Lymphoproliferative disorders and hematologic malignancies following organ transplantation

Eleven allograft recipients (one cardiac, one hepatic, nine renal) at the Massachusetts General Hospital developed a lymphoproliferative disorder or leukemia. Six (all renal) patients received conventional immunosuppressive therapy (CIT), four received cyclosporin A (CsA) (one cardiac, one hepatic, two renal), and one received CIT for his first transplant and CsA for his second transplant (both renal). The interval from transplant to onset of the hematologic disorder ranged from 2 mo to 3 yr in the CsA group and from 6 mo to 9 yr in the CIT group and was 16 yr in the patient with two allografts. There were eight malignant lymphomas, seven of which were extranodal, (four immunoblastic, one large noncleaved cell, one small noncleaved cell, one plasmacytoma, one unclassifiable), one case of polymorphic diffuse B cell hyperplasia and two cases of acute myeloid leukemia. Frozen section immunohistochemistry in six cases showed monotypic immunoglobulin in four lymphomas, (including the plasmacytoma), an immunoglobulin-negative B cell phenotype in one lymphoma, and polytypic immunoglobulin in the case of polymorphic hyperplasia. One lymphoma showed a monotypic immunoglobulin-producing B cell population in one site and an immunoglobulin-negative B cell population in another site. With an immunoglobulin heavy chain gene-specific probe, Southern blot analysis of tissue from these two sites revealed two distinct rearrangements. When tissue from a second case of lymphoma was analyzed by Southern blot, identical rearrangements of the heavy chain gene were found in tumor from two separate sites. Similar to the experience of others, we find an increased incidence of lymphoma and a slightly increased incidence of acute myeloid leukemia in allograft recipients. In contrast to other reports, we found a predominance of monoclonal B cell malignancies, a more polymorphous histologic appearance of the lymphoproliferative disorders in CsA patients, and one case each of "multiclonal" and "monoclonal" lymphomas when tumor from separate sites was tested for gene rearrangement.     

Lymphoproliferative disease of turkeys 1. Clinical aspects

Several outbreaks of a lymphoproliferative disease of turkeys were investigated. The disease affected birds from 10 weeks of age onwards and resulted in mortality figures often in excess of 20%. The disease was characterised clinically by gross splenomegaly with focal lesions in most organs, and infiltration of the peripheral nerves. Microscopically lesions consisted of focal proliferations of lymphoid cells and plasma cells. Ultrastructural studies confirmed the pleomorphism of the proliferating cells and virus particles were demonstrated in spleen, liver and thymus.     

Hyperparathyroidism and bone disease after renal transplantation

Metabolic bone disease is one of the most frequent complications of chronic renal failure. Numerous disorders leading to the metabolic bone disease can be reversed by successful renal transplantation. However, in some patients, in spite of satisfactory renal function, some disorders may persist for months after successful transplantation, e.g. increased parathyroid hormone secretion. Besides, drugs used in immunossuppressive therapy may cause metabolic bone disease or reduction of of bone mass. Therefore, significant loss of mass takes place in the majority of patients during the first six months. Among drugs used in the prevention of bone disease after transplantation of solid organs the most important role have biphosphonates and vitamin D, i.e. calcitriol.     

Lymphoproliferative disease of the kidney developing in fibro-inflammatory lesion

An 80-year-old man presented with continuous spike fever and night sweats. Computed tomographic scans revealed a poorly demarcated mass in the upper part of the right kidney, which was resected. At surgery, tumorous lesions were not found in the abdominal cavity. Serum IgG4 level measured after surgery was 40.1 mg/dl. Macroscopically, renal parenchyma of the upper part was replaced by an irregularly shaped grayish-white lesion of elastic, firm consistency. Histologically, the lesion consisted mostly of fibrous tissue in which small lymphoid cells, often with formation of aggregates, were evident. IgG4-positive plasma cells were few in number. Careful macroscopic examination revealed several minute nodules, which histologically consisted of large lymphoid cells, small lymphoid cells, and macrophages. These large lymphoid cells were positive for CD20 and contained Epstein-Barr virus (EBV) genome. Taken together, a diagnosis of EBV-positive B-cell lymphoproliferative disease (LPD) developing in inflammatory pseudotumor (IPT) of the kidney was made. This is the first report of B-LPD in IPT of the kidney. In addition, a presence of EBV in renal lymphoma cells has not yet been reported.     

Lymphoproliferative disease in antibody deficiency: a multi-centre study

We have undertaken a retrospective study of antibody deficient patients, with and without lymphoma, and assessed the ability of specific polymerase chain reaction (PCR) primers to determine if the detection of clonal lymphocyte populations correlates with clinical and immunohistochemical diagnosis of lymphoma. We identified 158 cases with antibody deficiency presenting during the past 20 years. Paraffin-embedded biopsy specimens or slides were available for analysis in a cohort of 34 patients. Of these patients, 29 had common variable immunodeficiency, one X-linked agammaglobulinaemia, one X-linked immunoglobulin deficiency of uncertain cause and three isolated IgG subclass deficiency. We have confirmed that lymphoma in antibody deficiency is predominantly B cell in origin. Clonal lymphocyte populations were demonstrated in biopsies irrespective of histology (16/19 with lymphoma and 11/15 without). Isolated evidence of clonality in biopsy material is therefore an insufficient diagnostic criterion to determine malignancy. Furthermore, our data suggest that clonal expansions are rarely the result of Epstein-Barr virus-driven disease.     

Autoimmune disease after autologous hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) is an effective treatment for refractory autoimmune diseases. The safety and long-term outcome have been also acceptable. Infectious diseases under immune suppressive state after autologous HSCT are common transplantation related complications whereas autoimmune diseases are uncommon. Organ specific autoimmune diseases, such as immune mediated thrombocytopenia and thyroid dysfunction, are the most common after autologous HSCT. Systemic autoimmune diseases can also develop after autologous HSCT in patients with hematological disorders with genetic predisposition to autoimmune diseases. Although the mechanism of autoimmunity after HSCT is not well-known, long-term follow-up is essential in patients with autoimmune diseases treated with autologous HSCT.     

Lymphoproliferative disease after allogeneic stem cell transplantation--pre-emptive diagnosis by quantification of Epstein-Barr virus DNA in serum.

BACKGROUND: Lymphoproliferative disease (PTLD) is a life-threatening complication of organ transplantation. In matched, allogeneic, non-T-cell-depleted stem-cell transplantations (SCT) the disease develops early but has been thought to be rare. OBJECTIVES: We determined by strict histopathological criteria the incidence of fatal Epstein-Barr-virus (EBV)-related PTLD in a large number of SCT, and assessed the diagnostic value of a real-time quantitative polymerase chain reaction (qPCR) for EBV-DNA in serum specimens. STUDY DESIGN: Of the 257 SCT performed in Helsinki during 1994-1999, 132 (51%) recipients were alive and 125 (49%) had succumbed by June 2001. The necropsies were analyzed for EBV-related PTLD as evidenced by disseminated lymphocytic infiltrates labeled histochemically for antigens and RNA (EBER 1 and 2) detectable by in situ technology. From a subset of the PTLD cases (N=12) and a series of corresponding stem-cell recipient controls (N=36), consecutive samples of serum (N=103 and 364, respectively) were studied by qPCR for EBV-DNA, and the clinical data were reviewed. RESULTS: The post-mortem analysis revealed 18 cases of PTLD (14% of the deceased), all of whom had received intensive immunosuppressive treatment including anti-thymocyte globulin for treatment or prophylaxis of graft versus host disease (GVHD). By using qPCR all the PTLD patients became EBV-DNA positive, in progressively rising copy numbers. EBV-DNA was first detectable 70 (median; range 24-154) days after SCT or 23 (4-86) days before death; i.e. earlier than the symptoms which appeared 15 (2-85) days before death. Among the SCT controls, EBV-DNA occurred sporadically (in only 3.9% sera). CONCLUSIONS: qPCR for EBV-DNA in serum is a highly sensitive (100%) and specific (96%) diagnostic approach. Intensely immunosuppressed stem-cell recipients are at a great risk of developing PTLD, and should be carefully monitored for EBV-DNA, for pre-emptive treatment of this life-threatening disorder.     

Lymphoproliferative disorder of granular lymphocytes. A heterogeneous disease.

Lymphoproliferative disorders of granular lymphocytes (LDGLs) represent a family of diseases that are morphologically similar but diverse with regard to immunophenotype, function, and clonality. In this article, we report three informative cases and propose a modification of the current classification of LDGLs. Our first case is an example of natural killer cell LDGLs (CD2+, CD3-, CD16+, CD57+/-). Based on a review of the literature, we suggest that natural killer cell LDGLs can be divided into two subgroups (types 1 and 2) according to the expression of CD57. Reduced expression of CD57 may distinguish between patients with a poorer prognosis. The remaining two cases illustrate examples of T-cell LDGLs (CD2+, CD3+, CD8+, CD57+) that differ mainly in their expression of CD16. The CD16+ T-cell LDGLs (type 1) usually show a clonal rearrangement of the T-cell receptor-beta chain gene, whereas CD16- T-cell LDGLs (type 2) may show a germline configuration, suggesting a reactive rather than a neoplastic process. Pathologists should differentiate LDGLs from other chronic lymphoproliferative diseases, since most cases evolve slowly and aggressive cytoreductive therapy is usually unwarranted.     

Lymphoproliferative disease in mice infected with murine gammaherpesvirus 68.

Murine gammaherpesvirus is a natural pathogen of wild rodents. In the laboratory it establishes an infection of epithelial cells and persists in B lymphocytes in a latent form. Inbred mice chronically infected with the virus develop a lymphoproliferative disease (LPD) similar to that seen in patients infected with Epstein-Barr virus. The frequency of LPD over a period of 3 years was 9% of all infected animals, with 50% of these displaying high grade lymphomas. The incidence of LPD was greatly increased when infected mice were treated with cyclosporin A. The majority of mice used in the experiments were BALB/c, although lymphomas were detected in mice on other genetic backgrounds, ie, CBA and B10Br. Lymphomas were associated with both lymphoid and nonlymphoid tissues (liver, lung, and kidney). In all cases of lymphomas studied thus far, there was a mixed B cell (B220+ve) and T cell (CD3+ve) phenotype. The B cells were light chain restricted, indicative of a clonal origin. Variable numbers of virus genome-positive cells were detected by in situ hybridization in and around the lymphomas. In contrast, no lytic antigen-positive cells were detected, indicating that genome-positive cells were either latently infected or undergoing an abortive infection. These observations suggest that murine gammaherpesvirus-infected mice may be an important model to study the pathogenesis of LPD associated with other gammaherpesviruses, such as Epstein-Barr virus.     

Chronic kidney disease after liver transplantation: Recent evidence

Chronic kidney disease is a common complication after liver transplantation with an incidence ranging between 20% and 80%. Studies of renal function after liver transplantation have yielded conflicting results: the wide range in incidence rates of chronic kidney disease (CKD) following liver transplantation is related to the methods for measuring kidney function, and various criteria for defining renal dysfunction, among others. An important cause of CKD among liver transplant recipients is calcineurin inhibitor-based immunosuppression. Additional predictors of CKD post-liver transplantation include pre-transplant kidney function, peri-operative acute kidney failure, age, and hepatitis C. A recent meta-analysis of observational studies revealed that, in the subgroup of studies provided with glomerular filtration rate at baseline, the summary estimate of relative risk and 95% confidence intervals (CI) for developing chronic renal failure among liver transplant recipients with diminished renal function at transplant was 2.12 (95% CI, 1.01-4.46, p=0.047). Acute renal insufficiency is common immediately after liver transplantation, whereas the course of CKD after liver transplantation appears progressive over time. Only preliminary information exists on kidney pathological findings in recipients of liver transplants with CKD. Introduction of the Model for End-stage Liver Disease for the allocation of liver grafts has not increased the occurrence of renal dysfunction following liver transplantation. Chronic kidney disease following liver transplantation increases cardiovascular burden dramatically. The use of mycophenolic acid- or sirolimus-based immunosuppression in calcineurin-inhibitors sparing protocols is an area of intense research.     

Cytomegalovirus disease before hematopoietic cell transplantation as a risk for complications after transplantation.

Cytomegalovirus (CMV) disease in candidates for hematopoietic cell transplantation (HCT) is increasingly observed. Among 22 patients with CMV disease before HCT, the incidence of CMV disease before HCT was significantly higher in patients with severe underlying immune deficiency syndromes compared with patients with hematologic malignancies (P < .001). The lung was the most commonly involved site of infection, followed by the gastrointestinal tract and the retina. Fourteen of 22 patients with CMV disease before HCT responded to treatment and proceeded to HCT; 8 of 22 did not receive an HCT because of fatal CMV disease (n = 2) or other complications (n = 6). Of 14 patients with CMV disease who subsequently underwent HCT, 6 (42%) had CMV disease diagnosed after transplantation despite antiviral prophylaxis or preemptive therapy, and 1 patient had evidence of persistent CMV disease before day 100 after HCT. This proportion was significantly higher than that in patients without CMV disease before HCT during the same time period (day 30, adjusted P = .003; day 100, adjusted P = .02). Thirteen of 14 patients with pretransplantation CMV disease died a median of 36 days after transplantation (range, 19-399 days; adjusted P = .005 compared with CMV-seropositive transplant recipients without a history of pretransplantation CMV disease). In summary, although CMV disease before HCT may be mild and responsive to treatment, it is associated with a high risk of early CMV disease and death after transplantation.     

Lymphoproliferative disease of turkeys. II. Experimental transmission and aetiology

The clinical and pathological features of a previously reported lympho-proliferative disease of turkeys were reproduced by inoculation of 4-week-old poults, and spread to in contact turkeys was demonstrated. From studies on the development of the lesions in inoculated turkeys, it was possible to assay the causative agent based on microscopic examination of early lesions. Poults were more susceptible to inoculation when 4 weeks old than to inoculation at 1 day old, and different strains of turkey varied in their susceptibility to inoculation. The causative agent did not appear to be antigenically related to avian leukosis virus, to Marek's disease virus or to reticuloendotheliosis virus. Preliminary characterisation studies indicated a virus with properties similar to those of oncoviruses.     

Autoantibodies in human chronic graft-versus-host disease after hematopoietic cell transplantation

Primary biliary cirrhosis (PBC) and graft-versus-host disease (GVHD) are thought to have common immunopathologic features and previous studies have reported that 5.2 to 81% of patients with chronic GVHD after allogeneic hematopoietic cell transplant have antimitochondrial antibodies (AMA). We studied a total of 89 patients with chronic GVHD and 60 controls for AMA reactivity by ELISA and immunoblotting using recombinant PDC-E2, BCOADC-E2, and OGDC-E2, immunoblotting of beef heart mitochondrial proteins, and reactivity to nuclei, smooth muscle (ASMA), ribonucleoprotein JO-1, extractable nuclear antigen, nuclear proteins SSA/ SSB, ribonucleic P proteinase III, cardiolipin (ACA), liver kidney microsomal, thyroid microsomal, myeloperoxidase, and the reactivity of rheumatoid factor. A subset of 60 chronic GVHD sera were tested for reactivity to gp210 and LBR. Finally, liver tissue from patients with chronic GVHD and PBC was studied by immunohistochemistry to determine whether there was comparable abnormal apical staining of biliary epithelial cells using PDC-E2-specific monoclonal antibodies. Surprisingly, there were no AMA found in the sera from the 89 patients with chronic GVHD. Review of published data on AMA in GVHD suggests that previous results were primarily false positives. In contrast, sera from the patients with GVHD did have a variety of other autoantibodies and, in particular, 20/89 (22.4%) positive ANA, 23/89 (25.8%) positive ASMA, and 9/89 (10.1%) positive ACA. The other autoantibodies assayed were not statistically different from controls. Finally, abnormal biliary epithelial luminal staining of bile ducts was found, as expected, in liver tissue of patients with PBC but was absent in chronic GVHD.