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Germinotropic lymphoproliferative disorder: a systematic review

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Abstract

Germinotropic lymphoproliferative disorder is a rare and rather enigmatic novel entity with distinctive clinicopathological features, one of which is the typical co-infection by Human herpesvirus 8 and Epstein-Barr virus. Human herpesvirus 8 is a lymphotropic virus detected in Kaposi sarcoma, multicentric Castleman disease, primary effusion lymphoma, Human herpesvirus 8-positive diffuse large B cell lymphoma not otherwise specified, and germinotropic lymphoproliferative disorder. Co-infection by Human herpesvirus 8 and Epstein-Barr virus is identified only in two lymphoproliferative diseases: germinotropic lymphoproliferative disorder and primary effusion lymphoma, which are otherwise diseases with totally different clinical presentations and outcomes. Unlike primary effusion lymphoma mostly occurring in immunocompromised individuals and following an aggressive course, germinotropic lymphoproliferative disorder usually presents with single or multiple lymphadenopathy affecting mainly immunocompetent individuals and mostly follows an indolent course. Based on the PRISMA guidelines, we carried out a systematic search on PubMed/MEDLINE, Web of Science, Scopus, EMBASE, and Cochrane Library using the search terms “germinotropic” and “lymphoproliferative disorder.” Current scientific literature reports just 19 cases of germinotropic lymphoproliferative disorder. The purpose of our systematic review is to improve our understanding of the disease, focusing on epidemiology, clinical presentation, pathological features, treatment, and outcome. In addition, we discuss the differential diagnosis with the other Human herpesvirus 8-related lymphoproliferative diseases as currently recognized in the World Health Organization classification, adding a focus on lymphoproliferative disorders showing overlapping features.

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References

  1. Swerdlow SH (2017) WHO classification of tumours of haematopoietic and lymphoid tissues, 4th edn. International Agency for Research on Cancer, Lyon, France

    Google Scholar 

  2. Du MQ, Diss TC, Liu H et al (2002) KSHV and EBV-associated germinotropic lymphoproliferative disorder. Blood. 100:3415–3418

    Article  CAS  Google Scholar 

  3. D’Antonio A, Boscaino A, Addesso M et al (2007) KSHV and EBV-associated germinotropic lymphoproliferative disorder: a rare lymphoproliferative disease of HIV patients with plasmablastic morphology, indolent course and favourable response to therapy. Leuk Lymphoma 48(7):1444–1447

    Article  Google Scholar 

  4. Oh J, Yoon H, Shin DK, Jang MJ, Kim GI, Chong SY, Oh D (2012) A case of successful management of HHV-8+, EBV+ germinotropic lymphoproliferative disorder (GLD). Int J Hematol 95:107–111

    Article  Google Scholar 

  5. Courville EL, Sohani AR, Hasserjian RP, Zukerberg LR, Harris NL, Ferry JA (2014) Diverse clinicopathologic features in Human herpesvirus 8-associated lymphomas lead to diagnostic problems. Am J Clin Pathol 142:816–829

    Article  Google Scholar 

  6. Taris M, de Mascarel A, Riols M, Delwail V, Milpied N, Dubus P, Parrens M (2014) KHSV/EBV associated germinotropic lymphoproliferative disorder: a rare entity, case report and review of the literature. Ann Pathol 34(5):373–377

    Article  Google Scholar 

  7. Papoudou-Bai A, Hetzimichael E, Kyriazopoulou L et al (2015) Rare variants in the spectrum of Human herpesvirus 8/Epstein-Barr virus-co-positive lymphoproliferations. Hum Pathol 46:1566–1571

    Article  CAS  Google Scholar 

  8. Bhavsar T, Lee JC, Perner Y, Raffeld M, Xi L, Pittaluga S, Jaffe ES (2017) KSHV and EBV-associated germinotropic lymphoproliferative disorder: new findings and review of the literature. Am J Surg Pathol 41(6):795–800

    Article  Google Scholar 

  9. Bacha D, Chelly B, Kilani H, Charfi L, Douggaz A, Chatti S, Chelbi E (2017) HHV8/EBV coinfection lymphoproliferative disorder: rare entity with a favorable outcome. Case Rep Hematol 2017:1–8. https://doi.org/10.1155/2017/1578429

    Article  Google Scholar 

  10. Ronaghy A, Wang HY, Thorson JA, Medeiros LJ, Xie Y, Zhang X, Sheikh-Fayyaz S (2017) PD-L1 and Notch1 expression in KSHV/HHV-8 and EBV associated germinotropic lymphoproliferative disorder: case report and review of the literature. Pathology. 49(4):430–434

    Article  CAS  Google Scholar 

  11. Gonzalez-Farre B, Martinez D, Lopez-Guerra M, Xipell M, Monclus E, Rovira J, Garcia F, Lopez-Guillermo A, Colomo L, Campo E, Martinez A (2017) HHV8-related lymphoid proliferations: a broad spectrum of lesions from reactive lymphoid hyperplasia to overt lymphoma. Mod Pathol 30:745–760

    Article  CAS  Google Scholar 

  12. Zanelli M, Fraternali Orcioni G, Zizzo M, de Marco L, Martino G, Cerrone G, Cabras AD, Ascani S (2019) HHV-8 and EBV-positive germinotropic lymphoproliferative disorder. Ann Hematol 98(10):2439–2441

    Article  Google Scholar 

  13. Calabrò ML, Sarid R (2018) Human herpesvirus 8 lymphoproliferative disorders. Mediterr J Hematol Infect Dis 10(1). https://doi.org/10.4084/MJHD.2018.061

  14. Vega F, Miranda RN, Medeiros LJ (2019) KSHV/HHV8-positive large B-cell lymphomas and associated diseases: a heterogeneous group of lymphoproliferative processes with significant clinicopathological overlap. Mod Pathol 33(1):18–28

  15. Wang W, Kanagal-Shamanna R, Medeiros LJ (2018) Lymphoproliferative disorders with concurrent HHV8 and EBV infection: beyond primary effusion lymphoma and germinotropic lymphoproliferative disorder. Histopathology. 72:855–861

    Article  Google Scholar 

  16. Simonelli C, Spina M, Cinelli R, Talamini R, Tedeschi R, Gloghini A, Vaccher E, Carbone A, Tirelli U (2003) Clinical features and outcome of primary effusion lymphoma in HIV-infected patients: a single institution study. J Clin Oncol 21:3948–3954

    Article  Google Scholar 

  17. Chadburn A, Hyjek E, Mathew S, Cesarman E, Said J, Knowles DM (2004) KSHV-positive solid lymphomas represent an extracavitary variant of primary effusion lymphoma. Am J Surg Pathol 28:1401–1416

    Article  Google Scholar 

  18. Lorenzi L, Lonardi S, Essatari MHM, Pellegrini V, Fisogni S, Gazzola A, Agostinelli C, Vermi W, Rossi G, Massarelli G, Pileri SA, Facchetti F (2016) Intrafollicular Epstein-Barr virus-positive large B cell lymphoma. A variant of “germinotropic” lymphoproliferative disorder. Virchows Arch 468:441–450

    Article  CAS  Google Scholar 

  19. Suster S (1992) Large cell lymphoma of the mediastinum with marked tropism for germinal centers. Cancer 69(12):2910–2916

    Article  CAS  Google Scholar 

  20. Ferry JA, Sohani AR, Longtine JA, Schwartz RA, Harris NL (2009) HHV8-positive, EBV-positive Hodgkin lymphoma-like large B cell lymphoma and HHV8-positive intravascular large B-cell lymphoma. Mod Pathol 22:618–626

    Article  Google Scholar 

  21. Crane GM, Ambinder RF, Shirley CM, Fishman EK, Kasamon YL, Taube JM, Borowitz MJ, Duffield AS (2014) HHV8-positive and EBV-positive intravascular lymphoma: an unusual presentation of extracavitary primary effusion lymphoma. Am J Surg Pathol 38:426–432

    Article  Google Scholar 

  22. Seliem RM, Griffith RC, Harris NL, Beheshti J, Schiffman FJ, Longtine J, Kutok J, Ferry JA (2007) HHV8+, EBV+ multicentric plasmablastic microlymphoma in an HIV+ man: the spectrum of HHV8+ lymphoproliferative disorders expands. Am J Surg Pathol 31:1439–1445

    Article  Google Scholar 

  23. Peker D, Alkan S, Zhang L et al (2012) HIV-associated plasmablastic multicentric Castleman disease with microlymphoma coinfected with hhv8 and EBV. J Hematop 6:109–114

    Article  Google Scholar 

  24. Lee YM, Kim JM, Kim SY (2017) Human herpes virus 8/Epstein-Barr virus-copositive, plasmablastic microlymphoma arising in multicentric Castleman disease of an immunocompetent patient. J Pathol Transl Med 51:99–102

    Article  Google Scholar 

  25. Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles D, Moore P (1994) Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma. Science. 266:1865–1869

    Article  CAS  Google Scholar 

  26. Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM (1995) Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med 332:1186–1191

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We are grateful to Christen Kisch for the linguistic support to the manuscript.

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Authors and Affiliations

  1. Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy

    Magda Zanelli, Alessandra Bisagni, Elisabetta Froio, Loredana De Marco & Riccardo Valli

  2. Surgical Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy

    Maurizio Zizzo

  3. Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy

    Maurizio Zizzo

  4. Pathology Unit, Area Vasta 5 (Ascoli Piceno-San Benedetto del Tronto), Ascoli Piceno, Italy

    Alessandra Filosa

  5. Hematology, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy

    Stefano Luminari & Fulvio Massaro

  6. Hematology Unit, CREO, Azienda Ospedaliera di Perugia, University of Perugia, Perugia, Italy

    Giovanni Martino

  7. Pathology Unit, St. Eugenio Hospital, Rome, Italy

    Stefano Fratoni

  8. Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, Terni, Italy

    Stefano Ascani

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  1. Magda Zanelli
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  2. Maurizio Zizzo
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  9. Giovanni Martino
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  11. Stefano Fratoni
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Contributions

ZaM and AS had the idea for the article. ZiM, BA, FE, DL, VR, FA, LS, MG, MF, and FS performed the literature search. ZiM performed the data analysis. ZaM drafted the work. AS critically revised the work.

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Correspondence to Magda Zanelli.

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Zanelli, M., Zizzo, M., Bisagni, A. et al. Germinotropic lymphoproliferative disorder: a systematic review. Ann Hematol 99, 2243–2253 (2020). https://doi.org/10.1007/s00277-020-04024-3

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  • DOI: https://doi.org/10.1007/s00277-020-04024-3

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