eMedicine Specialties > Pediatrics: General Medicine > Oncology

Lymphoproliferative Disorders

Author: Stuart S Winter, MD, Associate Professor, Department of Pediatrics, University of New Mexico Health Sciences Center
Contributor Information and Disclosures

Updated: Nov 24, 2009

Introduction

Background

Lymphoproliferative disorders (LPDs) in children represent a heterogeneous group of expanding, monoclonal or oligoclonal, lymphoid neoplasms that occur in the setting of immune dysfunction. The risk of true malignancy in affected children is significantly higher than the risk in immunocompetent children. Treatment must be tailored to the child's underlying immune disorder, to the aggressiveness of the clone, and to the likelihood of causing clinically significant toxicity.

In this article, underlying immunodeficiency disorders are reviewed in the context of the type of lymphoproliferative disorder encountered.

Pathophysiology

See Causes.

Frequency

United States

Lymphoproliferative disorders occur in children with immunodysfunction. Because this is a heterogeneous disease group, the incidence rate is difficult to estimate.

Mortality/Morbidity

Mortality and morbidity in children vary considerably and depend on the underlying immunodeficiency syndrome.

Race

Overall, no significant racial predilection has been reported.

Sex

The overall male-to-female ratio is 1:1, except for X-linked immunodeficiency syndromes, which primarily affect male individuals; however, X-linked immunodeficiency syndrome occasionally affects female individuals. In scenarios such as this, hypermorphic mutations in the gene that encodes NFkappaB essential modifier (NEMO), which can be inherited in autosomal dominant fashion, lead to immunodeficiency syndromes in members of both sexes.

Age

Lymphoproliferative disorders can occur in any age group but are relatively uncommon in infants and toddlers. They become progressively more common with age.

Clinical

Physical

• Physical findings of lymphoproliferative disorders (LPDs) most commonly include adenopathy, splenomegaly, or symptoms attributable to organ infiltration by an expanding lymphoid clone.
• Because the GI tract or lungs may be preferentially affected in certain subtypes, abdominal bloating or pulmonary findings may dominate the physical examination.

Causes

• Childhood immunodeficiency syndromes
  • Although the clinical features are somewhat similar among patients, the predisposing abnormalities of lymphocyte-mediated immune function stems from a heterogeneous group of childhood immunodeficiency syndromes.
  • These inherited, acquired, or iatrogenically induced immunodeficiency syndromes predispose the person to the formation of a pool of lymphocytes that proliferate unchecked, that infiltrate various lymphoid organs, and that have the distinct ability to undergo malignant transformation into true lymphoid malignancies.
  • Indeed, the risk of mortality from cancer is higher in affected patients than in immunocompetent children.
  • Approximately 60% of the tumors identified in patients in the Immunodeficiency Disease Registry are lymphoid neoplasms, most of which manifest by the age of 11 years.¹
• Inherited molecular causes of lymphoproliferative disorders
  • X-linked lymphoproliferative disorders 
    • These disorders are characterized by an extreme susceptibility to Epstein-Barr virus (EBV) infection. Three main phenotypes of X-linked lymphoproliferative disorders are noted: fulminant infectious mononucleosis (50%), B-cell lymphoma (30%), and dysgammaglobulinemia (30%).²
    • On a molecular basis, these disorders are divided in 2 distinct diseases: XLP-1 and XLP-2, which represent 80% and 20% of cases, respectively.³ XLP-1 is caused by mutations in the gene SAP. The gene SAP encodes a small signaling adaptor protein that is expressed in T, natural killer (NK), and NKT cells. Defects in SAP signaling pathways are thought to be responsible for these disorders; however, the details are still not clearly understood. XLP-2 is caused by mutations in the gene XIAP. The gene XIAP encodes an antiapoptotic molecules and is broadly expressed in hematopoietic cells, including lymphocytes and NK cells. Both SAP and XIAP are closely located at chromosome Xq25, suggesting a possible functional link between the genes.
  • Autoimmune lymphoproliferative syndrome (ALPS): ALPS is characterized by lymphoproliferative disorder, autoimmune cytopenias, and a susceptibility to malignancy. The pathogenesis involves defective FAS -induced apoptosis, which, in turn, leads to dysregulation of lymphocyte homeostasis. Most patients have heterozygous mutations in the FAS gene, but mutations in FAS ligand, caspase-8, and caspase-10, all of which are involved in FAS- mediated signaling, have been identified.⁴
• Other inherited causes
  • Most lymphoproliferative disorders in children with X-linked agammaglobulinemia are non-Hodgkin lymphoreticular B cell neoplasms. This immunodeficiency syndrome is caused by a defect in the BTK gene, a member of the SRC gene family localized to Xq21.3-Xq22. This genetic abnormality impairs B-cell maturation. Boys with X-linked immunodeficiency syndrome are at high risk for mortality associated with EBV infections and are predisposed to develop lymphoproliferative disorders and lymphoma.
  • Among children with common variable immune deficiency (CVID), the incidence of lymphoreticular malignancies also increases and frequently results in intestinal lymphomas. Approximately 30% of children with CVID have splenomegaly, diffuse adenopathy, and even extranodal infiltration into intestinal tissue that mimics lymphoma. EBV-containing B-cell lymphoproliferative disorders commonly occur in children with severe combined immunodeficiency (SCID). Of interest, immunoreconstitution with bone marrow transplantation in children with SCID can prevent lymphoproliferative disorders and other sequelae of extreme immunodysfunction.
  • Chédiak-Higashi syndrome (CHS) is an autosomal recessive disorder characterized by severe immunodeficiency, bleeding tendency, frequent bacterial infections, variable albinism, and progressive neurologic dysfunction. Patients eventually develop an "accelerated phase," which is characterized by a lymphocytic infiltration of the major organs of the body. Classical pathology is giant lysosome in all cell types. Mutations in the gene CHS1/LYST are associated with CHS; however, the mechanism is unknown.⁵
  • Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by thrombocytopenia, small platelets, eczema, recurrent infections, immunodeficiency, and a high incidence of autoimmune disease and malignancies. It is caused by mutations of the WAS protein (WASP) gene. WASP is involved in signaling, cell locomotion, and immune synapse formation.⁶
  • Ataxia telangiectasia is inherited as an autosomal recessive disorder due to genetic mutations of the ATM gene on band 11q22-23. ATM is a member of the large phosphatidylinositol-3 kinase family and plays an important role in mediating the cellular response to DNA damage. As a result of ATM mutations, patients with ataxia telangiectasia present with cerebellar degeneration, immunodeficiency, sensitivity to radiation, and a predisposition to develop lymphoproliferative disorders bearing a T-cell phenotype. Mutations also result in abnormalities in cell-cycle control because of S-phase progression. This syndrome is due to increased chromosomal breakage, which commonly affects rearrangement of lymphoid antigen-receptor genes.
• Acquired causes
  • Congenital HIV infection is the most common cause for acquired immunodeficiency in children.
  • Affected children can present with diffuse adenopathy as a prodrome of AIDS, but cases of lymphadenopathic forms of Kaposi sarcoma have been reported.
• Posttransplant lymphoproliferative disorder (PTLD)
  • Lymphoproliferative disorders associated with transplantation and concomitant immunosuppressive therapy are increasingly common. PTLDs are varied and somewhat depend on the nature of the allograft and on the immunosuppressive agents used to prevent graft (or host) rejection. In most cases, the lymphoproliferative disorder is of B-cell origin; however, in rare cases, T-cell lymphoproliferative disorders are described.
  • Most PTLDs occur in the setting of a solid organ transplantation. The primary risk factor appears to be EBV seronegativity at time of transplant. The type of organ transplanted has also been identified as a risk factor. Lung, small bowel, and multiple organ grafts are identified as high risk compared with kidney, heart,⁷ and liver. The more T-cell specific the immunosuppression used, the higher the incidence of PTLD.
  • The incidence of PTLD following bone marrow transplantation is lower than PTLD following solid organ transplantation. Essentially all PTLD following bone marrow transplantation is associated with EBV. Any factors that either stimulate B-cell proliferation and/or decrease or delay T-cell immunity increase the risk of PTLD. For allogeneic recipients, the risk of PTLD has consistently been found to be strongly associated with human leukocyte antigen (HLA) disparity.

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