POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER

 

Case prepared by Meridith Hossfield, Student Intern in Pathology, Met School, Providence, RI

along with N. Peter Libbey, MD

 

Case History

A 52 year-old man was diagnosed in September 2007 with acute myeloid leukemia, which initially responded well to Cytarabine and adriamycin but then became resistant to treatment. He underwent reinduction with methotrexate, epirubicin and cisplatin followed by consolidation with high-dose Cytarabine. Five months after beginning treatment, he received bone marrow stem cells and fully engrafted. In May 2008, he was readmitted to the bone marrow transplant unit with diarrhea and was found to have graft-versus-host disease (GVHD) of the gastrointestinal tract and skin as well as a number of other complications, including pulmonary nocardiasis, C. difficile enteritis and CMV viremia. In late August 2008, he was noted to have slight con­fusion.  An MRI showed an enhancing nodule in the left temporal lobe. A brain biopsy was performed.

Microscopic Findings

The histologic sections show cerebral cortex with an infiltrate of primitive-appearing cells that have large vesicular nuclei. The cells are densely packed around blood vessels and are scattered in the surrounding neuropil [Images 1,2]. Lack of staining for myeloperoxidase and CD34 suggest that the tumor cells are not myelogenous and thus not a recurrence of the patient's AML, while positive CD45 and CD20 stains [Images 3, 4] prove that the cells are lymphoid cells of B-cell lineage. Immunostain for Epstein-Barr viral antigen (LMP-1) and in-situ hybridization for EBER (E-B Early RNA) are positive in many of the tumor cells [Images 5,6]. Polymerase chain reaction (PCR) for immoglobulin heavy chain (IgH) gene rearrangement on a sample of the brain lesion was positive for a clonal B-cell population. The histologic, immunochemical  and other diagnostic findings are indicative of EBV-associated posttransplant large B-cell lymphoma.

Diagnosis

POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER

Discussion

Posttransplant lymphoproliferative disorder (PTLD) comprises a spectrum of abnormal B-cell proliferation ranging from atypical lymphocytosis (infectious mononucleosis) to polyclonal B-cell proliferation with nodal or extranodal tumors to monoclonal B-cell proliferation or lymphoma. It is an uncommon complication of transplantation with an overall incidence of 1-10% in solid organ transplant and 1.6% in allogenic bone marrow transplant. The vast majority of PTLD is caused by Epstein-Barr Virus. Most cases of PTLD following solid organ transplant are due to reactivation of EBV, which is latent in B-cells of 95% of the adult population, but in bone marrow transplant cases EBV is usually aquired from the donor cells. In an immunocompetent host, EBV evokes a cellular immune response in which the proliferation of infected B-cells is controlled by CD4- and CD8-positive cytotoxic T-cells. In immunosupressed patients, depletion of the T-cells causes this mechanism to fail.

B-cells with latent EBV DNA express nine EBV-related proteins, including latent membrane proteins (LMP-1and 2), which are believed to function as oncogenes. LMP-1 expression causes an increase in CD23, which causes B-cell activation, and induces expression of bcl-2, which inhibits apotosis in an infected cell. LMP-1 and EBV nuclear antigens, EBNA-1 and EBNA-2, which maintain the episomal configuration of the latent virus and upregulate the expression of the viral proteins respectively, are often expressed in PTLD. The classic 8;14 and 8;22 translocations found in EBV-associated Burkitt's lymphoma are not found in PTLD. Non-EBV-associated PTLD and T-cell and natural killer (NK)-cell PTLD have also been reported. 

Clinically, EBV-PTLD may be difficult to recognize, because symptoms are highly varied and nonspecific. Common findings are fever, weight loss, neurological symptoms, abdominal pain, shortness of breath, lethargy, lymphadenopathy, diarrhea and sore throat. The typical onset is six months to a year posttransplant. Many diseases that occur posttransplant, from fungal and viral infections to GVHD, may have similar symptoms. However, in a patient who has recently undergone transplantation and suddenly presents with lymphadenopathy, unexplained weight loss and hepatosplenomegaly, PTLD should readily be suspected.

Diagnostic studies for EBV-PTLD depend on where the symptoms first manifest themselves. MRI, CT scan and ultrasonography on areas of interest can detect tumors and the extent of tumor growth. Serological analysis for EBV capsid antigen may detect recent EBV infection, and appropriate serology may exclude other infections, such as cat scratch fever, which may have similar symptoms. Bone marrow examination may detect marrow involvement or provide other useful information , but the standard for diagnosing PTLD is histopathologic analysis, and biopsy of the affected site is usually needed, e.g. brain biopsy in the case of the patient. Immunostain for CD20 detects neoplastic cells of B-cells lineage, though some B-cells may not react to CD20 and may require CD19, CD21 or CD22 staining. Immunostain for LMP-1 and in-situ hybridization for EBER detect the presence of EBV in the neoplastic cells.  PCR may also be used to detect the presence of EBV DNA, though tests results are often nonspecific, and PCR may also distinguish polyclonal from monoclonal lymphoid proliferation.  

Treatment of EBV-PTLD is also highly varied and depends on the presenation. In the most mild cases, presenting as infectious mononucleosis, the disease may resolve or progress to a polyclonal B-cell tumor. Either of these may be reversed by reducing or stopping immunosupressive treatment and using antiviral drugs such as acyclovir. If the disease progresses or presents as lympoma, it is often fatal with mortality rates as high as 60-100%. Chemotherapy may be used, though this may not be possible for patients with low blood counts. In addition to this, reduction of immunosupression may lead to loss of transplanted cells. Anti-CD20 monoclonal antibody therapy has shown promising results in at least one study, though it is not useful if the lesional cells do not express CD20. Antiviral agents have not been helpful in the treatment of lymphomas.

 References

1. Dharnidharka, V. et al (2008, Apr. 22). Posttranplant Lymphoproliferative Disease. from eMedicine Pediatrics Web site: http://emedicine.medscape.com/article/1013758-overview

2. Mukherjee, S. et al (2008, Oct. 28th). Posttransplant Lymphoproliferative Disease. from eMedicine Tranplantation Web site: http://emedicine.medscape.com/article/431364-overview

3. Nalesnik, M. et al (2000). Posttransplant Lymphoproliferative Disorder. Retrieved May 28, 2009, from TransplantBuddies Web site: http://www.transplantbuddies.org/library/ptld.html   

Postscript

Unable to tolerate the chemotherapy due to low blood count, the patient was treated with anti-B-cell antibody Rituxan. He became increasingly confused over the course of the next few weeks, and this was compounded by a decrease in blood pressure and hypothermia. He died within two weeks of sepsis and EBV-associated posttransplant lymphoma.

[1] H&E stain of cerebral cortex at low power magnification shows a predominantly perivascular infiltrate
[2] H&E stain of cerebral cortex at high power magnification shows large primitive neoplastic cells around a blood vessel
[3] Immunostain for CD45 (leukocyte common antigen) is positive in the neoplastic cells
[4] Positive CD20 stain indicates that the cells are of B-cell lineage
[5] (LMP-1) stain is positive in many of the tumor cells
[6] In-situ hybridization for EBER is positive in many of the tumor cell nuclei