Advertisement

Prognostic markers for immunodeficiency-associated primary central nervous system lymphoma

  • Leon D. Kaulen
  • Daniela Galluzzo
  • Pei Hui
  • Frank Barbiero
  • Philipp Karschnia
  • Anita Huttner
  • Robert Fulbright
  • Joachim M. BaehringEmail author
Clinical Study

Abstract

Background

Immunodeficiency is a major risk factor for primary central nervous system lymphoma (PCNSL), but data on the disease in immunocompromised hosts are scarce. We aimed to define clinical and imaging features and determine prognostic factors for immunodeficiency-associated PCNSL.

Methods

All PCNSL cases seen at Yale-New Haven Hospital between 2002 and 2017 were retrospectively screened for immunodeficiency. For patients with immunosuppression, biopsies were evaluated and clinical data were collected. Predictors of survival were identified using Kaplan–Meier survival analysis and log-rank test. p values < 0.05 were considered significant.

Results

23 patients with immunodeficiencies were identified: eleven on immunosuppressants after solid organ transplantation, seven with human immunodeficiency virus infection, and five on immunosuppressive treatment due to various autoimmune disorders. PCNSL cases were largely Epstein-Barr-Virus positive (78%), histologically classified as diffuse large B cell lymphomas (87%), and showed peripheral contrast enhancement (81%) and corresponding heterogeneous diffusion-weighted imaging patterns (DWI) on magnetic resonance imaging (MRI) (71%). Median overall survival was 31 months. Age > 60 years at diagnosis (p < 0.01), peripheral enhancement of the mass on MRI (p = 0.04), heterogeneous DWI patterns (p = 0.04), and clonal immunoglobulin heavy chain gene rearrangement (IgHR) (p = 0.03) were found to be negative prognostic markers.

Conclusions

Immunodeficiency-associated PCNSL presents with similar clinical, pathological and imaging features. Age > 60 years, clonal IgHR, heterogeneous DWI pattern and peripheral enhancement on MRI may serve as predictors of less favorable outcome.

Keywords

Primary central nervous system (CNS) lymphoma Organ transplantation HIV Autoimmune diseases Immunosuppression Diffusion-weighted imaging Gene rearrangement 

Notes

Acknowledgements

The abstract was previously presented at the 2017 annual meeting of the Society of Neuro-Oncology and was published in Neuro-Oncology, Volume 19, Issue suppl_6, Pages vi212.

Author contributions

LDK and JMB designed the study, analyzed and interpreted data, and drafted the manuscript. LDK and FB acquired patient records. DG carried out ADC measurements. PH conducted immunoglobulin G heavy chain rearrangement analysis. AH provided pathological evaluation and review. RF oversaw ADC measurements and provided radiological review. All authors critically revised, read and approved the final manuscript.

Compliance with ethical standards

Conflict of interests

Authors declare that they have competing interest.

Supplementary material

11060_2019_3208_MOESM1_ESM.docx (18 kb)
Supplementary material 1 (DOCX 17 kb)

References

  1. 1.
    Ostrom QT, Gittleman H, Liao P et al (2017) CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2010–2014. Neuro Oncol 19:1–88Google Scholar
  2. 2.
    Hochberg FH, Baehring JM, Hochberg EP (2007) Primary CNS lymphoma. Nat Clin Pract Neurol 3(1):24–35Google Scholar
  3. 3.
    Han CH, Batchelor TT (2017) Diagnosis and management of primary central nervous system lymphoma. Cancer 123(22):4314–4324Google Scholar
  4. 4.
    Tran H, Nourse J, Hall S, Green M, Griffiths L, Gandhi MK (2008) Immunodeficiency-associated lymphomas. Blood Rev 22(5):261–281Google Scholar
  5. 5.
    Moulignier A, Lamirel C, Picard H et al (2017) Long-term AIDS-related PCNSL outcomes with HD-MTX and combined antiretroviral therapy. Neurology 89(8):796–804Google Scholar
  6. 6.
    Navarro WH, Kaplan LD (2006) AIDS-related lymphoproliferative disease. Blood 107(1):13–20Google Scholar
  7. 7.
    Kleinschmidt-DeMasters BK, Damek DM, Lillehei KO, Dogan A, Giannini C (2008) Epstein Barr virus-associated primary CNS lymphomas in elderly patients on immunosuppressive medications. J Neuropathol Exp Neurol 67(11):1103–1111Google Scholar
  8. 8.
    O’Neill BP, Vernino S, Dogan A, Giannini C (2007) EBV-associated lymphoproliferative disorder of CNS associated with the use of mycophenolate mofetil. Neuro-oncology 9(3):364–369Google Scholar
  9. 9.
    Cavaliere R, Petroni G, Lopes MB, Schiff D, International Primary Central Nervous System Lymphoma Collaborative G (2010) Primary central nervous system post-transplantation lymphoproliferative disorder: an International Primary Central Nervous System Lymphoma Collaborative Group Report. Cancer 116(4):863–870Google Scholar
  10. 10.
    Evens AM, Choquet S, Kroll-Desrosiers AR et al (2013) Primary CNS posttransplant lymphoproliferative disease (PTLD): an international report of 84 cases in the modern era. Am J Transpl 13:1512–1522Google Scholar
  11. 11.
    Phan TG, O’Neill BP, Kurtin PJ (2000) Posttransplant primary CNS lymphoma. Neuro Oncol 2(4):229–238Google Scholar
  12. 12.
    Nagai H, Odawara T, Ajisawa A et al (2010) Whole brain radiation alone produces favourable outcomes for AIDS-related primary central nervous system lymphoma in the HAART era. Eur J Haematol 84(6):499–505Google Scholar
  13. 13.
    Newell ME, Hoy JF, Cooper SG et al (2004) Human immunodeficiency virus-related primary central nervous system lymphoma: factors influencing survival in 111 patients. Cancer 100(12):2627–2636Google Scholar
  14. 14.
    Opelz G, Döhler B (2004) Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transpl 4(2):222–230Google Scholar
  15. 15.
    Pluda JM, Venzon DJ, Tosato G et al (1993) Parameters affecting the development of non-Hodgkin’s lymphoma in patients with severe human immunodeficiency virus infection receiving antiretroviral therapy. J Clin Oncol 11(6):1099–1107Google Scholar
  16. 16.
    Snanoudj R, Durrbach A, Leblond V et al (2003) Primary brain lymphomas after kidney transplantation: presentation and outcome. Transplantation 76(6):930–937Google Scholar
  17. 17.
    Park MJ, Kim HS, Jahng GH, Ryu CW, Park SM, Kim SY (2009) Semiquantitative assessment of intratumoral susceptibility signals using non-contrast-enhanced high-field high-resolution susceptibility-weighted imaging in patients with gliomas: comparison with MR perfusion imaging. AJNR Am J Neuroradiol 30(7):1402–1408Google Scholar
  18. 18.
    Tang W, David FB, Wilson MM et al (2009) DNA extraction from formalin-fixed, paraffin-embedded tissue. Cold Spring Harb Protoc 2009(2):pdb.prot5138Google Scholar
  19. 19.
    Ramasamy I, Brisco M, Morley A (1992) Improved PCR method for detecting monoclonal immunoglobulin heavy chain rearrangement in B cell neoplasms. J Clin Pathol 45(9):770–775Google Scholar
  20. 20.
    Baehring JM, Androudi S, Longtine JJ et al (2005) Analysis of clonal immunoglobulin heavy chain rearrangements in ocular lymphoma. Cancer 104(3):591–597Google Scholar
  21. 21.
    Ferreri AJ, Blay JY, Reni M et al (2003) Prognostic scoring system for primary CNS lymphomas: the International Extranodal Lymphoma Study Group experience. J Clin Oncol 21(2):266–272Google Scholar
  22. 22.
    Ginat DT, Purakal A, Pytel P (2015) Susceptibility-weighted imaging and diffusion-weighted imaging findings in central nervous system monomorphic B cell post-transplant lymphoproliferative disorder before and after treatment and comparison with primary B cell central nervous system lymphoma. J Neurooncol 125(2):297–305Google Scholar
  23. 23.
    Gupta NK, Nolan A, Omuro A et al (2017) Long-term survival in AIDS-related primary central nervous system lymphoma. Neuro Oncol 19(1):99–108Google Scholar
  24. 24.
    Haldorsen IS, Krakenes J, Goplen AK, Dunlop O, Mella O, Espeland A (2008) AIDS-related primary central nervous system lymphoma: a Norwegian national survey 1989-2003. BMC Cancer 8:225Google Scholar
  25. 25.
    Swinnen LJ, Costanzo-Nordin MR, Fisher SG et al (1990) Increased incidence of lymphoproliferative disorder after immunosuppression with the monoclonal antibody OKT3 in cardiac-transplant recipients. N Engl J Med 323(25):1723–1728Google Scholar
  26. 26.
    Wilkinson AH, Smith JL, Hunsicker LG et al (1989) Increased frequency of posttransplant lymphomas in patients treated with cyclosporine, azathioprine, and prednisone. Transplantation 47(2):293–296Google Scholar
  27. 27.
    de Mattos AM, Olyaei AJ, Bennett WM (2000) Nephrotoxicity of immunosuppressive drugs: long-term consequences and challenges for the future. Am J Kidney Dis 35(2):333–346Google Scholar
  28. 28.
    Crane GM, Powell H, Kostadinov R et al (2015) Primary CNS lymphoproliferative disease, mycophenolate and calcineurin inhibitor usage. Oncotarget 6(32):33849–33866Google Scholar
  29. 29.
    Besson C, Goubar A, Gabarre J et al (2001) Changes in AIDS-related lymphoma since the era of highly active antiretroviral therapy. Blood 98(8):2339–2344Google Scholar
  30. 30.
    Guo AC, Cummings TJ, Dash RC et al (2002) Lymphomas and high-grade astrocytomas: comparison of water diffusibility and histologic characteristics. Radiology 224(1):177–183Google Scholar
  31. 31.
    Dunleavy K, Wilson WH (2012) How I treat HIV-associated lymphoma. Blood 119(14):3245–3255Google Scholar
  32. 32.
    Salloum E, Cooper DL, Howe G et al (1996) Spontaneous regression of lymphoproliferative disorders in patients treated with methotrexate for rheumatoid arthritis and other rheumatic diseases. J Clin Oncol 14(6):1943–1949Google Scholar
  33. 33.
    Widemann BC, Adamson PC (2006) Understanding and managing methotrexate nephrotoxicity. Oncologist 11(6):694–703Google Scholar
  34. 34.
    Gleissner B, Siehl J, Korfel A, Reinhardt R, Thiel E (2002) CSF evaluation in primary CNS lymphoma patients by PCR of the CDR III IgH genes. Neurology 58(3):390–396Google Scholar
  35. 35.
    Mitterbauer-Hohendanner G, Mannhalter C, Winkler K et al (2004) Prognostic significance of molecular staging by PCR-amplification of immunoglobulin gene rearrangements in diffuse large B-cell lymphoma (DLBCL). Leukemia 18(6):1102–1107Google Scholar
  36. 36.
    Bagg A, Braziel RM, Arber DA, Bijwaard KE, Chu AY (2002) Immunoglobulin heavy chain gene analysis in lymphomas: a multi-center study demonstrating the heterogeneity of performance of polymerase chain reaction assays. JMD 4(2):81–89Google Scholar
  37. 37.
    Burger PC, Dubois PJ, Schold SC et al (1983) Computerized tomographic and pathologic studies of the untreated, quiescent, and recurrent glioblastoma multiforme. J Neurosurg 58(2):159–169Google Scholar
  38. 38.
    Barajas RF Jr, Rubenstein JL, Chang JS, Hwang J, Cha S (2010) Diffusion-weighted MR imaging derived apparent diffusion coefficient is predictive of clinical outcome in primary central nervous system lymphoma. AJNR 31(1):60–66Google Scholar
  39. 39.
    Cinque P, Brytting M, Vago L et al (1993) Epstein-Barr virus DNA in cerebrospinal fluid from patients with AIDS-related primary lymphoma of the central nervous system. Lancet 342(8868):398–401Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of NeurologyYale School of MedicineNew HavenUSA
  2. 2.Department of PathologyYale School of MedicineNew HavenUSA
  3. 3.Department of Radiology and Biomedical ImagingYale School of MedicineNew HavenUSA
  4. 4.Department of NeurosurgeryYale School of MedicineNew HavenUSA
  5. 5.Departments of Neurology and Neurosurgery, Section of Neuro-OncologyYale School of Medicine, Yale Cancer CenterNew HavenUSA

Personalised recommendations