Jeffrey D. Cao

Hodgkin lymphoma-like posttransplant lymphoproliferative disorder (HL-like PTLD) simulates monomorphic B-cell PTLD both clinically and pathologically.

Although Hodgkin lymphoma-like posttransplantation lymphoproliferative disorder (HL-like PTLD) has been grouped with classic Hodgkin lymphoma type PTLD (HL-PTLD), controversy remains as to whether it is truly a form of HL or whether it should be more appropriately classified as a form of B-cell PTLD. Because only few cases of HL-like PTLD have been reported, their pathologic nature and clinical behavior have not been well defined. This report characterized 5 cases of HL-like PTLD with respect to their immunophenotype, EBV status, clonality, and clinical outcome. All of the patients were male, with ages ranging from 1.5 to 55 years at diagnosis. PTLD developed from 4 months to 6 years following solid organ transplantation (3 hearts, 1 kidney, 1 liver), and involved both nodal and extranodal sites. All were EBV-related (EBER+) with the large neoplastic cells CD20/CD79a positive but CD15 negative. Immunoglobulin gene rearrangements were detected in 3 of 5 tested. All patients were managed by initial reduction/withdrawal of immunosuppression, with 2 also receiving chemotherapy for non-HL. Three patients died of progressive disease within 2 to 3 months after diagnosis, 1 is alive and well 2 years later, and the fifth was disease free but died of unrelated causes (graft coronary disease) 2 years later. We conclude that, although HL-like PTLD morphologically simulates classic HL PTLD, there are important immunophenotypic, molecular genetic, and clinical differences, suggesting it is in fact most often a B-cell PTLD. Distinction between HL and HL-like PTLD may be important for clinical management and prognosis.

Anaplastic large cell lymphoma associated with Epstein-Barr virus following cardiac transplant.

Posttransplantation lymphoproliferative disorders (PTLDs) eventually occur in approximately 5% of all organ transplant recipients. Most of cases are B-cell proliferations associated with the Epstein-Barr virus (EBV). T-cell PTLDs are relatively rare, although some estimate that up to 14% of posttransplantation malignant lymphomas are T-cell lymphomas even though only a few of these cases are described in the literature. A literature review found only 77 cases of T-cell PTLD, including 1 case following cardiac transplant, 15 cases associated with EBV, and only 1 case of anaplastic large cell lymphoma (ALCL). This single ALCL case followed a liver transplant, was of the T-cell phenotype, and was EBV negative. In this report, we describe a 14-year-old male who developed an EBV-positive, T-cell PTLD of the ALCL subtype after a period of 14 years following cardiac transplant. Immunohistochemical staining established the T-cell origin of the neoplasm with strong expression of CD45, CD3, CD43, and CD2 and also showed expression of CD30 consistent with the histologic features that suggested ALCL. EBER in situ hybridization detected the presence of the EBV. Polymerase chain reaction analysis for T-cell receptor-gamma gene rearrangements confirmed the T-cell lineage of this lymphoma. To our knowledge, this is the first reported case of an EBV-positive T cell lymphoma of the anaplastic large cell subtype following organ transplant.

Proton Radiation and TNF-α/Bax Gene Therapy for Orthotopic C6 Brain Tumor in Wistar Rats

High-grade tumors of the brain remain virtually incurable with current therapeutic regimens, new approaches to augment existing therapies need to be explored. The major goal of this pilot study was to evaluate the feasibility of gene therapy using plasmid DNA encoding tumor necrosis factor-α and bax together with proton radiation in an immunocompetent animal model with orthotopic brain tumor. C6 glioma cells were stereotactically implanted into the left hemibrain of Wistar rats (day 0). On day 5, the appropriate groups received intratumoral pGL1-TNF-α and pGL1-Bax (10 μg each), parental plasmid pWS4 (20 μg), or PBS. Hemibrain proton irradiation (10 Gy, 90 MeV, single fraction) was delivered 18–20 hr later. Rats were euthanized when signs of illness appeared. In addition, a subset of animals from each group was euthanized on day 9 for immune and other assays. By day 9, 25%, 20%, and 10% of rats treated with PBS, pWS4, or pGL1-TNF-μ/pGL1-Bax, respectively, had been euthanized due to weight loss or other signs of illness, whereas all rats treated with pGL1-TNF-μ/pGL1-Bax + radiation or radiation alone were healthy (P<0.05). At this same time, the pGL1-TNF-μ/pGL1-Bax + radiation group had significantly elevated lymphocyte percentages (P<0.005 or less) and a relatively high level of lymphocytic infiltrate within tumors. Although the rats treated with pGL1-TNF-μ/pGL1-Bax had the highest levels of activated T helper (CD4+/CD71+) and T cytotoxic (CD8+/CD71+) cells, the values were not significantly different compared to the pWS4-injected control group. Splenocytes in all tumor cell-injected groups had higher mean values for DNA and protein synthesis compared to the non-tumor cell injected control group, whereas oxygen radical production by phagocytes was consistently higher in groups injected with plasmid or treated with radiation. Body, hemibrain, and spleen masses, white blood cell, red blood cell and platelet counts, hemoglobin, hematocrit, and transforming growth factor-β1 levels in plasma were similar among groups. The results demonstrate that treatment with pGL1-TNF-α/pGL1-Bax combined with proton hemibrain irradiation is safe under the conditions used. Overall, these data support further investigation of this unique combination therapy.

Protracted low-dose radiation priming and response of liver to acute gamma and proton radiation

Abstract This study evaluated liver from C57BL/6 mice irradiated with low-dose/low-dose-rate (LDR) γ-rays (0.01 Gy, 0.03 cGy/h), with and without subsequent exposure to acute 2 Gy gamma or proton radiation. Analyses were performed on day 56 post-exposure. Expression patterns of apoptosis-related genes were strikingly different among irradiated groups compared with 0 Gy (p < 0.05). Two genes were affected in the Gamma group, whereas 10 were modified in the LDR + Gamma group. In Proton and LDR + Proton groups, there were six and 12 affected genes, respectively. Expression of genes in the Gamma (Traf3) and Proton (Bak1, Birc2, Birc3, Mcl1) groups was no longer different from 0 Gy control group when mice were pre-exposed to LDR γ-rays. When each combined regimen was compared with the corresponding group that received acute radiation alone, two genes in the LDR + Gamma group and 17 genes in the LDR + Proton group were modified; greatest effect was on Birc2 and Nol3 (> 5-fold up-regulated by LDR + Protons). Oxygen radical production in livers from the LDR + Proton group was higher in LDR, Gamma, and LDR + Gamma groups (p < 0.05 vs. 0 Gy), but there were no differences in phagocytosis of E. coli. Sections stained with hematoxylin and eosin (H&E) suggested more inflammation, with and without necrosis, in some irradiated groups. The data demonstrate that response to acute radiation is dependent on radiation quality and regimen and that some LDR γ-ray-induced modifications in liver response were still evident nearly 2 months after exposure.

Primary Anaplastic Lymphoma Kinase-Negative Anaplastic Large Cell Lymphoma of the Brain in a Patient With Acquired Immunodeficiency Syndrome

Anaplastic large cell lymphoma is a unique diagnostic subcategory of the T-cell lymphomas in the current World Health Organization classification. Representing approximately 3% of adult and 10% to 30% of childhood non-Hodgkin lymphomas, anaplastic large cell lymphoma classically consists of CD30+ large lymphoid cells with abundant cytoplasm and pleomorphic, often horseshoe-shaped or kidney-shaped nuclei. Among the reported nodal and extranodal sites of occurrence, the gastrointestinal tract and central nervous system have rarely been noted. We report a case of primary anaplastic lymphoma kinase-negative anaplastic large cell lymphoma in the brain of a 46-year-old patient with acquired immunodeficiency syndrome. T-cell lineage was confirmed by T-cell receptor gamma chain gene rearrangements using polymerase chain reaction, and extra copies of the anaplastic lymphoma kinase gene of chromosome 2 were demonstrated by fluorescence in situ hybridization analysis. To our knowledge, primary anaplastic large cell lymphoma of the brain has not previously been reported in acquired immunodeficiency syndrome.

Primary diffuse large B-cell lymphoma of the uterus presenting solely as an endometrial polyp.

Summary:We report a primary diffuse large B-cell lymphoma of endometrial polyp in a 44-year-old woman who presented with irregular vaginal spotting and was found to have a polyp protruding from the cervical os. Histology of the polyp showed an atypical diffuse infiltration by large, mononuclear cells within the stroma and between endometrial glands in one of the polypoid fragments. Immunohistochemistry and testing for immunoglobulin heavy chain gene rearrangement showed a B-cell lineage, consistent with diffuse large B-cell lymphoma. Staging procedures including detailed gynecology examination, body computed tomography scan, and bone marrow examination, as well as total hysterectomy, showed no evidence of lymphoma outside of the polyp. To our knowledge, this represents the first well-documented instance of primary lymphoma of the uterus presenting as an endometrial polyp. The differential diagnosis of endometrial biopsies containing an atypical lymphoid infiltrate should include the rather rare possibility of primary uterine lymphoma arising in an endometrial polyp. Immunohistochemistry and/or molecular analysis for antigen receptor gene rearrangements are critical in arriving at the correct diagnosis.

What Is Anaplastic Large Cell Lymphoma

To the Editor: We read with interest the recent case report entitled ‘‘Anaplastic large cell lymphoma associated with Epstein-Barr virus following cardiac transplant by Pitman et al. The authors presented a case of EBVassociated CD30-positive large cell lymphoma with anaplastic morphology developing in a cardiac transplant patient. Based on the immunohistochemical and molecular studies which demonstrated CD30, CD43, CD2, and CD45 expression in tumor cells and a monoclonal TCR gamma chain gene rearrangement, the authors interpret this lymphoma as an EBV-associated anaplastic large cell lymphoma, T cell type. We believe the data presented as evidence for a diagnosis of anaplastic large cell lymphoma (ALCL) of T cell origin in this EBV-associated CD30positive lymphoma are not sufficient for this conclusion. First, the immunophenotype reported for this tumor (the tumor cells being positive for CD43 and CD2) is not sufficient evidence for a T cell origin since these antigens are not lineage specific and can be seen in EBV-associated B cell lymphomas. Furthermore, there is some ambiguity in the expression of other Tcell markers, since CD3 and CD5 are reported as positive in the text, but Table 1 indicates that CD3 and CD5 stained only small T-cells with occasional large atypical cells stained for CD3 with high background. The demonstration of other T cell markers commonly expressed in ALCL, such as perforin or granzyme B would add further supportive evidence for a T cell origin and a diagnosis of ALCL. Second, molecular analysis for rearrangements of the immunoglobulin heavy chain gene was not performed. These data are crucial because dual immunoglobulin and T cell receptor gene rearrangements have been described in immunodeficiencyassociated B cell lymphomas. Third, the FISH data, which demonstrate more than 2 signals for ALK-gene expression in the tumor cells do not prove ALK translocation or amplification since more than two signals may be due to hyperdiploidy of chromosome 2. The marked nuclear pleomorphism, with frequent multinucleated forms, would be expected to be associated with aneuploidy. In conclusion, this case highlights many of the pitfalls in making an accurate diagnosis of anaplastic large cell lymphoma. We recently saw a case of an EBV-associated, CD30-positive, B-cell marker negative large cell lymphoma in a 68 year-old female who had chronic lymphocytic leukemia, was being treated with cyclosporine for pure red cell aplasia and developed rapidly growing abdominal lymphadenopathy. The tumor cells had anaplastic morphology, expressed CD30, were EBER-positive and were negative for CD20 (Figure 1. A-D), CD79a, Pax5, CD15, fascin, ALK-protein, CD3, CD5, ZAP70, and granzyme B. Moreover the cells were weakly positive for CD4, and CD43. By PCR, the tumor cells had the same pattern of immunoglobulin heavy chain gene rearrangement as peripheral blood CLL cells and lacked clonal TCR gene rearrangement. Although cases similar to this one have been interpreted as EBV-positive

Epstein-Barr virus associated secondary hemophagocytic lymphohistiocytosis with an unusual presentation of abdominal compartment syndrome

Hemophagocytic lymphohistiocytosis (HLH) is a cytokine storm syndrome caused by an overactive but ineffective immune reaction. Without prompt diagnosis and treatment, HLH is life-threatening. However, presenting symptoms are often nonspecific, with fatigue and fever being the most common. A high index of suspicion is therefore critical for early diagnosis and timely management. A previously healthy, 65-year-old female who initially presented with fever and abdominal pain developed abdominal compartment syndrome (ACS) requiring decompressive laparotomy on hospital day 6. Intraoperative frozen sections of biopsied liver showed intense portal lymphohistiocytic infiltrates. Epstein-Barr virus DNA copy numbers escalated from 600 copies/ mL after admission to 134,000 copies/mL before death. The diagnostic criteria of HLH-2004 were met. Patient expired on hospital day 12. It is important to raise awareness of ACS being an unusual presentation of HLH. Recent changes in diagnostic criteria tailored to adult HLH cases are reviewed.