Using molecular techniques to confirm donor-derived post-transplant lymphoproliferative disorder

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Fig. 2. Histology showing primary CNS diffuse large B-cell lymphoma, PTLD. A) Low-power H&E showing brain tissue with large lymphoid cell infiltrate. B) Perivascular lymphoid infiltrate. C) 20× H&E showing large diffuse lymphoid cells. D) Immunohistochemical stain showing large lymphoid cells are CD20+. E) Immunohistochemical stain showing large lymphoid cells are BCL2+. F) Ki-67 showing proliferation index of 50 to 60 percent. G) Low-power view of EBER-ISH showing positive large cells. H) High-power view of EBER-ISH showing nuclear staining of EBV+ cells.

CNS-PTLD is a rare condition. Other than reducing or discontinuing immunosuppressive therapy, there are very few treatment options.4 Methotrexate offers some positive results, and rituximab is effective in systemic PTLD without CNS involvement, but does not cross the blood-brain barrier.4 At the time of admission, the working differential diagnosis in this patient was CNS lymphoma or viral encephalitis. MRI showed multiple abnormalities without enhancement. Brain biopsy was performed and revealed diffuse large lymphoid cells that were CD20 positive and BCL-2 positive, consistent with diffuse large B-cell lymphoma, with a proliferation index (based on Ki-67 immunohistochemical staining of tumor nuclei) of 50 to 60 percent. With a preliminary working diagnosis of CNS-PTLD, methotrexate was immediately started. EBER-ISH (EBV-encoded messenger RNA by in situ hybridization) was performed and showed positivity, confirming EBV-associated PTLD lymphoma (Fig. 2). Chimerism analysis, using STR-based multiplex PCR, revealed donor DNA in the lymphoma as compared with recipient DNA retrieved from a swab of the buccal mucosa (Fig. 1). In contrast to solid organ transplant PTLD, which is recipient DNA derived, most post-allogeneic bone marrow transplant PTLDs are donor derived.
Conclusion
This case emphasizes the role of molecular techniques in confirming a diagnosis of donor-derived post-transplantation lymphoproliferative disorder, following bone marrow transplantation. It also emphasizes the importance of this determination, given the differences in treatment of PTLD of recipient origin versus PTLD of donor origin.

1. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer; 2008.
2. Ng IO, Shek TW, Thung SN, et al. Microsatellite analysis in post-transplantation lymphoproliferative disorder to determine donor/recipient origin. Mod Pathol. 2000;13(11):1180–1185.
3. Knight JS, Tsodikov A, Cibrik DM, et al. Lymphoma after solid organ transplantation: risk, response to therapy, and survival at a transplantation center. J Clin Oncol. 2009;27(20):3354–3362.
4. Yaginuma T, Yamamoto H, Mitome J, et al. Successful treatment of monomorphic primary central nervous system post-transplantation lymphoproliferative disorder 5 years after kidney transplantation. Transpl Infect Dis. 2012;14(5):E102–E106.

Dr. Katava is a PGY3 resident in anatomic and clinical pathology at the University of Medicine and Dentistry of New Jersey, Newark. Dr. Donato is medical director of the Blood and Marrow Collection Facility at John Theurer Cancer Center, Dr. Hong is chief of microbiology and molecular diagnostics, Dr. Mannion is chairman of the Department of Pathology and Laboratory Medicine, and Dr. Bhattacharyya is director of hematopathology and molecular pathology—all at Hackensack University Medical Center, Hackensack, NJ.