Lymphoproliferative Disease Associated With Immune Deficiency in Children

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1 Lymphoproliferative Disease Associated With Immune Deficiency in Children Joannes H. van Krieken, MD, PhD Key Words: Immune deficiency; Lymphoproliferative disease; Epstein-Barr virus Abstract Lymphoproliferations in patients with immune deficiency form a challenge for the pathologist. The histologic features often are not specific and might even be deceptive. The demonstration of the presence of the Epstein-Barr virus is important, preferably by the most sensitive technique, Epstein-Barr virus encoded small RNA in situ hybridization. In more aggressive cases, a lymphoma can be diagnosed and classified according to the standard criteria, but in contrast with lymphomas that arise in immunocompetent patients, not all cases are monoclonal. Although light-chain restriction often can be demonstrated, even on paraffin, thanks to the plasmacytic differentiation that often is present, the most reliable technique is molecular demonstration of a clonal antigen receptor rearrangement. The workshop showed in addition that many unusual cases arise in immunodeficient patients. The immunodeficient state predisposes a patient not only to infectious diseases but also to cancer, in particular cancer of the immune system. Patients with various forms of immune deficiency have an increased risk especially for malignant lymphomas, and these lymphomas have special features. 1 In fact, lymphoproliferation in immunodeficient patients forms a spectrum from benign-appearing polymorphic, polyclonal processes to monomorphic, monoclonal processes with morphologic features of large cell or Burkitt lymphoma. 2,3 These lymphoproliferations are, in most cases, driven by the Epstein-Barr virus (EBV), and without intervention, the clinical course is dismal. It is important, therefore, that the pathologist recognize these lesions, ideally with the knowledge of the immune status. The present review focuses on pediatric patients and incorporates cases from the Society for Hematopathology/European Association for Haematopathology Workshop held in October 2003, Memphis, TN, as examples, although, given the nature of a workshop like this, this leads to examples with special features. The case description is ordered according to the underlying immune deficiency, rather than according to lymphoma type, because the underlying disorder determines the clinical management and also should guide the pathologist in making a diagnosis. Histologic Features Lymphoproliferations in patients with immune deficiency have a very heterogeneous aspect. They generally manifest as rapidly growing nodal or extranodal masses, but also can be encountered in biopsy specimens that were obtained without suspicion for this process but rather for rejection in patients after transplantation or for colitis. The biopsy specimens show very variable morphologic features S122 S122

2 A B Image 1 A (Case 1), Polymorphous infiltrate with occasional large atypical cells. This is an abdominal lymph node of a 7- year-old boy after heart transplantation. The large cells contain Epstein-Barr virus (EBV), and there is a clonal population using molecular testing. After decreasing immune suppression, the lesion resolved, but 8 months later, a monomorphic posttransplantation lymphoproliferative disorder developed (H&E, 100). B (Case 30), A 2-year-old girl after umbilical cord blood transplantation for juvenile myelomonocytic leukemia. This diffuse large B-cell lymphoma was EBV-encoded small RNA positive; clonality testing, however, was unsuccessful (H&E, 250). ranging from a polymorphic infiltrate with many plasma cells to a clear-cut lymphoma Image 1 (case 1). The lymphoma cases show often a clear plasma cell differentiation. The phenotype most often is that of a mature B-cell (CD20+, CD79a+, CD138 ) and sometimes of a plasma cell (CD20, CD79a, CD138+) type. In many cases, intracytoplasmic immunoglobulin can be detected and the polyclonality or monoclonality of the process can be determined Image 2 (case 52). Occasional T-cell lymphomas and Hodgkin lymphomas occur with the common phenotype. Epstein-Barr Virus EBV has a key role in these cases, 4 although few lymphomas in immunodeficient patients are EBV. EBV can A B Image 2 (Case 52) Clonality was detected by paraffin κ (A) and λ (B) staining in a 21-month-old girl after umbilical cord blood transplantation for familial hemophagocytic syndrome (A, 100; B, 100). S123 S123

3 van Krieken / LYMPHOPROLIFERATIVE DISEASE ASSOCIATED WITH IMMUNE DEFICIENCY IN CHILDREN be detected in tissues by several techniques. Although immunohistochemical analysis using several antibodies on frozen tissue samples can detect most latent forms of the virus, EBV-encoded small RNA (EBER) in situ hybridization (EBER-ISH) is the most reliable technique. By using EBER-ISH, all EBV-infected cells are detected. In immunocompetent patients who have had EBV infection (>95% of the adult population), occasional positive cells can be found in reactive lymphoid tissues, but in patients with an immune deficiency, many cells are positive Image 3 (case 27). The pathogenesis is as follows: EBV infects a B cell by binding to a receptor (CD21). The virus can take over cell cycle regulation, leading to immortalization of the cell but also to expression of viral antigens by the cell. These antigens are recognized by T cells, leading to cell death and abrogation of the infection. In patients with a T-cell defect, the EBV+ cells keep expanding, leading to tumor growth and dissemination and death of the patient unless treatment is given. The treatment generally consists of multiple factors, including diminishment of the immune suppression (when possible), antiviral treatment, and the monoclonal antibody against CD Clonality Assessment During the disease, the nature of the lymphoproliferation changes from a polyclonal to a monoclonal process; the Image 3 (Case 27) A 7-year-old boy with Wiskott-Aldrich syndrome. He had an abdominal lesion that, on biopsy, seemed to be diffuse large B-cell lymphoma. This Epstein- Barr virus (EBV)-encoded small RNA (EBER) stain showed that the great majority of the tumor cells contain the EBV genome (EBER, 400). latter is more aggressive. Clonality often can be detected by immunohistochemical analysis for immunoglobulins because there often is cytoplasmic immunoglobulin. However, immunoglobulin-negative cases that are clonal occur. The most reliable method for clonality assessment is by using polymerase chain reaction for the complete spectrum of possible rearrangements 8 Figure 1. Even relatively small clones in a reactive background can then be detected. Primary Immune Deficiency Common Variable Immune Deficiency Patients with common variable immune deficiency have an increased risk for lymphoproliferations (between 1.4% and 7% of patients), 9 including the complete spectrum described, but also smooth muscle neoplasms. 10 Owing to the relatively benign course of the disease in many patients, this can be seen over time in 1 patient, as illustrated by case 19. Also, EBV+ T-cell lymphoproliferations can occur (case 94), and mild treatment might be effective. The aggressive lymphomas in these patients in general resemble diffuse large B-cell lymphomas in patients without immune deficiency. 11 Chromosomal Breakage Syndromes (Ataxia Telangiectasia and Nijmegen Breakage Syndrome) In these syndromes, lymphomas are the most common malignant neoplasms, often leading to death of the patients. The lymphomas arise in the pediatric age group (mean age, 9 years) and include a variety of histologic features 12,13 ; the majority are B-cell lymphomas, but T-cell lymphomas and, occasionally, Hodgkin disease occur. 14 The prognosis for all types is worse compared with cases that arise in immunocompetent patients. 13 The sole case in the workshop of a patient with a chromosomal breakage syndrome (case 118) exemplified the difficulties in making a diagnosis. There was a slowly evolving lymphadenopathy without other complaints in a 9-year-old boy with ataxia telangiectasia. Histologic examination revealed a polymorphous infiltrate with many large B and T cells and some without Reed-Sternberg like features, including CD30 and CD15 positivity. The B cells were clonal by immunohistochemical analysis and molecular analysis, and EBV was demonstrated. The karyotype was complex but not specific for a lymphoma type. A complete analysis of the case was necessary to reach a final diagnosis. Wiskott-Aldrich Syndrome There were 2 cases in the workshop of patients with Wiskott-Aldrich syndrome, one a diffuse large B-cell lymphoma and the other the only rarely described large S124 S124

4 Vβ D β1 J β1 C β1 C β2 J β2 C β n D to J joining n V to DJ joining Transcription/ RNA splicing Figure 1 Schematic representation of the T-cell receptor (TCR) β gene complex showing the germline configuration (row 1) and the complete rearranged gene after VDJ joining (row 3). By using primers for the different V segments and the different D segments with J β 1 or J β 2, one can detect all complete and incomplete TCRβ rearrangements (courtesy of P. Groenen, Nijmegen, the Netherlands). granular lymphocytosis (in this syndrome). Case 27 involved a 7-year-old boy with Wiskott-Aldrich syndrome in whom an EBV+, monoclonal, diffuse large B-cell lymphoma developed; he died after intensive chemotherapy for pulmonary aspergillosis. Case 141 was a 10-month-old boy with large granular lymphocytosis (CD3+, CD8+, CD57+). Owing to the rarity of both diseases, this association may go unrecognized. Human Immunodeficiency Virus Only 1 case of HIV-related lymphoma was submitted to the workshop. The case involved an 11-year-old girl who had acquired HIV perinatally and had developed AIDS with several complications. She developed a gastric mass with a plasmablastic proliferation. The cells were positive for CD 79a and CD138, but lacked CD20, which might be an important pitfall when only a limited panel of antibodies is used. The tumor cells contained EBV as demonstrated by EBER- ISH. This case is similar to the cases described in the oral cavity, and other (mainly extranodal) primary sites have been described. 15 The morphologic features and phenotype of these cases are typical, and EBV is demonstrated. When positive, HIV infection is likely also in patients in whom it was not diagnosed clinically. Chemotherapy in this patient was not effective, and she died after 7 months. Posttransplantation Lymphoproliferative Disorders This group exemplifies the category of lymphoproliferative disorders in immunodeficient patients. 16 There is ample literature on this topic, and most cases in this part of the workshop were in this category. Nevertheless, there is a continuous change in pathology and treatment owing to changing clinical aspects. New developments that were illustrated included altered immune suppression, the monitoring of peripheral blood for the EBV genome, and the development of lymphoproliferative disease after stem cell transplantation from umbilical cord blood. Several reviews appeared recently in the pediatric literature The disease is an important complication of transplantation, occurring more frequently in children than in adults. Risk factors include young age and the use of tacrolimus. 21 When the lymphoproliferation occurs within 6 months after transplantation, the prognosis is very poor. Lowering the dose of immunosuppressive drug can decrease the incidence of posttransplantation lymphoproliferative disorders. 22 There is no good correlation between serologic findings for EBV and tissue EBER-ISH; the latter is more sensitive. However, when seroconversion is demonstrated, the S125 S125

5 van Krieken / LYMPHOPROLIFERATIVE DISEASE ASSOCIATED WITH IMMUNE DEFICIENCY IN CHILDREN prognosis is much better. An important new development is the monitoring of the EBV genome in the peripheral blood by quantitative polymerase chain reaction. This method can indicate patients at very high risk, and early treatment might prevent the occurrence of clinically detectable lymphoproliferative disease However, false-negative cases have been described. 27 The addition of the measurement of EBVspecific T-cell response can increase the specificity of the test. 28 It was indicated that the use of umbilical cord blood as a source for stem cell transplantation might decrease the occurrence of posttransplantation lymphoproliferative disorder, 29 but more recently, several cases have been described, 30 including cases in the workshop (cases 30, 41, 52). The prognosis has improved during the last few years, thanks to a better understanding of the pathogenesis, better recognition of the disease, and earlier, less intensive treatment. This latter feature clearly was the case in the series demonstrated in the workshop. Most patients (often older patients) who were treated with aggressive chemotherapy had died, whereas more recently and less intensively treated patients (anti-cd20 therapy, EBV-specific cytotoxic T-cell infusion) often were cured. This was true not only for cases that had developed after transplantation but also in cases of other immunodeficient states. The incidence is dependent on the organ that was transplanted (kidney, <5%; liver, >15%). An interesting case (case 43) showed that after anti- CD20 treatment, loss of expression of the CD20 epitope might occur, which can be a pitfall in the diagnosis. By far the most cases are B-cell lymphoproliferations, but other lymphoma types might occur, like different types of T-cell lymphomas 31 (cases 13, 15, 56, 133) and Hodgkin disease 32 (case 6). These latter types of lymphoma often occur years after the transplantation, and the strength of the relation between transplantation and the lymphomas is not clear. Most, however, carry the EBV genome. The prognosis seems similar to the lymphoma that develops in immunocompetent patients. Because rare cases often are included in workshops, there is an overrepresentation of them in the present report. The B-cell cases vary from polymorphous, innocent-looking infiltrates to the aggressive Burkitt lymphoma, and there is a relation with prognosis. 21 Most cases are mature, germinal center, or post germinal center lymphomas. 33 The pathologic diagnosis in these cases might be difficult, especially in early cases with a polymorphous infiltrate (case 1), which has features of reactive processes such as infection or rejection. The demonstration of EBV in these cases is important for the diagnosis. Iatrogenic Immune Deficiency Apart from the immunosuppression in the posttransplant situation, there are several other iatrogenic immunodeficient states. Although the literature on this topic in the pediatric age group is sparse, there were 2 cases of Crohn disease complicated by an EBV-driven lymphoproliferation (cases 48 and 53), one with Hodgkin-like features (case 53). More awareness of this complication is important, especially because more potent immunosuppressive drugs are used nowadays. From the Department of Pathology, University Medical Center Nijmegen, Nijmegen, the Netherlands. Address reprint requests to Dr van Krieken: Dept of Pathology, University Medical Center Nijmegen, PO Box 9101, 6500 HB Nijmegen, the Netherlands. References 1. Oertel SH, Riess H. Immunosurveillance, immunodeficiency and lymphoproliferations. Recent Results Cancer Res. 2002;159: Jaffe ES, Harris NL, Stein H, et al, eds. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; World Health Organization Classification of Tumours. 3. Pinkerton CR, Hann I, Weston CL, et al. Immunodeficiencyrelated lymphoproliferative disorders: prospective data from the United Kingdom Children s Cancer Study Group Registry. Br J Haematol. 2002;118: Okano M. Epstein-Barr virus in patients with immunodeficiency disorders. Biomed Pharmacother. 2001;55: Ganne V, Siddiqi N, Kamaplath B, et al. Humanized anti- CD20 monoclonal antibody (rituximab) treatment for posttransplant lymphoproliferative disorder. Clin Transpl. 2003;17: Serinet MO, Jacquemin E, Habes D, et al. Anti-CD20 monoclonal antibody (rituximab) treatment for Epstein-Barr virus associated, B-cell lymphoproliferative disease in pediatric liver transplant recipients. J Pediatr Gastroenterol Nutr. 2002;34: Schaar CG, van der Pijl JW, van Hoek B, et al. Successful outcome with a quintuple approach of posttransplant lymphoproliferative disorder. Transplantation. 2001;5;71: van Dongen JJ, Langerak AW, Bruggemann M, et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT Leukemia. 2003;17: Cunningham-Rundles C, Cooper DL, Duffy TP, et al. Lymphomas of mucosal-associated lymphoid tissue in common variable immunodeficiency. 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