Abstract

Background. Inborn errors of immunity (IEIs) frequently manifest with lymphoproliferative disorders (LPDs) ranging from benign polyclonal hyperplasia to aggressive lymphomas. Distinguishing reactive from neoplastic LPDs is challenging due to overlapping clinical presentations, atypical histology and viral drivers, especially EBV.

Scope. This review summarizes evidence on benign and malignant LPDs in IEIs, delineating pathogenic mechanisms (genetic defects, viral oncogenesis, microenvironmental changes) and highlighting diagnostic pitfalls, including Hodgkin-like masquerades, paracortical immunoblastic proliferations, polymorphic EBV-positive lesions with clonal findings, T-cell expansions and gastrointestinal or granulomatous mimics.

Recommendations. We advocate a structured, multidisciplinary approach — comprehensive clinical and immunologic assessment, routine EBV/HHV-8 testing (EBER and quantitative PCR), excisional biopsy with detailed histology, immunophenotyping, clonality and targeted genomic analyses. Management should be individualized, balancing immune-directed therapy and targeted agents (e.g., PI3Kδ inhibitors, abatacept, sirolimus) with conventional oncologic treatment and hematopoietic stem cell transplantation when appropriate.

Conclusions. Integrated clinicopathologic and molecular evaluation, registries, and validated biomarkers are essential to improve diagnosis, guide therapy, and reduce morbidity in patients with IEI-associated LPDs

References

  1. Bousfiha AA, Jeddane L, Moundir A, et al. The 2024 update of IUIS phenotypic classification of human inborn errors of immunity. J Hum Immun 2025;1:e20250002. https://doi.org/10.70962/jhi.20250002.
  2. Poli MC, Aksentijevich I, Bousfiha AA, et al. Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee. J Hum Immun 2025;1:e20250003. https://doi.org/10.70962/jhi.20250003.
  3. Sharma S, Pilania RK, Anjani G, et al. Lymphoproliferation in Inborn Errors of Immunity: The Eye Does Not See What the Mind Does Not Know. Front Immunol 2022;13:856601. https://doi.org/10.3389/fimmu.2022.856601.
  4. Costagliola G, Peroni DG, Consolini R. Beyond Infections: New Warning Signs for Inborn Errors of Immunity in Children. Front Pediatr 2022;10:855445. https://doi.org/10.3389/fped.2022.855445.
  5. Mauracher AA, Gujer E, Bachmann LM, et al. Patterns of Immune Dysregulation in Primary Immunodeficiencies: a Systematic Review. J Allergy Clin Immunol Pract 2021;9:792-802.e10. https://doi.org/10.1016/j.jaip.2020.10.057.
  6. Hägele P, Staus P, Scheible R, et al. Diagnostic evaluation of paediatric autoimmune lymphoproliferative immunodeficiencies (ALPID): a prospective cohort study. Lancet Haematol 2024;11:e114-e126. https://doi.org/10.1016/S2352-3026(23)00362-9.
  7. Natkunam Y, Gratzinger D, Chadburn A, et al. Immunodeficiency-associated lymphoproliferative disorders: time for reappraisal? Blood 2018;132:1871-1878. https://doi.org/10.1182/blood-2018-04-842559.
  8. Forbes LR, Eckstein OS, Gulati N, et al. Genetic errors of immunity distinguish pediatric non-malignant lymphoproliferative disorders. J Allergy Clin Immunol 2022;149:758-766. https://doi.org/10.1016/j.jaci.2021.07.015.
  9. Costagliola G, De Marco E, Consonni F, et al. Inborn errors of immunity presenting with lymphoproliferation: lessons from a case series. Ann Hematol 2025;104:3117-3127. https://doi.org/10.1007/s00277-025-06456-1.
  10. Kiykim A, Eker N, Surekli O, et al. Malignancy and lymphoid proliferation in primary immune deficiencies; hard to define, hard to treat. Pediatr Blood Cancer 2020;67:e28091. https://doi.org/10.1002/pbc.28091.
  11. Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia 2022;36:1720-1748. https://doi.org/10.1038/s41375-022-01620-2.
  12. Smith T, Cunningham-Rundles C. Lymphoid malignancy in common variable immunodeficiency in a single-center cohort. Eur J Haematol 2021;107:503-516. https://doi.org/10.1111/ejh.13687.
  13. Tralongo P, Bakacs A, Larocca LM. EBV-related lymphoproliferative diseases: a review in light of new classifications. Mediterr J Hematol Infect Dis 2024;16:e2024042. https://doi.org/10.4084/MJHID.2024.042.
  14. Costagliola G, Consolini R. Lymphadenopathy at the crossroad between immunodeficiency and autoinflammation: an intriguing challenge. Clin Exp Immunol 2021;205:288-305. https://doi.org/10.1111/cei.13620.
  15. Hauck F, Voss R, Urban C, et al. Intrinsic and extrinsic causes of malignancies in patients with primary immunodeficiency disorders. J Allergy Clin Immunol 2018;141:59-68.e4. https://doi.org/10.1016/j.jaci.2017.06.009.
  16. Herber M, Mertz P, Dieudonné Y, et al. Primary immunodeficiencies and lymphoma: a systematic review of literature. Leuk Lymphoma 2020;61:274-284. https://doi.org/10.1080/10428194.2019.1672056.
  17. Riaz IB, Faridi W, Patnaik MM, et al. A Systematic Review on Predisposition to Lymphoid (B and T cell) Neoplasias in Patients With Primary Immunodeficiencies and Immune Dysregulatory Disorders (Inborn Errors of Immunity). Front Immunol 2019;10:777. https://doi.org/10.3389/fimmu.2019.00777.
  18. Maccari ME, Wolkewitz M, Schwab C, et al. Activated phosphoinositide 3-kinase δ syndrome: Update from the ESID Registry and comparison with other autoimmune-lymphoproliferative inborn errors of immunity. J Allergy Clin Immunol 2023;152:984-996.e10. https://doi.org/10.1016/j.jaci.2023.06.015.
  19. Yakaboski E, Fuleihan RL, Sullivan KE, et al. Lymphoproliferative Disease in CVID: a Report of Types and Frequencies from a US Patient Registry. J Clin Immunol. 2020;40:524-530. https://doi.org/10.1007/s10875-020-00769-8.
  20. Moratti M, Schifino G, Baccelli F, et al. Granulomatous lymphocytic interstitial lung disease in common variable immune deficiency: an in-depth clinical, immunological, functional and radiological exploration with a focus on its management, challenged by chronic CMV infection. Front Immunol 2025;16:1589052. https://doi.org/10.3389/fimmu.2025.1589052.
  21. Weiss LM, O’Malley D. Benign lymphadenopathies. Mod Pathol. 2013;26:S88-S96. https://doi.org/10.1038/modpathol.2012.176.
  22. Toskov V, Ehl S. Autoimmune lymphoproliferative immunodeficiencies (ALPID) in childhood: breakdown of immune homeostasis and immune dysregulation. Mol Cell Pediatr 2023;10:11. https://doi.org/10.1186/s40348-023-00167-1.
  23. Carbone A, Chadburn A, Gloghini A, et al. Immune deficiency/dysregulation -associated lymphoproliferative disorders. Revised classification and management. Blood Rev 2024;64:101167. https://doi.org/10.1016/j.blre.2023.101167.
  24. Suarez F, Mahlaoui N, Canioni D, et al. Incidence, presentation, and prognosis of malignancies in ataxia-telangiectasia: a report from the French national registry of primary immune deficiencies. J Clin Oncol Off J Am Soc Clin Oncol 2015;33:202-208. https://doi.org/10.1200/JCO.2014.56.5101.
  25. Mortaz E, Tabarsi P, Mansouri D, et al. Cancers Related to Immunodeficiencies: Update and Perspectives. Front Immunol 2016;7:365-365. https://doi.org/10.3389/fimmu.2016.00365.
  26. Bleesing JJ, Nagaraj CB, Zhang K. Autoimmune Lymphoproliferative Syndrome. In: GeneReviews® [Internet]. University of Washington, Seattle, 2017. https://www.ncbi.nlm.nih.gov/sites/books/NBK1108/ (Accessed on: August 19, 2025).
  27. Lucas CL, Kuehn HS, Zhao F, et al. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency. Nat Immunol 2014;15:88-97. https://doi.org/10.1038/ni.2771.
  28. Bomken S, van der Werff Ten Bosch J, Attarbaschi A, et al. Current Understanding and Future Research Priorities in Malignancy Associated With Inborn Errors of Immunity and DNA Repair Disorders: The Perspective of an Interdisciplinary Working Group. Front Immunol 2018;9:2912. https://doi.org/10.3389/fimmu.2018.02912.
  29. Ravell JC, Chauvin SD, He T, et al. An Update on XMEN Disease. J Clin Immunol 2020;40:671-681. https://doi.org/10.1007/s10875-020-00790-x.
  30. Tatfi M, Hermine O, Suarez F. Epstein-Barr Virus (EBV)-Related Lymphoproliferative Disorders in Ataxia Telangiectasia: Does ATM Regulate EBV Life Cycle? Front Immunol 2019;9:3060. https://doi.org/10.3389/fimmu.2018.03060.
  31. Farrell PJ. Epstein-Barr Virus and Cancer. Annu Rev Pathol 2019;14:29-53. https://doi.org/10.1146/annurev-pathmechdis-012418-013023.
  32. Carpier JM, Lucas CL. Epstein-Barr Virus Susceptibility in Activated PI3Kδ Syndrome (APDS) Immunodeficiency. Front Immunol 2017;8:2005. https://doi.org/10.3389/fimmu.2017.02005.
  33. Takahara T, Satou A, Tsuzuki T, et al. Hodgkin Lymphoma: Biology and Differential Diagnostic Problem. Diagnostics 2022;12:1507. https://doi.org/10.3390/diagnostics12061507.
  34. Bertuzzi C, Righi S, Motta G, et al. Microenvironmental Traits of Classical Hodgkin’s Lymphoma in Adolescents and Their Prognostic Impact. Cancers. 2024;16:4210. https://doi.org/10.3390/cancers16244210.
  35. Chan JKC, Kwong YL. Common misdiagnoses in lymphomas and avoidance strategies. Lancet Oncol 2010;11:579-588. https://doi.org/10.1016/S1470-2045(09)70351-1.
  36. Costagliola G, De Marco E, Massei F, et al. The Etiologic Landscape of Lymphoproliferation in Childhood: Proposal for a Diagnostic Approach Exploring from Infections to Inborn Errors of Immunity and Metabolic Diseases. Ther Clin Risk Manag 2024;20:261-274. https://doi.org/10.2147/TCRM.S462996.
  37. Catelli A, Nanni C, Mulè R, et al. The Dark Side of Activated Phosphoinositide 3-Kinase-δ Syndrome 2: a Story Rewritten through FDG-PET. J Clin Med 2024;13:2203. https://doi.org/10.3390/jcm13082203.
  38. Slatter MA, Angus B, Windebank K, et al. Polymorphous lymphoproliferative disorder with Hodgkin-like features in common γ-chain-deficient severe combined immunodeficiency. J Allergy Clin Immunol 2011;127:533-535. https://doi.org/10.1016/j.jaci.2010.09.036.
  39. Conti F, Catelli A, Cifaldi C, et al. Case Report: Hodgkin Lymphoma and Refractory Systemic Lupus Erythematosus Unveil Activated Phosphoinositide 3-Kinase-δ Syndrome 2 in an Adult Patient. Front Pediatr 2021;9:702546. https://doi.org/10.3389/fped.2021.702546.
  40. Barzaghi F, Moratti M, Panza G, et al. Report of the Italian Cohort with Activated Phosphoinositide 3-Kinase δ Syndrome in the Target Therapy Era. J Clin Immunol 2024;45:58. https://doi.org/10.1007/s10875-024-01835-1.
  41. Nicolae A, Sabattini E, Ponzoni M, et al. Lymphadenitis/Reactive-Hyperplasia, Mimickers of Lymphomas, Low-Grade B-Cell Lymphomas, and Hodgkin Lymphoma. Hemato 2024;5:350-379. https://doi.org/10.3390/hemato5030026.
  42. Bosch-Schips J, Granai M, Quintanilla-Martinez L, et al. The Grey Zones of Classic Hodgkin Lymphoma. Cancers 2022;14:742. https://doi.org/10.3390/cancers14030742.
  43. Gibson SE, Dojcinov S, Dotlic S, et al. Mediastinal large B cell lymphoma and surrounding gray areas: a report of the lymphoma workshop of the 20th meeting of the European Association for Haematopathology. Virchows Arch Int J Pathol 2023;483:733-749. https://doi.org/10.1007/s00428-023-03550-5.
  44. Rieux-Laucat F, Bahadoran P, Brousse N, et al. Highly restricted human T cell repertoire in peripheral blood and tissue-infiltrating lymphocytes in Omenn’s syndrome. J Clin Invest 1998;102:312-321. https://doi.org/10.1172/JCI332.
  45. Lim MS, Straus SE, Dale JK, et al. Pathological findings in human autoimmune lymphoproliferative syndrome. Am J Pathol 1998;153:1541-1550. https://doi.org/10.1016/S0002-9440(10)65742-2.
  46. Ho H en, Cunningham-Rundles C. Non-infectious Complications of Common Variable Immunodeficiency: Updated Clinical Spectrum, Sequelae, and Insights to Pathogenesis. Front Immunol 2020;11:149. https://doi.org/10.3389/fimmu.2020.00149.
  47. Fevang B, Fagerli UM, Sorte H, et al. Runaway Train: a Leaky Radiosensitive SCID with Skin Lesions and Multiple Lymphomas. Case Rep Immunol 2018;2018:2053716. https://doi.org/10.1155/2018/2053716.
  48. Taylor AM, Metcalfe JA, Thick J, et al. Leukemia and lymphoma in ataxia telangiectasia. Blood 1996;87:423-438.
  49. Velthof L, Geldof J, Truyens M, et al. Gastrointestinal Disease in Common Variable Immunodeficiency Disorder (CVID): Histological Patterns, Diagnostic Clues and Pitfalls for the Pathologist and Gastroenterologist. J Clin Med 2025;14:497. https://doi.org/10.3390/jcm14020497.
  50. Buchbinder D, Hauck F, Albert MH, et al. Rubella Virus-Associated Cutaneous Granulomatous Disease: a Unique Complication in Immune-Deficient Patients, Not Limited to DNA Repair Disorders. J Clin Immunol 2019;39:81-89. https://doi.org/10.1007/s10875-018-0581-0.
  51. Thomas Junior DS, Chai J, Lu YJ. The development and applications of circulating tumour cells, circulating tumour DNA and other emerging biomarkers for early cancer detection. Explor Target Anti-Tumor Ther 2025;6:1002314. https://doi.org/10.37349/etat.2025.1002314.
  52. Rivalta B, Moratti M, Conti F. I disordini linfoproliferativi come espressione di immunodeficit primitivi: dalla diagnosi alla terapia mirata. Ital J Pediatr Allergy Immunol 2022;:9-16. https://doi.org/10.53151/2531-3916/2022-2.
  53. Albert MH, Sirait T, Eikema DJ, et al. Hematopoietic stem cell transplantation for adolescents and adults with inborn errors of immunity: an EBMT IEWP study. Blood 2022;140:1635-1649. https://doi.org/10.1182/blood.2022015506.
  54. Fox TA, Massey V, Lever C, et al. Pre-Transplant Immune Dysregulation Predicts for Poor Outcome Following Allogeneic Haematopoietic Stem Cell Transplantation in Adolescents and Adults with Inborn Errors of Immunity (IEI). J Clin Immunol 2025;45:64. https://doi.org/10.1007/s10875-024-01854-y.

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Mattia Moratti - Department of Biomedicine and Prevention, PhD in Immunology, Molecular Medicine and Applied Biotechnology, University of Rome Tor Vergata, Rome, Italy https://orcid.org/0000-0003-1133-9563

Francesca Conti - Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, University of Bologna, Bologna, Italy https://orcid.org/0000-0002-3665-8926

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Moratti, M., & Conti, F. (2025). Lymphoproliferative Patterns as Diagnostic Dilemmas in Inborn Errors of Immunity . Italian Journal of Pediatric Allergy and Immunology, 39(3). https://doi.org/10.53151/2531-3916/2025-1627
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