The Etiology of EBV-Negative Post-Transplantation Lymphoproliferative Disorder Remains Unclear
Stephen L Cook, Nadine S Aguilera, Grant C Bullock, Zina Meridan, Hugo Bonatti, Helen P Cathro. University of Virginia, Charlottesville, VA; University of Pittsburgh, Pittsburgh, PA; Johns Hopkins University, Baltimore, MD; Vanderbilt University, Nashville, TN
Background: While the majority of post-transplantation lymphoproliferative disorder (PTLD) cases are associated with Epstein-Barr virus (EBV) infection, up to 42% are EBV-negative (EBV-N). The antigenic stimulus that drives EBV-N PTLD is unknown. Although hepatitis C virus (HCV), human herpesvirus 8, BK virus and simian virus 40 have all been investigated as possible driving factors in EBV-N, none has been convincingly proven. PTLD and IgG4 syndrome have common features, including plasma cell proliferation driven by chronic antigenic stimulation. We postulated that a subgroup of EBV-N PTLD may be causally related to autoimmune IgG4 disease.
Design: Histology was reviewed on 38 retrievable, formalin-fixed paraffin-embedded cases of PTLD, diagnosed between 1990 and 2012 at the University of Virginia. Cases were classified according to the 2008 World Health Organization Classification. Tissue to evaluate EBV status was available in 33 cases, by immunohistochemistry (IHC) for LMP and/or in situ hybridization for EBER. Plasma cell-rich PTLD were defined as either plasmacytoma/plasma cell myeloma or polymorphous types. IHC for IgG4 was performed on samples containing PTLD and available benign biopsies taken prior to the PTLD diagnosis.
Results: Nine of 33 PTLD cases were EBV-N (27%). The mean time to diagnosis was significantly longer in EBV-N versus EBV-P cases at 86 (6-155) months and 24 (3-103) months respectively (p= 0.02). Three EBV-N patients had available serologic testing for viral infection; two were HCV non-reactive, one had evidence of previous parvovirus B19 (PVB19) infection, and one of the two HCV-negative patients had evidence of a recent PVB19 infection. One of 8 plasma cell-rich PTLD cases was EBV-N. Twenty-eight cases had sufficient tissue to evaluate IgG4 plasma cells by IHC. None of the 28 cases had more than rare IgG4 positive cells. A benign duodenal biopsy from a lung transplant patient, taken six days prior to a biopsy demonstrating duodenal EBV-N PTLD, showed focal staining (a single HPF field with >30 IgG4-positive plasma cells).
Conclusions: Our study serves as a reminder that EBV-N PTLD is more common than is often clinically recognized, and usually occurs late in the post-transplant course. The unknown antigens that play a role in EBV-N PTLD are likely unrelated to those that drive IgG4 disease. Hitherto untested viruses in transplant patients may play an etiologic role in EBV-N PTLD.
Monday, March 4, 2013 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 245, Monday Morning