Childhood Lymphoproliferative Disorders with Inborn Errors of Immunity from the Perspective of Oncology

Year 2025, Volume: 22 Issue: 3, 426 - 434, 29.09.2025

Elif Habibe Aktekin , Bermal Hasbay , Nalan Yazıcı , Nazım Emrah Koçer , Ayşe Erbay

https://doi.org/10.35440/hutfd.1625940

Abstract

Background: Malignancy is an important issue for immunodeficiency patients and management could be challenging. This study aims to review inborn errors of immunity (IEI) patients with lymphoprolife-rative disorders.
Materials and Methods: Age at diagnosis, gender, type of immunodeficiency, tumor type and loca-tion, Ebstein-Barr virus (EBV) status, comorbidity, treatment schemes for malignancy, and follow-up time were evaluated in 12 patients between 2007-2023, retrospectively.
Results: Ten of twelve patients (83,3%) were male. Median age was 8 years. In terms of immunodefi-ciency type, 11 had a definitive diagnosis of IEI, 5 of which had DNA repair defects. One had been diagnosed with DOCK8 disorder without any history of frequent and/or severe infections previously. Nine patients (75%) were diagnosed with IEI after malignancy. Lymphoma was the leading lymphopro-liferative disorder (n=10) and most of them were diffuse large B-cell lymphoma (n=4). Lymphoid nodal involvement was the prominent location (n=9), but primary central nervous system and gastric mucosal involvement were unusual. Three patients were EBV positive. All patients were treated with several chemotherapy regimens. Median follow-up time was 32,6 months. Seven patients (58.3%) died because of infection or malignancy or other causes. All other patients are still under follow-up with disease-free. The 5-year event-free survival was 38.9% and overall survival was 51.9%.
Conclusions: All patients with IEI should be monitored for malignancy. Furthermore patients with unusual findings of malignancy shouldalso be examined for IEI.

Keywords

Ebstein-Barr virus , inborn errors of immunity , DOCK8 disorder , lymphoproliferative disorder , malignancy

Onkoloji Perspektifinden Konjenital İmmün Yetmezliklerle Birlikteliği Olan Çocukluk Çağı Lenfoproliferatif Bozuklukları

Abstract

Amaç: Malignite, immün yetmezlik hastaları için önemli bir sorundur ve yönetimi zor olabilir. Bu çalışma, lenfoproliferatif bozuklukları olan konjenital immun yetmezlik (KIY) hastalarını incelemeyi amaçlamaktadır.
Materyal ve Metod: 2007-2023 yılları arasında 12 hastada tanı yaşı, cinsiyet, immün yetmezlik türü, tümör çeşidi ve yeri, Ebstein-Barr virüs (EBV) durumu, eşlik eden hastalıklar, malignite için tedavi şemaları ve takip süresi retrospektif olarak değerlendirildi.
Bulgular: On iki hastanın on tanesi (%83,3) erkekti. Ortanca yaş 8 idi. İmmün yetmezlik türü açısından 11 hastaya kesin KIY tanısı kondu, bunların beşinde DNA onarım kusurları vardı. Birine daha önce sık ve/veya şiddetli enfeksiyon öyküsü olmadan DOCK8 bozukluğu tanısı konuldu. Dokuz hastaya (%75) malignite tanısından sonra KIY tanısı kondu. Lenfoma en sık saptanan lenfoproliferatif bozukluk (n=10) olup çoğu diffüz büyük B hücreli lenfomaydı (n=4). Lenfoid nodal tutulum en sık tümör yerleşim yeri (n=9) olmakla birlikte primer merkezi sinir sistemi ve gastrik mukozal tutulumlar alışılmışın dışında idi. Üç hastada EBV pozitif saptandı. Tüm hastalara çeşitli kemoterapi rejimleri uygulandı. Ortanca takip süresi 32,6 aydır. Yedi hasta (%58,3) enfeksiyon veya malignite veya diğer nedenlerden dolayı öldü. Diğer tüm hastalar hala hastalıksız olarak takip altındadır. 5 yıllık olaysız sağkalım %38,9 ve genel sağkalım %51,9 idi.
Sonuç: Konjenital immun yetmezlik tanılı tüm hastalar malignite gelişimi açısından izlenmelidir. Ayrıca, beklenenden farklı malignite özellikleri sergileyen hastalar da immun yetmezlikler açısından incelenmelidir.

Keywords

Ebstein-Barr virüs , konjenital immun yetmezlikler , DOCK8 bozukluğu , lenfoproliferatif hastalıklar , malignite

References

• 1. Mueller BU, Pizzo PA. Cancer in children with primary or secondary immunodeficiency. J Pediatr. 1995;126:1-10.
• 2. Sanchez-Ramon S, Bermudez A, Gonzalez-Granado LI, ID-Signal Onco-Haematology Group. Primary and secondary im-munodeficiency diseases in oncohaematology: Warning signs, diagnosis, and management. Front Immunol. 2019;10:586.
• 3. Notarangelo LD. PIDs and cancer: an evolving story. Blood. 2010;116(8):1189-90.
• 4. Hsu JL, Glaser SL. Epstein-Barr virus-associated malignancies: epidemiologic patterns and etiologic implications. Crit Rev Oncol/Hematol. 2000;34:27-53.
• 5. Kebudi R, Kiykim A, Şahin MK. Primary immunodeficiency and cancer in children: a review of the literature. Curr Pedi-atr Rev. 2019;15(4):245-50.
• 6. Seidel MG, Kindle G, Gathmann B,Quinti I, Buckland M, vanMontfrans J, et al. The European Society for Immunodefi-ciencies (ESID) registry working definitions for the clinical di-agnosis of inborn errors of immunity. J Allergy Clin Immunol Pract. 2019;7:1763-70.
• 7. Bousfiha A, Moundir A, Tangye SG, Picard C, Jeddane L, Al-Herz W, et al. The 2022 update of IUIS phenotypical classifi-cation for human inborn errors of immunity. J Clin Immunol. 2022;42(7):1508-20.
• 8. Chapel H, Lucas M, Lee M,Bjorkander J, Webster D, Grim-bacher B, et al. Common variable immunodeficiency disor-ders: division into distinct clinical phenotypes. Blood. 2008;112(2):277-286.
• 9. Leeksma OC, de Miranda NF, Veelken H. Germline mutations predisposing to diffuse large B-cell lymphoma. Blood Cancer J. 2017;7(2):e532.
• 10. Ballow M, Sanchez-Ramon S, Walter JE. Secondary immune-deficiency and primary immunodeficiency crossovers: hema-tological malignancies and autoimmune diseases. Front Im-munol. 2022;13:928062.
• 11. Wimmer K, Etzler J. Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg? Hum Genet. 2008;124(2):105-122.
• 12. Tesch VK, IJspeert H, Raicht A, Rueda D, Dominguez-Pinilla N, Allende LM, et al. No overt clinical immunodeficiency despi-te immune biological abnormalities in patients with consti-tutional mismatch repair deficiency. Front Immunol. 2018;9:1506.
• 13. Peron S, Metin A, Gardes P, Alyanakian MA, Sheridan E, Kratz CP, et al. Human PMS2 deficiency is associated with impai-red immunoglobulin class switch recombination. J Exp Med. 2008;205(11):2465-72.
• 14. Gardes P, Forveille M, Alyanakian MA, Aucouturier P, Ilenci-kova D, Leroux D, et al. Human MSH6 deficiency is associa-ted with impaired antibody maturation. J Immunol. 2012;188(4):2023-29.
• 15. Wehr C, Houet L, Unger S,Kindle G, Golgacker S, Grimbacher B, et al. Altered spectrum of lymphoid neoplasms in a single-center cohort of common variable immunodeficiency with immunedysregulation. J Clin Immunol. 2021;41(6):1250-65.
• 16. Herber M, Mertz P, Dieudonne Y,Guffroy B, Jung S, Gies V, et al. Primary immunodeficiencies and lymphoma: a systematic review of literature. Leuk Lymphoma. 2020;61(2):274-84.
• 17. Latour S, Winter S. Inherited immunodeficiencies with high predisposition to Epstein-Barr Virus-driven lymphoprolifera-tive diseases. Front Immunol. 2018;9:1103.
• 18. Aydin SE, Kilic SS, Aytekin C, Kumar A, Porras O, Renner ED, et al. DOCK8 deficiency: clinical and immunological phe-notype and treatment options – a review of 136 patients. J Clin Immunol. 2015;35(2):189- 198.
• 19. Engelhardt KR, Gertz ME, Keles S, Schaffer AA, Sigmund EC, Glocker C, et al. The extended clinical phenotype of 64 pa-tients with dedicator of cytokinesis 8 deficiency. J Allergy Clin Immunol. 2015; 136(2):402-12.
• 20. Keles S, Chatila T. Combine immunodeficiency due to DOCK8 deficiency: a tribute to Prof. Isil Berat Barlan, M.D. Turkish Journal of Immunology. 2015;3(2):76-83.
• 21. Al Shekaili L, Sheikh F, Al Gazlan S, Al Dhekri H, Al Mousa H, Al Ghonaium A, et al. Novel mutation in DOCK8-HIES with severe phenotype and successful transplantation. Clin Im-munol. 2017;178:39-44.
• 22. Kienzler AK, vanSchouwenburg PA, Taylor J, Marwah I, Shar-ma RU, Noakes C, et al. Hypomorphic function and somatic reversion of DOCK8 cause combined immunodeficiency wit-hout hyper-IgE. Clin Immunol. 2016;163:17-21.
• 23. Krgovic D, Vokac NK, Zagorac A, Kumperscak HG. Rare struc-tural variants in the DOCK8 gene identified in a cohort of 439 patients with neurodevelopmental disorders. Sci Rep. 2018;8(1):9449.
• 24. Glessner JT, Li J, Wang D, March M, March M, Lima L, Desai A, et al. ; Janssen-CHOP Neuropsychiatric Genomics Working Group. Copy number variation meta-analysis reveals a novel duplication at 9p24 associated with multipl neurodevelop-mental disorders. Genome Med. 2017;9(1):106.