disease was evaluated post CVP to asses early response to chemotherapy (regarding reduction of the mass assessed by CT scan) and post CYM I (for group B) and post CYVE II (for group C) by PET-CT as per protocol. BMA morphology, immunophenotyping and Cmyc re-arrangement by FISH were repeated for patients who were initially positive. Biopsy from a residual disease either CT-guided or open surgery. If residual proved by pathology in group B, upgrade to group C while if residual in group C , upgrade to salvage RICE and arrange for Allo-BMT. Definitions of disease according to the International Pediatric NHL staging system Response Criteria definitions [77]. CR : disappearance of all disease by imaging ,resected residual mass pathologically negative , BM and CSF free of disease CR b : residual mass has no morphological evidence of disease and no new lesions by imaging , BM and CSF free , no new or progressive disease elsewhere. CR u : residual mass is negative by PET-CT , but not confirmed by biopsy , no new lesions , BM and CSF free of disease PR : partial remission >50 % decrease in lesions size on Computed topography (CT) or magnetic resonant imaging (MRI), may have evidence of disease in BM or CSF, if present at diagnosis, but should have 50 % reduction in percentage of lymphoma cells. no new and /or progressive disease Follow-up and Outcomes Patients were monitored throughout treatment and during follow-up visits every 3 months for the first 2 years and every 6 months thereafter. Median FU=25 months. The primary endpoints were event-free survival (EFS) and overall survival (OS). EFS was defined as the time from diagnosis to disease progression, relapse, secondary malignancy, or death from any cause. OS was defined as the time from diagnosis to death from any cause or last follow-up. Statistical Analysis . All statistical analyses were performed using R version 4.4.1 Descriptive statistics were used to summarize baseline characteristics, including means and standard deviations for Continuous variables (e. g, age) and frequencies with percentages for categorical variables. The primary outcome was Event-Free Survival (EFS), defined as the time from diagnosis to the first event (relapse, disease progression, or death from any cause) or the date of last follow-up. Overall Survival (OS), defined as the time from diagnosis to time of death or the date of last follow-up. OS and EFS was estimated using the Kaplan-Meier method, and survival curves were compared between groups using the log-rank test. Associations between categorical variables using the Chi-square test or Fishers exact test as appropriate. A two-sided p -value <0.05 was considered statistically significant for all analyses. Results The median age of the entire cohort was 9 years (range 3-18),52 % of patients were between 5 and 10 years, with a male: female ratio of 5:1. Sixty percent of patients had high LDH (more than double the normal level) at initial diagnosis. As regards stage distribution, most patients were in Stage III, with 91% according to the Murphy Staging System and 74% by the IPNHLSS. Stage IV had a higher percentage in the IPNHLSS compared to the Murphy Staging System (23% vs 6%). Initial patient and disease characteristics are shown in Table 1. Table (1): Patient demographics and initial presentation N =100 Gender Male 83 (83 %) Female 17 (17 %) Age, y, (mean±SD) (9.65 ±3.7) Age Category 5 < 10 52 (52%) 10 = 15 14 (14%) < 5 3 (3%) Murphy staging system II 3 (3 %) III 91 (91 %) IV 6 (6 %) IPSS staging system II 3 (3%) III 74 (74%) IV 23(23%) LDH Range High 60 (60%) Low 40 (40%) Treatment Grouping Group B 69 (69 %) Group C 31 (31 %) Regarding response to treatment, based on the Murphy Staging System 82 % achieved complete remission (CR), while, as per the IPNHLSS, they divided the reponse criteria into CR ,CR b and CR u , only 28% for CR , and the remaining patients were CRb and CRu (24% and 30%respectively). Eleven patients achieved PR, 6 patients had progressive disease, and 4 patients experienced relapse according to both staging systems. Only one patient died before the assessment time point. (Table 2) , The EFS according to response criteria show that CR which applied in both systems has a 3-year EFS of 85.2% , %). In the IPNHL system, the CRu group has a notably high 3-year EFS of 94.4% (95% CI: 86.95% to 100%), and no events occurred in the CRb group. The CRb category in the IPNHL system represents patients who have achieved a complete response with a biopsy confirming the absence of disease . The absence of events in this group suggests that these patients have a very favorable prognosis, that the CRu group has a higher EFS than the CR group, it is important to consider the sample sizes and the definitions of these categories. The CRu category in the IPNHL system represents patients with an unconfirmed complete response, which might include patients who are very close to achieving a confirmed complete response but have not yet met all the criteria. The high EFS in the CRu group could be influenced by the smaller sample size, which can lead to wider confidence intervals and potentially skewed results. Table (2): Response criteria in both staging systems, and correlation with EFS. Response Criteria Murphy Staging System IPNHL Staging System CR 82(82%) 28(28%) CRb - 24(24%) Cru - 30(30%) PR 11 (11%) 11(11%) PD 6 (6 %) 6 (6%) Total 99 (99%) 99 (99%) Relapse 4(4%) 4(4%) Response Criteria Murphy Staging System EFS IPNHL Staging System EFS CR 3 years=85.2% CRb - No events happen in this group Cru - 94.4% Survival analysis: The median follow-up period of the entire cohort was 25.5 months, with a range of 1.38-59.5 months. The 3-year overall survival (OS) and event-free survival (EFS) for the whole group of patients were 85.8 % and 79.7 % respectively, regardless of the staging system, as shown Figure 1A and Figure 1B Event-Free Survival (EFS) based on Bone Marrow (BM) Infiltration by morphology , Immunophenotyping and PET-CT at initial diagnosis. By applying the IPNHLSS in staging patients at initial diagnosis, among the 100 Burkitt lymphoma patients. EFS according to BM status determined by morphology, comparing patients with positive (n=11) versus negative (n=89) infiltration (p = 0.01) as in figure 2A. EFS according to BM status determined by IPT, comparing patients with positive (n=12) versus negative (n=88) infiltration (p = 0.18) as in figure 2B . and by comparing PET _CT marrow infiltration detection , positive (n=14) versus negative (n=86) infiltration (p = 0.002). By assessing response to treatment at evaluation time points according toLMB 96 Protocol : When disease response to treatment was evaluated by PET-CT and correlated with EFS , patients who achieved a negative PET-CT (n=92) demonstrated significantly better EFS , than positive response (n=7) , (log-rank p = 0.003). One patient was excluded from the analysis as they did not undergo the evaluation scan., as shown in Figure 3. Event free survival according to stages once by Murphy staging system and other IPNHLSS , Figure 4A , 4B . Discussion Burkitt lymphoma (BL) remains the most common subtype of pediatric non-Hodgkin lymphoma, with survival outcomes greatly improved in recent decades due to advances in risk-adapted chemotherapy protocols. However, accurate staging continues to be essential for optimizing therapy while minimizing treatment-related toxicity. In our cohort, the International Pediatric Non-Hodgkin Lymphoma Staging System (IPNHLSS) demonstrated a superior ability to define disease extent compared with the traditional St. Jude/Murphy system. Notably, IPNHLSS identified a higher proportion of patients with bone marrow involvement (44% vs. 32%), resulting in more patients being classified as stage IV. This finding aligns with previous reports suggesting that IPNHLSS provides a more comprehensive assessment of extra nodal disease [59,77].The prognostic significance of IPNHLSS was further reflected in survival analysis, as patients classified as stage IV had significantly inferior EFS and OS compared with stages I–III. Similar results were observed by Cairo et al. [ 16 ], who demonstrated that IPNHLSS stratification correlated more strongly with treatment outcomes than the Murphy system. In contrast, Mechinaud et al. reported comparable predictive value between the two systems, emphasizing the need for validation across diverse cohorts. Recent analyses, including those by Jeon et al.[42] and Kyriakidis et al.[50] support the growing evidence that IPNHLSS can better distinguish high-risk subgroups, reinforcing its clinical utility. Surprisingly, our study results show that, PET-CT–based assessment of treatment response showed no significant correlation with event-free survival (EFS). Patients who were PET-CT negative had an EFS of 77.8%, compared with 80% among PET-CT–positive patients, with a non-significant p-value of 0.73. In pediatric non-Hodgkin lymphoma (NHL), accurate assessment of disease extent is critical for risk stratification and treatment planning. Traditional staging systems, such as the St. Jude/Murphy classification, may underestimate bone marrow involvement, potentially leading to under-staging of patients[16,32]. Recent studies suggest that the International Pediatric Non-Hodgkin Lymphoma Staging System (IPNHLSS) provides a more comprehensive evaluation, identifying a higher proportion of patients with bone marrow infiltration and thus more stage IV cases[2,77] .Bone marrow biopsy remains the gold standard for detecting marrow involvement; however, 18F-FDG PET/CT has emerged as a non-invasive alternative, offering high sensitivity and the ability to assess disease at multiple sites simultaneously [4,43,92].Despite its advantages, PET/CT may yield false-positive results due to inflammatory or reactive changes, highlighting the importance of correlating imaging findings with histopathology for accurate staging [44,68] Accurate identification of bone marrow involvement has prognostic significance, as marrow-positive disease is associated with higher risk and guides the intensity of chemotherapy regimens [24,59].Therefore, combining functional imaging with histopathological evaluation optimizes staging accuracy and supports individualized treatment strategies, ultimately improving survival outcomes in children with NHL [8,33]. Our findings also highlight the feasibility of implementing IPNHLSS in a resource-limited setting. Although advanced imaging modalities such as PET/CT are not universally available, the use of standard radiology combined with bone marrow and CSF evaluation was sufficient to apply the system effectively. This supports its potential for broader use in low- and middle-income countries, where pediatric BL incidence is disproportionately high. Despite these strengths, several limitations should be acknowledged. This was a single-center study with a relatively small sample size, which may restrict the generalizability of results. Furthermore, molecular and genetic markers—such as MYC rearrangements or minimal residual disease evaluation—that may refine prognostic stratification were not routinely assessed. Future multicenter studies integrating biological parameters alongside IPNHLSS are warranted to confirm and extend its prognostic utility. Conclusion In conclusion, the International Pediatric Non-Hodgkin Lymphoma Staging System provides a more precise assessment of disease extent in pediatric Burkitt lymphoma compared with the Murphy system, particularly in detecting bone marrow involvement. Its ability to predict survival outcomes supports its adoption into routine clinical practice. Wider use of IPNHLSS may enhance risk stratification and guide therapeutic decision-making, especially in resource-limited settings. Declarations Author Contribution M.A recruited data , types manuscript , analyze results , typed discussion . A.H. revised results and manuscript , H.A. revised results , discussion and manuscript , S.B did statistical analysis , S.A. revised results and manuscript , N.M. did pathology review and typed report References Adhikary, S. D., Bernard, S., Lopez, H. & Chin, K. J. 2018. Erector spinae plane block versus retrolaminar block: A magnetic resonance imaging and anatomical study. Reg Anesth Pain Med, 43, 756-62. Akhter, S., Bashir, N., Mir, M. H., Manzoor, F., Ayub, M., Rasool, M. T., et al., 2024. Pattern of Bone Marrow Involvement in B-cell Non-Hodgkin’s Lymphoma-Experience from a Tertiary Care Center in North India. J Radiat Res, 15, 64-8. Allen, U. D. & Dierickx, D. 2021. Clinical Features and Diagnostic Considerations. Post-Transplant Lymphoproliferative Disorders. 129-48. Almaimani, J., Tsoumpas, C., Feltbower, R. & Polycarpou, I. 2022. FDG PET/CT versus Bone Marrow Biopsy for Diagnosis of Bone Marrow Involvement in Non-Hodgkin Lymphoma: A Systematic Review. Appl Sc, 12, 540. Badr, S., Abdelwahab, M. & Moustafa, H. 2016. PET/CT in Evaluation Bone Marrow Infiltration in Malignant Lymphoma. Egyptian J Nucl Med, 13, 20. Banerjee, A., Bhuller, K., Sudhir, R. & Bajaj, A. 2021. Diagnostic dilemma of Hodgkin’s lymphoma versus tuberculosis: a case report and review of the literature. J Med Case Rep 15, 1-8. Bedair, H. M., Hendy, O., Wahba, M., Mohsen, Y. & Abuelela, S. 2022. Relationship between C-MYC, BCL-2 and BCL-6 Genetic Abnormalities and Bone Marrow Biopsy in B-Non-Hodgkin Lymphoma. Egypt J Hosp Med, 89, 6239-46. Beishuizen, A., Mellgren, K., Andrés, M., Auperin, A., Bacon, C. M., Bomken, S., et al., 2023. Improving outcomes of childhood and young adult non-Hodgkin lymphoma: 25 years of research and collaboration within the framework of the European Intergroup for Childhood Non-Hodgkin Lymphoma. Lancet Haematol, 10, 213-24. Bender, J. G. 2023. Principles of chemotherapy. J Pediatr Hematol Oncol, 20, 63. Berhan, A., Bayleyegn, B. & Getaneh, Z. 2022. HIV/AIDS Associated Lymphoma. J Pediatr Hematol Oncol, 52, 31-45. Cairo MS, Gerrard M, Sposto R, Auperin A, Pinkerton CR, Michon J, et al. Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents. Blood. 2007;109(7):2736–43. Chu, Y., Liu, Y., Fang, X., Jiang, Y., Ding, M., Ge, X., et al., 2023. The epidemiological patterns of non-Hodgkin lymphoma: global estimates of disease burden, risk factors, and temporal trends. Front oncol, 13, 1059914. Davies, K., Barth, M., Armenian, S., Audino, A. N., Barnette, P., Cuglievan, B., et al., 2020. Pediatric aggressive mature B-cell lymphomas, version 2.2020, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw, 18, 1105-23. A. Sun, N., Zhao, J., Qiao, W., Wang, T. 2015. Predictive Value of Interim PET/CT in DLBCL Treated with R-CHOP: Meta-Analysis. Biomed Res Int, 2015:648572. PMC B. Burggraaff, C., et al. 2018. Predictive value of interim positron emission tomography in diffuse large B-cell lymphoma: a systematic review and meta-analysis. Eur J Nucl Med Mol Imaging, 45(9):1536-48. CYing, Z., Wang, X., Song, Y., et al. 2013. Prognostic value of interim 18F-FDG PET/CT in diffuse large B-cell lymphoma. Chin J Cancer Res, 25(2):188-94. D. Li, H., et al. 2019. Interim PET/CT based on visual and semiquantitative analysis predicts survival in patients with DLBCL. Cancer Med, 8(17):7397-7404. E. Cheng, R., et al. 2024. Prognostic Value of 18F-FDG PET/CT in DLBCL Treated with a Risk-Adapted Immunochemotherapy Regimen. J Nucl Med, 65(5):738-745. F. Adams, H. J. A., Kwee, T. C., et al. 2021. Interim and end-of-treatment PET-CT suffers from high false-positive rates in DLBCL: Biopsy is needed prior to treatment decisions. CancerMed,10(4):1455-1463.PMCG. van der Kouwe, K. M., et al. 2014. The use of FDG-PET in DLBCL: predicting outcome following first line therapy. Cancer Imaging, 14:3. H. Kwon, M., et al. 2016. Different predictive values of interim 18F-FDG PET/CT in germinal center like and non-germinal center like DLBCL. Ann Hematol, 95(3):423-432. Ganapathi, K. A., Brown, L. E., Prakash, S. & Bhargava, P. 2021. New developments in non-Hodgkin lymphoid malignancies. Pathology, 53, 349-66. Gerrard M, Cairo MS, Weston C, McCarthy K, Pinkerton R, Lambilliotte A, et al. Excellent survival following two courses of COPAD chemotherapy in children and adolescents with resected localized B-cell non-Hodgkin's lymphoma: results of the FAB/LMB 96 international study. Br J Haematol. 2008;141(6):840–7. Göçer, M. & Kurtoğlu, E. 2021. Comparison of Bone Marrow Involvement with Bone Marrow Biopsy and PET–CT and Evaluation of Any Effects on Survival in Patients Diagnosed with Hodgkin and Non-Hodgkin Lymphoma. Indian J Hematol Blood Jemal, A., Siegel, R., Ward, E., Hao, Y., Xu, J., Murray, T., et al., 2008. Cancer statistics, 2008. CA Cancer J Clin, 58, 71-96. Jeon, W., Koh, Y. K., Kang, S., Kim, H., Koh, K.-N. & Im, H. J. 2022. Clinical characteristics and treatment outcomes of children and adolescents with aggressive mature B-cell lymphoma: a single-center analysis. Korean Soc Hematol, 57, 41-50. Jitani, A. K., Dutta, S., Mandal, P. K., De, R., Jajodia, E., Baul, S., et al., 2021. Utility of 18F-fluorodeoxyglucose PET-CT scan in detecting bone marrow involvement in lymphoma. Indian J Med Res, 154, 691-8. Kwok, H., Ng, F., Chau, C., Lam, S. & Ma, J. 2022. Multimodality imaging of extra-nodal lymphoma in the head and neck. Clin Radiol, 77, 549-59. Michael, A. A., Balakrishnan, P. & Velusamy, T. 2023. Drug repurposing for hematological malignancies. Drug Repurposing for Emerging Infectious Diseases and Cancer. Springer. 217-52. Prakash, A. 2020. A Comparative Study of Bone Marrow Aspiration, Imprints and Biopsy in Pancytopenia. BLDE (DU). Salem, A. E., Shah, H. R., Covington, M. F., Koppula, B. R., Fine, G. C., Wiggins, R. H., et al., 2022. PET-CT in clinical adult oncology: I. Hematologic malignancies. Cancers, 14, 5941. Sandlund, J. T., Guillerman, R. P., Perkins, S. L., Pinkerton, C. R., Rosolen, A., Patte, C., et al., 2015. International Pediatric Non-Hodgkin Lymphoma Response Criteria. J Clin Oncol, 33, 2106-11. Twa, D. D. 2020. Characterization of programmed death ligands in B-cell non-Hodgkin lymphomas. University of British Columbia. Zanoni, L., Bezzi, D., Nanni, C., Paccagnella, A., Farina, A., Broccoli, A., et al. PET/CT in non-Hodgkin lymphoma: an update. Seminars in nuclear medicine, 2023. Elsevier, 320-51. Additional Declarations No competing interests reported. Supplementary Files annalssupplementary.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 27 Feb, 2026 Reviewers invited by journal 26 Feb, 2026 Editor assigned by journal 20 Feb, 2026 Submission checks completed at journal 20 Feb, 2026 First submitted to journal 12 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8586186","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":598027527,"identity":"95f62531-1af8-4cfe-b2e0-345ed885a153","order_by":0,"name":"Mai Adel","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5ElEQVRIie3OvarCQBCG4ZFAqpG0I0q8hZWFiCB6KxFB21NZT6WNYBs7L2UhhU3QNqCFITfg4VQW/mysxMLd8oD7VlvswzcALtc/TKgaQ+xDK2jv/8rLzYL0KnL2ARsJRBJ8CzJUALVEE5GDaFqRaJuyh7M+ygPH8gch7K42BpKNNNlNMDoqVSYEspWfDERpUp+nWD0EChglpD4TsS/Yu87vKHkMhLENyZ8rCgVNoIlKk4BNpOAUd2OkLPM7ayZJ9Fnow6ZFibNBGCyW3umX+yEFhsOqXr/oCYrN5C2bFZfL5fqqHkAWRssLcsMoAAAAAElFTkSuQmCC","orcid":"","institution":"Children’s Cancer Hospital","correspondingAuthor":true,"prefix":"","firstName":"Mai","middleName":"","lastName":"Adel","suffix":""},{"id":598027528,"identity":"fdd7ffa1-3d1f-43f1-905c-475aac6a4727","order_by":1,"name":"Asmaa Hamoda","email":"","orcid":"","institution":"Children’s Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Asmaa","middleName":"","lastName":"Hamoda","suffix":""},{"id":598027529,"identity":"ded25cc8-0f87-4433-8dc7-cfed2270785e","order_by":2,"name":"Sherif Abou Elnaga","email":"","orcid":"","institution":"Children’s Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Sherif","middleName":"Abou","lastName":"Elnaga","suffix":""},{"id":598027532,"identity":"cbf3d256-a4d1-4db5-9d52-21da42a3d82b","order_by":3,"name":"Naglaa Mostafa","email":"","orcid":"","institution":"Children’s Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Naglaa","middleName":"","lastName":"Mostafa","suffix":""},{"id":598027533,"identity":"398e0cfd-2eb0-41f8-be27-925502642df0","order_by":4,"name":"Amal Refaat","email":"","orcid":"","institution":"Children’s Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Amal","middleName":"","lastName":"Refaat","suffix":""},{"id":598027539,"identity":"c6522f7d-c2c2-42db-97f2-cf1464ab4dda","order_by":5,"name":"Sarah Badawy","email":"","orcid":"","institution":"Children’s Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Sarah","middleName":"","lastName":"Badawy","suffix":""},{"id":598027540,"identity":"0ccdccc5-9f5e-47da-b13c-e14f7deed287","order_by":6,"name":"Hany Abdel Rahman","email":"","orcid":"","institution":"Children’s Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hany","middleName":"Abdel","lastName":"Rahman","suffix":""}],"badges":[],"createdAt":"2026-01-13 01:53:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8586186/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8586186/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104012626,"identity":"ab97357c-c44e-48d1-9e57-153f063fcad8","added_by":"auto","created_at":"2026-03-05 16:10:41","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":87483,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSurvival analysis of the entire Cohort.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA) 3 years Overall survival =85.8 %. \u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eB) 3 years Event-free survival=79.7%.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8586186/v1/3b6cfe4d5bd542286dbe588d.png"},{"id":104012665,"identity":"0bdc3d7a-8dd0-4de7-8e62-87180f43061c","added_by":"auto","created_at":"2026-03-05 16:10:51","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":180554,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA -Impact of positive bone marrow infiltration by morphology , at initial presentation on event-free survival , with p value =0.01\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e. B- Impact of positive bone marrow infiltration by immunophenotyping at initial presentation , on event-free survival.p value 0.18.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eC- Impact of positive bone marrow infiltration at initial presentation ,by PET-CT on event-free survival P.value = 0.002.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8586186/v1/4d1372d2fd0fe77e8a228009.png"},{"id":104012637,"identity":"b0d21a5e-9eeb-408c-97ee-171140646c1b","added_by":"auto","created_at":"2026-03-05 16:10:48","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":43449,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCorrelation of PET-CT-assessed treatment response , with EFS \u0026nbsp;at evaluation time points according to protocol , revealed that a negative PET-CT was associated with significantly superior EFS ( P = 0.003).\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8586186/v1/77a3565f522976b46a4e2802.png"},{"id":104012631,"identity":"28b4b54f-a36b-4bf3-8b8c-a11f934e915b","added_by":"auto","created_at":"2026-03-05 16:10:44","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":61894,"visible":true,"origin":"","legend":"\u003cp\u003eDescribes EFS according to disease stages in both systems , A)EFS stage III in comparison to stage IV ;81.1% VS 50 % ( by Murphy ) .B)EFS stage III in comparison to stage IV; 85% VS 59.5% , by IPSS .with P value \u0026lt;0.005.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8586186/v1/79c715499efe3777f9cf03cb.png"},{"id":106401622,"identity":"085e2a98-7813-4ddd-afcd-4a5da2a8587c","added_by":"auto","created_at":"2026-04-08 09:08:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1451257,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8586186/v1/0f778830-dac7-4e43-aa37-e41ed3af148d.pdf"},{"id":104012633,"identity":"e53b1f25-a997-4079-8c75-a1ef81bf43fb","added_by":"auto","created_at":"2026-03-05 16:10:45","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":377659,"visible":true,"origin":"","legend":"","description":"","filename":"annalssupplementary.docx","url":"https://assets-eu.researchsquare.com/files/rs-8586186/v1/087e65bc1d93565c29d6428c.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Restaging Pediatric Patients Diagnosed with Burkitt Lymphoma using the International Pediatric Non-Hodgkin Lymphoma Staging System and Applying its new Response Criteria","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNon-Hodgkin lymphomas (NHLs) represent the third most common childhood malignancy, accounting for approximately 7\u0026ndash;10% of pediatric cancers worldwide [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Burkitt lymphoma (BL) is the most frequent subtype, characterized by its highly aggressive clinical course and rapid doubling time[34]. Although the disease is potentially curable with intensive, short-duration chemotherapy, accurate staging remains critical for treatment allocation and prognostic assessment.\u003c/p\u003e \u003cp\u003eThe St. Jude/Murphy staging system, developed in the 1980s, has been the standard approach for classification Murphy [32].While widely adopted, this system primarily reflects tumor bulk and distribution, but it has limitations in describing the complex anatomical and biological features of BL, particularly with regard to bone marrow and central nervous system (CNS) involvement. These limitations may contribute to variability in treatment response and survival outcomes among patients with the same stage.\u003c/p\u003e \u003cp\u003eTo address these shortcomings, the International Pediatric Non-Hodgkin Lymphoma Staging System (IPNHLSS) was proposed in 2015 to provide a more detailed and standardized framework [77] .Unlike the Murphy system, IPNHLSS incorporates comprehensive radiological, clinical, and pathological criteria, with particular emphasis on extra nodal disease and bone marrow. Early reports suggested that IPNHLSS improved the accuracy of disease stratification and may better reflect prognosis in children with BL and other NHL subtypes [59,77].\u003c/p\u003e \u003cp\u003eHowever, evidence regarding the practical application and prognostic utility of IPNHLSS in pediatric BL, especially in low- and middle-income countries, remains limited. Evaluating its impact on treatment outcomes compared with the Murphy system is therefore essential.\u003c/p\u003e \u003cp\u003eThis retrospective study aimed to restage newly diagnosed pediatric BL patients using IPNHLSS and to assess its prognostic value in predicting survival outcomes in a single-institution cohort treated according to the modified LMB 96 protocol.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Methodology ","content":"\u003cp\u003e\u003cstrong\u003eStudy Design and Patients\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;This \u0026nbsp;retrospective study included 100 consecutive pediatric patients newly diagnosed with Burkitt lymphoma (BL) Children Cancer Hospital Egypt (CCHE-57357) ,between January 2019 to December 2023. Eligible patients were aged ≤18 years and had confirmed BL according to the World Health Organization (WHO) 2016 classification. Patients with prior chemotherapy or incomplete clinical records were excluded.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Considerations\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;The study was approved by the Institutional Review Board of Children Cancer Hospital Egypt (CCHE-5735).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWritten informed consent was obtained from parents or legal guardians, and Consent was obtained from patients when appropriate, in accordance with the Declaration of Helsinki.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThis research didn’t receive funding.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaterials and methods:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective study included 100 patients, with age less than18 years diagnosed with newly diagnosed mature B-Cell NHL (Burkitt lymphoma), treated at the Children’s Cancer Hospital Egypt (CCHE-5735) during the period from January 2019 to December 2023, with minimum one year follow-up from the end of treatment. The institutional review board approved the study, and informed consent was obtained before diagnostic assessment and therapy. Burkitt lymphoma proved by pathology and confirmed with immunophenotyping and Cmyc rearrangement by Fish technique.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe following data were collected\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;1- Serum Laboratory investigations: CBC, ESR, LDH, Kidney and \u0026nbsp;liver function test and electrolytes.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;2-Initial PET-CT whole body for staging.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3-Biopsy from primary site: morphology, immunophenotyping and C myc.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e4-BMA and biopsy: with morphology, immunophenotyping , Cmyc rearrangement detection by FISH on BMA sample to asses disease extent and for proper staging.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll patients were staged dually according to Murphy’s staging and IPNHLSS.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Patients were classified into 3 risk groups as per FAB LMB 96 protocols. Grouping depends on: stage, resection status, percentage of blasts in bone marrow and CNS involvement.\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003e1-Group A: resected stage I and abdominal stage II totally resected.\u003c/li\u003e\n \u003cli\u003eGroup B: Patients not eligible for inclusion in group B or C.\u003c/li\u003e\n \u003cli\u003eGroup C: Patients with CNS involvement and bone marrow infiltration, but more than 25 % blasts.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment and disease assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients were treated according to FAB LMB 96 protocols, details of chemotherapy received are shown in \u0026nbsp;(\u003cu\u003eSupplementary figure 2 )\u003c/u\u003e. Disease was evaluated post CVP to asses early response to chemotherapy (regarding reduction of the mass assessed by CT scan) and post CYM I (for group B) and post CYVE II (for group C) by PET-CT as per protocol. BMA morphology, immunophenotyping and Cmyc re-arrangement by FISH were repeated for patients who were initially positive.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBiopsy from a residual disease either CT-guided or open surgery. If residual proved by pathology in group B, upgrade to group C while if residual in group C , upgrade to salvage RICE and arrange for Allo-BMT.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDefinitions of disease according to the\u0026nbsp;\u003c/strong\u003eInternational Pediatric NHL staging system Response Criteria definitions [77].\u003c/p\u003e\n\u003cp\u003eCR \u0026nbsp;: disappearance of all disease by imaging ,resected \u0026nbsp;residual mass pathologically negative , BM and CSF free of disease\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCR b : residual mass has no morphological evidence of disease and no new lesions by imaging , BM and CSF free , no new or progressive disease elsewhere.\u003c/p\u003e\n\u003cp\u003eCR u : residual mass is negative by PET-CT , but not confirmed by biopsy , no new lesions , BM and CSF free of disease\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePR :\u003c/em\u003e partial remission \u0026gt;50 % decrease in lesions size on Computed topography (CT) or magnetic resonant imaging (MRI), may have evidence of disease in BM or CSF, if present at diagnosis, but should have 50 % reduction in percentage of lymphoma cells. no new and /or progressive disease\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-up and Outcomes\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Patients were monitored throughout treatment and during follow-up visits every 3 months for the first 2 years and every 6 months thereafter. Median FU=25 months. \u0026nbsp;The primary endpoints were event-free survival (EFS) and overall survival (OS). EFS was defined as the time from diagnosis to disease progression, relapse, secondary malignancy, or death from any cause. OS was defined as the time from diagnosis to death from any cause or last follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eAll statistical analyses were performed using R version 4.4.1 Descriptive statistics were used to summarize baseline characteristics, including means and standard deviations for Continuous variables (e. g, age) and frequencies with percentages for categorical variables. The primary outcome was Event-Free Survival (EFS), defined as the time from diagnosis to the first event (relapse, disease progression, or death from any cause) or the date of last follow-up. Overall Survival (OS), defined as the time from diagnosis to time of death or the date of last follow-up. OS and EFS was estimated using the Kaplan-Meier method, and survival curves were compared between groups using the log-rank test. Associations between categorical variables using the Chi-square test or Fishers exact test as appropriate. A two-sided \u003cem\u003ep\u003c/em\u003e-value\u0026nbsp;\u0026lt;0.05 was considered statistically significant for all analyses.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe median age of the entire cohort was 9 years (range 3-18),52 % of patients were between 5 and 10 years, with a male: female ratio of 5:1. Sixty percent of patients had high LDH (more than double the normal level) at initial diagnosis. As regards stage distribution, most patients were in Stage III, with 91% according to the Murphy Staging System and 74% by the IPNHLSS. Stage IV had a higher percentage in the IPNHLSS compared to the Murphy Staging System (23% vs 6%).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Initial patient and disease characteristics are shown in Table 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable (1):\u003c/strong\u003e Patient demographics and initial presentation\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" style=\"width: 100px;\"\u003e\n \u003cp\u003eN =100\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 26px;\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 73px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 26px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 73px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 26px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 73px;\"\u003e\n \u003cp\u003e83 (83 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 26px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 73px;\"\u003e\n \u003cp\u003e17 (17 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 26px;\"\u003e\n \u003cp\u003eAge, y, (mean\u0026plusmn;SD)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 73px;\"\u003e\n \u003cp\u003e\u0026nbsp;(9.65 \u0026plusmn;3.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 26px;\"\u003e\n \u003cp\u003eAge Category\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 73px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e5 \u0026lt; 10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 73px;\"\u003e\n \u003cp\u003e52 (52%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e10 \u0026lt; 15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e31 (31%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e\u0026gt;= 15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e14 (14%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e\u0026lt; 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e3 (3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 26px;\"\u003e\n \u003cp\u003eMurphy staging system\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 73px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 73px;\"\u003e\n \u003cp\u003e3 (3 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 73px;\"\u003e\n \u003cp\u003e91 (91 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 73px;\"\u003e\n \u003cp\u003e6 (6 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 26px;\"\u003e\n \u003cp\u003eIPSS staging system\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 73px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 26px;\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 73px;\"\u003e\n \u003cp\u003e3 (3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 26px;\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 73px;\"\u003e\n \u003cp\u003e74 (74%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 26px;\"\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 73px;\"\u003e\n \u003cp\u003e23(23%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" style=\"width: 100px;\"\u003e\n \u003cp\u003eLDH Range\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e60 (60%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e40 (40%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" style=\"width: 100px;\"\u003e\n \u003cp\u003eTreatment Grouping\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 26px;\"\u003e\n \u003cp\u003eGroup B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 73px;\"\u003e\n \u003cp\u003e69 (69 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 26px;\"\u003e\n \u003cp\u003eGroup C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 73px;\"\u003e\n \u003cp\u003e31 (31 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eRegarding response to treatment, based on the Murphy Staging System 82 % achieved complete remission (CR), while, as per the IPNHLSS, they divided the reponse criteria into CR ,CR b and CR u \u0026nbsp;, \u0026nbsp; only \u0026nbsp;28% for CR , and the remaining patients were CRb and CRu (24% and 30%respectively). Eleven patients achieved PR, 6 patients had progressive disease, and 4 patients experienced relapse according to both staging systems. Only one patient died before the assessment time point. (Table 2) , The EFS according to response criteria show that CR which applied in both systems has a 3-year EFS of 85.2% , %). In the IPNHL system, the CRu group has a notably high 3-year EFS of 94.4% (95% CI: 86.95% to 100%), and no events occurred in the CRb group.\u003c/p\u003e\n\u003cp\u003eThe CRb category in the IPNHL system represents patients who have achieved a complete response with a biopsy confirming the absence of disease . The absence of events in this group suggests that these patients have a very favorable prognosis, that the CRu group has a higher EFS than the CR group, it is important to consider the sample sizes and the definitions of these categories. The CRu category in the IPNHL system represents patients with an unconfirmed complete response, which might include patients who are very close to achieving a confirmed complete response but have not yet met all the criteria. The high EFS in the CRu group could be influenced by the smaller sample size, which can lead to wider confidence intervals and potentially skewed results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable (2):\u003c/strong\u003e Response criteria in both staging systems, and correlation with EFS.\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eResponse Criteria\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMurphy Staging System\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIPNHL Staging System\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e82(82%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003e28(28%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eCRb\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003e24(24%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eCru\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003e30(30%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003ePR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e11 (11%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003e11(11%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003ePD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e6 (6 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003e\u0026nbsp;6 (6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eTotal\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e99 (99%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003e99 (99%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eRelapse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e4(4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003e4(4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eResponse Criteria\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMurphy Staging System EFS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIPNHL Staging System EFS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e3 years=85.2%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eCRb\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003eNo events happen in this group\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eCru\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003e94.4%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eSurvival analysis:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe median follow-up period of the entire cohort was 25.5 months, with a range of 1.38-59.5 months. The 3-year overall survival (OS) and event-free survival (EFS) for the whole group of patients were 85.8 % and 79.7 % respectively, regardless of the staging system, as shown Figure 1A and Figure 1B\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eEvent-Free Survival (EFS) based on Bone Marrow (BM) Infiltration by morphology , Immunophenotyping and PET-CT at initial diagnosis.\u003c/strong\u003e\u003cbr\u003eBy applying the IPNHLSS in staging patients at initial diagnosis, among the 100 Burkitt lymphoma patients. EFS according to BM status determined by morphology, comparing patients with positive (n=11) versus negative (n=89) infiltration (p = 0.01) as in figure 2A. EFS according to BM status determined by IPT, comparing patients with positive (n=12) versus negative (n=88) infiltration (p = 0.18) as in figure 2B . and by comparing PET _CT marrow infiltration \u0026nbsp; detection , positive (n=14) versus negative (n=86) infiltration (p = 0.002).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eBy assessing response to treatment at evaluation time points according toLMB 96 Protocol :\u0026nbsp;\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWhen \u0026nbsp;disease response to treatment was evaluated by PET-CT \u0026nbsp;and correlated with EFS , patients who achieved a negative PET-CT (n=92) demonstrated significantly better EFS \u0026nbsp;, than positive response (n=7) , (log-rank p = 0.003). One patient was excluded from the analysis as they did not undergo the evaluation scan., as shown in Figure 3.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEvent free survival according to stages once by Murphy staging system and other IPNHLSS , Figure 4A , 4B .\u003c/strong\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eBurkitt lymphoma (BL) remains the most common subtype of pediatric non-Hodgkin lymphoma, with survival outcomes greatly improved in recent decades due to advances in risk-adapted chemotherapy protocols. However, accurate staging continues to be essential for optimizing therapy while minimizing treatment-related toxicity.\u003c/p\u003e \u003cp\u003eIn our cohort, the International Pediatric Non-Hodgkin Lymphoma Staging System (IPNHLSS) demonstrated a superior ability to define disease extent compared with the traditional St. Jude/Murphy system. Notably, IPNHLSS identified a higher proportion of patients with bone marrow involvement (44% vs. 32%), resulting in more patients being classified as stage IV. This finding aligns with previous reports suggesting that IPNHLSS provides a more comprehensive assessment of extra nodal disease [59,77].The prognostic significance of IPNHLSS was further reflected in survival analysis, as patients classified as stage IV had significantly inferior EFS and OS compared with stages I\u0026ndash;III. Similar results were observed by Cairo et al. [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e16\u003c/span\u003e], who demonstrated that IPNHLSS stratification correlated more strongly with treatment outcomes than the Murphy system. In contrast, Mechinaud et al. reported comparable predictive value between the two systems, emphasizing the need for validation across diverse cohorts. Recent analyses, including those by Jeon et al.[42] and Kyriakidis et al.[50] support the growing evidence that IPNHLSS can better distinguish high-risk subgroups, reinforcing its clinical utility.\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eSurprisingly, our study results show that, PET-CT\u0026ndash;based assessment of treatment response showed no significant correlation with event-free survival (EFS). Patients who were PET-CT negative had an EFS of 77.8%, compared with 80% among PET-CT\u0026ndash;positive patients, with a non-significant p-value of 0.73.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eIn pediatric non-Hodgkin lymphoma (NHL), accurate assessment of disease extent is critical for risk stratification and treatment planning. Traditional staging systems, such as the St. Jude/Murphy classification, may underestimate bone marrow involvement, potentially leading to under-staging of patients[16,32]. Recent studies suggest that the International Pediatric Non-Hodgkin Lymphoma Staging System (IPNHLSS) provides a more comprehensive evaluation, identifying a higher proportion of patients with bone marrow infiltration and thus more stage IV cases[2,77] .Bone marrow biopsy remains the gold standard for detecting marrow involvement; however, 18F-FDG PET/CT has emerged as a non-invasive alternative, offering high sensitivity and the ability to assess disease at multiple sites simultaneously [4,43,92].Despite its advantages, PET/CT may yield false-positive results due to inflammatory or reactive changes, highlighting the importance of correlating imaging findings with histopathology for accurate staging [44,68] Accurate identification of bone marrow involvement has prognostic significance, as marrow-positive disease is associated with higher risk and guides the intensity of chemotherapy regimens [24,59].Therefore, combining functional imaging with histopathological evaluation optimizes staging accuracy and supports individualized treatment strategies, ultimately improving survival outcomes in children with NHL [8,33].\u003c/p\u003e \u003cp\u003eOur findings also highlight the feasibility of implementing IPNHLSS in a resource-limited setting. Although advanced imaging modalities such as PET/CT are not universally available, the use of standard radiology combined with bone marrow and CSF evaluation was sufficient to apply the system effectively. This supports its potential for broader use in low- and middle-income countries, where pediatric BL incidence is disproportionately high.\u003c/p\u003e \u003cp\u003eDespite these strengths, several limitations should be acknowledged. This was a single-center study with a relatively small sample size, which may restrict the generalizability of results. Furthermore, molecular and genetic markers\u0026mdash;such as MYC rearrangements or minimal residual disease evaluation\u0026mdash;that may refine prognostic stratification were not routinely assessed. Future multicenter studies integrating biological parameters alongside IPNHLSS are warranted to confirm and extend its prognostic utility.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, the International Pediatric Non-Hodgkin Lymphoma Staging System provides a more precise assessment of disease extent in pediatric Burkitt lymphoma compared with the Murphy system, particularly in detecting bone marrow involvement. Its ability to predict survival outcomes supports its adoption into routine clinical practice. Wider use of IPNHLSS may enhance risk stratification and guide therapeutic decision-making, especially in resource-limited settings.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eM.A recruited data , types manuscript , analyze results , typed discussion . A.H. revised results and manuscript , H.A. revised results , discussion and manuscript , S.B did statistical analysis , S.A. revised results and manuscript , N.M. did pathology review and typed report\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eAdhikary, S. D., Bernard, S., Lopez, H. \u0026amp; Chin, K. J. 2018. Erector spinae plane block versus retrolaminar block: A magnetic resonance imaging and anatomical study. \u003cem\u003eReg Anesth Pain Med,\u003c/em\u003e 43, 756-62.\u003c/li\u003e\n \u003cli\u003eAkhter, S., Bashir, N., Mir, M. H., Manzoor, F., Ayub, M., Rasool, M. T., et al., 2024. Pattern of Bone Marrow Involvement in B-cell Non-Hodgkin\u0026rsquo;s Lymphoma-Experience from a Tertiary Care Center in North India. \u003cem\u003eJ Radiat Res,\u003c/em\u003e 15, 64-8.\u003c/li\u003e\n \u003cli\u003eAllen, U. D. \u0026amp; Dierickx, D. 2021. Clinical Features and Diagnostic Considerations. \u003cem\u003ePost-Transplant Lymphoproliferative Disorders.\u003c/em\u003e 129-48.\u003c/li\u003e\n \u003cli\u003eAlmaimani, J., Tsoumpas, C., Feltbower, R. \u0026amp; Polycarpou, I. 2022. FDG PET/CT versus Bone Marrow Biopsy for Diagnosis of Bone Marrow Involvement in Non-Hodgkin Lymphoma: A Systematic Review. \u003cem\u003eAppl Sc,\u003c/em\u003e 12, 540.\u003c/li\u003e\n \u003cli\u003eBadr, S., Abdelwahab, M. \u0026amp; Moustafa, H. 2016. PET/CT in Evaluation Bone Marrow Infiltration in Malignant Lymphoma. \u003cem\u003eEgyptian J Nucl Med,\u003c/em\u003e 13, 20.\u003c/li\u003e\n \u003cli\u003eBanerjee, A., Bhuller, K., Sudhir, R. \u0026amp; Bajaj, A. 2021. Diagnostic dilemma of Hodgkin\u0026rsquo;s lymphoma versus tuberculosis: a case report and review of the literature. \u003cem\u003eJ Med Case Rep\u0026nbsp;\u003c/em\u003e15, 1-8.\u003c/li\u003e\n \u003cli\u003eBedair, H. M., Hendy, O., Wahba, M., Mohsen, Y. \u0026amp; Abuelela, S. 2022. Relationship between C-MYC, BCL-2 and BCL-6 Genetic Abnormalities and Bone Marrow Biopsy in B-Non-Hodgkin Lymphoma. \u003cem\u003eEgypt J Hosp Med,\u003c/em\u003e 89, 6239-46.\u003c/li\u003e\n \u003cli\u003eBeishuizen, A., Mellgren, K., Andr\u0026eacute;s, M., Auperin, A., Bacon, C. M., Bomken, S., et al., 2023. Improving outcomes of childhood and young adult non-Hodgkin lymphoma: 25 years of research and collaboration within the framework of the European Intergroup for Childhood Non-Hodgkin Lymphoma. \u003cem\u003eLancet Haematol,\u003c/em\u003e 10, 213-24.\u003c/li\u003e\n \u003cli\u003eBender, J. G. 2023. Principles of chemotherapy. \u003cem\u003eJ Pediatr Hematol Oncol,\u003c/em\u003e 20, 63.\u003c/li\u003e\n \u003cli\u003eBerhan, A., Bayleyegn, B. \u0026amp; Getaneh, Z. 2022. HIV/AIDS Associated Lymphoma. \u003cem\u003eJ Pediatr Hematol Oncol,\u003c/em\u003e 52, 31-45.\u003c/li\u003e\n \u003cli\u003eCairo MS, Gerrard M, Sposto R, Auperin A, Pinkerton CR, Michon J, et al. Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents. \u003cem\u003eBlood.\u003c/em\u003e 2007;109(7):2736\u0026ndash;43.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eChu, Y., Liu, Y., Fang, X., Jiang, Y., Ding, M., Ge, X., et al., 2023. The epidemiological patterns of non-Hodgkin lymphoma: global estimates of disease burden, risk factors, and temporal trends. \u003cem\u003eFront oncol,\u003c/em\u003e 13, 1059914.\u003c/li\u003e\n \u003cli\u003eDavies, K., Barth, M., Armenian, S., Audino, A. N., Barnette, P., Cuglievan, B., et al., 2020. Pediatric aggressive mature B-cell lymphomas, version 2.2020, NCCN clinical practice guidelines in oncology. \u003cem\u003eJ Natl Compr Cancer Netw,\u003c/em\u003e 18, 1105-23.\u003c/li\u003e\n \u003cli\u003eA. Sun, N., Zhao, J., Qiao, W., Wang, T. 2015. Predictive Value of Interim PET/CT in DLBCL Treated with R-CHOP: Meta-Analysis. Biomed Res Int, 2015:648572. PMC\u003cbr\u003e B. Burggraaff, C., et al. 2018. Predictive value of interim positron emission tomography in diffuse large B-cell lymphoma: a systematic review and meta-analysis. Eur J Nucl Med Mol Imaging, 45(9):1536-48.\u003cbr\u003e CYing, Z., Wang, X., Song, Y., et al. 2013. Prognostic value of interim 18F-FDG PET/CT in diffuse large B-cell lymphoma. Chin J Cancer Res, 25(2):188-94.\u003cbr\u003e D. Li, H., et al. 2019. Interim PET/CT based on visual and semiquantitative analysis predicts survival in patients with DLBCL. Cancer Med, 8(17):7397-7404.\u003cbr\u003e E. Cheng, R., et al. 2024. Prognostic Value of 18F-FDG PET/CT in DLBCL Treated with a Risk-Adapted Immunochemotherapy Regimen. J Nucl Med, 65(5):738-745.\u003cbr\u003e F. Adams, H. J. A., Kwee, T. C., et al. 2021. Interim and end-of-treatment PET-CT suffers from high false-positive rates in DLBCL: Biopsy is needed prior to treatment decisions. CancerMed,10(4):1455-1463.PMCG. van der Kouwe, K. M., et al. 2014. The use of FDG-PET in DLBCL: predicting outcome following first line therapy. Cancer Imaging, 14:3.\u003cbr\u003e H. Kwon, M., et al. 2016. Different predictive values of interim 18F-FDG PET/CT in germinal center like and non-germinal center like DLBCL. Ann Hematol, 95(3):423-432.\u003c/li\u003e\n \u003cli\u003eGanapathi, K. A., Brown, L. E., Prakash, S. \u0026amp; Bhargava, P. 2021. New developments in non-Hodgkin lymphoid malignancies. \u003cem\u003ePathology,\u003c/em\u003e 53, 349-66.\u003c/li\u003e\n \u003cli\u003eGerrard M, Cairo MS, Weston C, McCarthy K, Pinkerton R, Lambilliotte A, et al. Excellent survival following two courses of COPAD chemotherapy in children and adolescents with resected localized B-cell non-Hodgkin\u0026apos;s lymphoma: results of the FAB/LMB 96 international study. \u003cem\u003eBr J Haematol.\u003c/em\u003e 2008;141(6):840\u0026ndash;7.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eG\u0026ouml;\u0026ccedil;er, M. \u0026amp; Kurtoğlu, E. 2021. Comparison of Bone Marrow Involvement with Bone Marrow Biopsy and PET\u0026ndash;CT and Evaluation of Any Effects on Survival in Patients Diagnosed with Hodgkin and Non-Hodgkin Lymphoma. \u003cem\u003eIndian J Hematol Blood\u0026nbsp;\u003c/em\u003e\u003c/li\u003e\n \u003cli\u003eJemal, A., Siegel, R., Ward, E., Hao, Y., Xu, J., Murray, T., et al., 2008. Cancer statistics, 2008. \u003cem\u003eCA Cancer J Clin,\u003c/em\u003e 58, 71-96.\u003c/li\u003e\n \u003cli\u003eJeon, W., Koh, Y. K., Kang, S., Kim, H., Koh, K.-N. \u0026amp; Im, H. J. 2022. Clinical characteristics and treatment outcomes of children and adolescents with aggressive mature B-cell lymphoma: a single-center analysis. \u003cem\u003eKorean Soc Hematol,\u003c/em\u003e 57, 41-50.\u003c/li\u003e\n \u003cli\u003eJitani, A. K., Dutta, S., Mandal, P. K., De, R., Jajodia, E., Baul, S., et al., 2021. Utility of 18F-fluorodeoxyglucose PET-CT scan in detecting bone marrow involvement in lymphoma. \u003cem\u003eIndian J Med Res,\u003c/em\u003e 154, 691-8.\u003c/li\u003e\n \u003cli\u003eKwok, H., Ng, F., Chau, C., Lam, S. \u0026amp; Ma, J. 2022. Multimodality imaging of extra-nodal lymphoma in the head and neck. \u003cem\u003eClin Radiol,\u003c/em\u003e 77, 549-59.\u003c/li\u003e\n \u003cli\u003eMichael, A. A., Balakrishnan, P. \u0026amp; Velusamy, T. 2023. Drug repurposing for hematological malignancies. \u003cem\u003eDrug Repurposing for Emerging Infectious Diseases and Cancer.\u003c/em\u003e Springer. 217-52.\u003c/li\u003e\n \u003cli\u003ePrakash, A. 2020. \u003cem\u003eA Comparative Study of Bone Marrow Aspiration, Imprints and Biopsy in Pancytopenia.\u003c/em\u003e BLDE (DU).\u003c/li\u003e\n \u003cli\u003eSalem, A. E., Shah, H. R., Covington, M. F., Koppula, B. R., Fine, G. C., Wiggins, R. H., et al., 2022. PET-CT in clinical adult oncology: I. Hematologic malignancies. \u003cem\u003eCancers,\u003c/em\u003e 14, 5941.\u003c/li\u003e\n \u003cli\u003eSandlund, J. T., Guillerman, R. P., Perkins, S. L., Pinkerton, C. R., Rosolen, A., Patte, C., et al., 2015. International Pediatric Non-Hodgkin Lymphoma Response Criteria. \u003cem\u003eJ Clin Oncol,\u003c/em\u003e 33, 2106-11.\u003c/li\u003e\n \u003cli\u003eTwa, D. D. 2020. \u003cem\u003eCharacterization of programmed death ligands in B-cell non-Hodgkin lymphomas.\u003c/em\u003e University of British Columbia.\u003c/li\u003e\n \u003cli\u003eZanoni, L., Bezzi, D., Nanni, C., Paccagnella, A., Farina, A., Broccoli, A., et al. PET/CT in non-Hodgkin lymphoma: an update. Seminars in nuclear medicine, 2023. Elsevier, 320-51.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Burkitt lymphoma, Pediatric oncology, International Pediatric Non-Hodgkin Lymphoma Staging System (IPNHLSS), St. Jude/Murphy staging, Prognosis, Survival outcomes","lastPublishedDoi":"10.21203/rs.3.rs-8586186/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8586186/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e\u003cbr\u003e\nBurkitt lymphoma is the most common mature B-cell lymphoma in children. Accurate staging is essential for risk stratification, treatment planning, and predicting outcomes. The International Pediatric Non-Hodgkin Lymphoma Staging System provides a more detailed assessment compared with the St. Jude/Murphy system.This \u003cstrong\u003eretrospective study\u003c/strong\u003e aimed to \u003cstrong\u003erestage newly diagnosed pediatric BL patients using IPNHLSS\u003c/strong\u003e and to \u003cstrong\u003eassess its prognostic value\u003c/strong\u003e in predicting survival outcomes in a single-institution cohort study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003cbr\u003e\nthe study included 100 pediatric BL patients treated according to LMB 96 protocol between 2018 and 2023. All patients were staged using both the St. Jude/Murphy system and IPNHLSS. Clinical characteristics, treatment response, and outcomes were analyzed, and the prognostic impact of the staging systems was compared.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003cbr\u003e\nUsing the St. Jude/Murphy system, patients were distributed as stage III (91%), and IV (6%). When restaged with IPNHLSS , stage III (74%), and stage IV (23%). At a median follow-up of 25months, the 3-year event-free survival (EFS) and overall survival (OS) were 79.7% and 85.8%, respectively. While EFS , according to staging system , 59.5 % stage IV by IPSS , VS 50 % by Murphy , in comparison to 85 % stage III by IPNHLSS , VS 81.1 % by Murphy , with significant p value (0.01).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003cbr\u003e\nIPNHLSS provides a more precise evaluation of disease extent in pediatric BL, particularly regarding bone marrow involvement, and demonstrates prognostic relevance.\u003c/p\u003e","manuscriptTitle":"Restaging Pediatric Patients Diagnosed with Burkitt Lymphoma using the International Pediatric Non-Hodgkin Lymphoma Staging System and Applying its new Response Criteria","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-05 16:10:00","doi":"10.21203/rs.3.rs-8586186/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"5622136959840580510273535198429034636","date":"2026-02-27T09:01:51+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-26T19:54:32+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-20T13:37:28+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-20T13:35:32+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Hematology","date":"2026-01-13T01:40:05+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"4b231246-30a9-4202-a675-a5be57e89160","owner":[],"postedDate":"March 5th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-05T16:10:01+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-05 16:10:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8586186","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8586186","identity":"rs-8586186","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}