Diagnosis of Metachronous Classical and Nodular Lymphocyte-Predominant Hodgkin Lymphomas: A Case Report and Pathogenetic Issues

Among В-cell tumors, there are composite/discordant lymphomas characterized by either synchronous or metachronous development, however, a combination of nodular lymphocyte-predominant Hodgkin lymphoma with classical Hodgkin lymphoma is extremely rare. This paper documents a similar case. It provides evidence for ‘plasticity’ of B-cell precursors, which can initiate lymphoid tumor growth at various stages of B-cell differentiation.

• Irina Aleksandrovna Shupletsova National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 https://orcid.org/0000-0003-0922-9314 (unauthenticated)
• A.M. Kovrigina National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; IM Sechenov First Moscow State Medical University, 2 korp. 4 Bolshaya Pirogovskaya ul., Moscow, Russian Federation, 119435 https://orcid.org/0000-0002-1082-8659 (unauthenticated)
• Yu.V. Sidorova National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 https://orcid.org/0000-0003-1936-0084 (unauthenticated)
• E.I. Dorokhina National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 https://orcid.org/0000-0002-5795-170X (unauthenticated)
• T.N. Moiseeva National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 https://orcid.org/0000-0001-9591-8508 (unauthenticated)

1. De Jong D, Gujral S. Hodgkin lymphoma: Introduction. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours. Revised 5th edn. Lyon: IARC Press; 2024. pp. 579.
2. Шуплецова И.А., Ковригина А.М. Характеристика и частота диагностики вариантов вирус Эпштейна—Барр-позитивной лимфомы Ходжкина с лимфоидным преобладанием в структуре лимфомы Ходжкина. Гематология и трансфузиология. 2021;66(4):567–79. doi: 10.35754/0234-5730-2021-66-4-567-579. [Shupletsova I.A., Kovrigina A.M. The characterization and frequency of diagnosis of EBV-positive variants with a lymphoid predominance in the structure of Hodgkin lymphoma. Russian journal of hematology and transfusiology. 2021;66(4):567–79. doi: 10.35754/0234-5730-2021-66-4-567-579. (In Russ)]. DOI: https://doi.org/10.35754/0234-5730-2021-66-4-567-579
3. Küppers R, Rajewsky K, Zhao M, et al. Hodgkin disease: Hodgkin and Reed-Sternberg cells picked from histological sections show clonal immunoglobulin gene rearrangements and appear to be derived from B cells at various stages of development. Proc Natl Acad Sci USA. 1994;91(23):10962–6. doi: 10.1073/pnas.91.23.10962. DOI: https://doi.org/10.1073/pnas.91.23.10962
4. Custer R. Pitfalls in the diagnosis of lymphoma and leukemia from the pathologist’s point of view. 2nd National Cancer Conference, New York; 1954. pp. 554–7.
5. Kim H, Hendrickson R, Dorfman RF. Composite lymphoma. Cancer. 1977;40(3):959–76. doi: 10.1002/1097-0142(197709)40:3<959::aid-cncr2820400302>3.0.co;2-3. DOI: https://doi.org/10.1002/1097-0142(197709)40:3<959::AID-CNCR2820400302>3.0.CO;2-3
6. Thirumala S, Esposito M, Fuchs A. An unusual variant of composite lymphoma: a short case report and review of the literature. Arch Pathol Lab Med. 2000;124(9):1376–8. doi: 10.5858/2000-124-1376-AUVOCL. DOI: https://doi.org/10.5858/2000-124-1376-AUVOCL
7. Gelb AB, Dorfman RF, Warnke RA. Coexistence of nodular lymphocyte predominance Hodgkin’s disease and Hodgkin’s disease of the usual type. Am J Surg Pathol. 1993;17(4):364–74. doi: 10.1097/00000478-199304000-00007. DOI: https://doi.org/10.1097/00000478-199304000-00007
8. Song JY, Eberle FC, Xi L, et al. Coexisting and clonally identical classic Hodgkin lymphoma and nodular lymphocyte predominant Hodgkin lymphoma. Am J Surg Pathol. 2011;35(5):767–72. doi: 10.1097/PAS.0b013e3182147f91. DOI: https://doi.org/10.1097/PAS.0b013e3182147f91
9. Szczepanowski M, Masqué-Soler N, Oschlies I, et al. Composite lymphoma of nodular lymphocyte-predominant and classical Hodgkin lymphoma-Epstein-Barr virus association suggests divergent pathogenesis despite clonal relatedness. Hum Pathol. 2013;44(7):1434–9. doi: 10.1016/j.humpath.2012.11.018. DOI: https://doi.org/10.1016/j.humpath.2012.11.018
10. Ding Y, Campbell A, Zhang X, et al. Metachronous and clonally related classic Hodgkin lymphoma and nodular lymphocyte predominant Hodgkin lymphoma. Pathology. 2021;53(2):285–8. doi: 10.1016/j.pathol.2020.06.019. DOI: https://doi.org/10.1016/j.pathol.2020.06.019
11. Miettinen M, Franssila KO, Saxén E. Hodgkin’s disease, lymphocytic predominance nodular. Increased risk for subsequent non-Hodgkin’s lymphomas. Cancer. 1983;51(12):2293–300. doi: 10.1002/1097-0142(19830615)51:12<2293::aid-cncr2820511221>3.0.co;2-x. DOI: https://doi.org/10.1002/1097-0142(19830615)51:12<2293::AID-CNCR2820511221>3.0.CO;2-X
12. Van Dongen JJ, Langerak AW, Brüggemann M, et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia. 2003;17(12):2257–317. doi: 10.1038/sj.leu.2403202. DOI: https://doi.org/10.1038/sj.leu.2403202
13. Jaffe ES, Zarate-Osorno A, Kingma DW, et al. The interrelationship between Hodgkin’s disease and non-Hodgkin’s lymphomas. Ann Oncol. 1994;5(Suppl 1):7–11. doi: 10.1093/annonc/5.suppl_1.s7. DOI: https://doi.org/10.1093/annonc/5.suppl_1.S7
14. Küppers R, Dührsen U, Hansmann ML. Pathogenesis, diagnosis, and treatment of composite lymphomas. Lancet Oncol. 2014;15(10):e435–e446. doi: 10.1016/S1470-2045(14)70153-6. DOI: https://doi.org/10.1016/S1470-2045(14)70153-6
15. Eichenauer DA, Engert A. How I treat nodular lymphocyte-predominant Hodgkin lymphoma. Blood. 2020;136(26):2987–93. doi: 10.1182/blood.2019004044. DOI: https://doi.org/10.1182/blood.2019004044
16. Lossos IS, Jiang X, Patel K, et al. Association Between Moraxella catarrhalis and Nodular Lymphocyte-Predominant Hodgkin Lymphoma. Am J Hematol. 2025;100(9):1543–56. doi: 10.1002/ajh.27762. DOI: https://doi.org/10.1002/ajh.27762
17. Jaffe ES, Carbone A. B- and T-/NK-Cell Lymphomas in the 2022 International Consensus Classification of Mature Lymphoid Neoplasms and Comparison with the WHO Fifth Edition. Hemato. 2024;5(2):157–70. doi: 10.3390/hemato5020013. DOI: https://doi.org/10.3390/hemato5020013
18. Hartmann S, Bronchmann P, Borges AM, et al. Nodular lymphocyte-predominant Hodgkin lymphoma: Introduction. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours. Revised 5th edn. Lyon: IARC Press; 2024. pp. 591–7.
19. Saarinen S, Pukkala E, Vahteristo P, et al. High familial risk in nodular lymphocyte-predominant Hodgkin lymphoma. J Clin Oncol. 2013;31(7):938–43. doi: 10.1200/JCO.2012.43.5958. DOI: https://doi.org/10.1200/JCO.2012.43.5958
20. Thurner L, Hartmann S, Fadle N, et al. Lymphocyte predominant cells detect Moraxella catarrhalis-derived antigens in nodular lymphocyte-predominant Hodgkin lymphoma. Nat Commun. 2020;11(1):2465. doi: 10.1038/s41467-020-16375-6. DOI: https://doi.org/10.1038/s41467-020-16375-6
21. Thurner L, Fadle N, Regitz E, et al. B-cell receptor reactivity against Rothia mucilaginosa in nodular lymphocyte-predominant Hodgkin lymphoma. Haematologica. 2023;108(12):3347–58. doi: 10.3324/haematol.2023.282698. DOI: https://doi.org/10.3324/haematol.2023.282698
22. Brune V, Tiacci E, Pfeil I, et al. Origin and pathogenesis of nodular lymphocyte-predominant Hodgkin lymphoma as revealed by global gene expression analysis. J Exp Med. 2008;205(10):2251–68. doi: 10.1084/jem.20080809. DOI: https://doi.org/10.1084/jem.20080809
23. Trecourt A, Mauduit C, Szablewski V, et al. Plasticity of Mature B Cells Between Follicular and Classic Hodgkin Lymphomas: A Series of 22 Cases Expanding the Spectrum of Transdifferentiation. Am J Surg Pathol. 2022;46(1):58–70. doi: 10.1097/PAS.0000000000001780. DOI: https://doi.org/10.1097/PAS.0000000000001780