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: Dec 20, 2006

Introduction

Background

Lymphoproliferative disorders (LPDs) in children represent a heterogeneous group of expanding, monoclonal or oligoclonal, and lymphoid neoplasms that only occur in the setting of immune dysfunction. The risk of true malignancy in affected children is 10- to 300-fold 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 LPD encountered.

Pathophysiology

Over the past 3 decades, scientific understanding of the human immune system has extraordinarily grown. Not all lymphocytes are the same, and they are broadly categorized as thymus-derived lymphocytes (T cells) or bone marrow–derived lymphocytes (B cells). Today, lymphocytes are easily measured and quantified from either peripheral blood or bone marrow by using panels of monoclonal antibodies that specifically recognize B- or T-cell antigens.

The 2 main functions of normal T cells are effector and regulatory. Effector functions include regulation of cell-mediated cytotoxicity, delayed hypersensitivity, and recognition of foreign antigens. Regulatory function includes cell-mediated and humoral immunity. Activated T cells produce a number of soluble factors termed chemokines and cytokines. These molecules locally and distantly modulate immune function in a wide variety of cell types. B cells are largely responsible for the synthesis and secretion of antibodies into blood, lymph, milk, and other interstitial tissues. T cells and B cells both undergo proliferation and then maturation, when rearrangements of T-cell receptors and immunoglobulin genes occur. These rearrangements allow for the complex interplay between the many cell subsets that make up the lymphocyte superfamily.

Although normal B cells synthesize immunoglobulins, B cells can undergo an abnormal expansion into a monoclonal B-cell lymphocytosis, which is morphologically indistinguishable from chronic lymphocytic leukemia (CLL). Longitudinal studies are required to determine whether monoclonal B cells are a heralding feature of CLL or other types of B-lymphoproliferative disease.

When any of the numerous control points of the immune system become dysfunctional, immunodeficiency or deregulation is likely to develop. LPDs in children occur in the setting of immunodysfunction.

Frequency

United States

LPDs only occur in children with immunodysfunction. The occurrence is difficult to track in children with inherited immunodeficiency states, but best estimates indicate that it represents <1 case per million children.

Mortality/Morbidity

Mortality and morbidity in children vary considerably and depend on the underlying immunodeficiency syndrome. As supportive care improves for patients after transplantation, the incidence of LPDs after transplantation is rising.

Race

Severe combined immune deficiency (SCID) syndrome appears to be slightly more prevalent in persons of Navajo descent than in others. However, no other evidence for racial predilection is reported.

Sex

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

Age

LPDs can occur in any age group, but they are relatively uncommon in infants and toddlers. They are progressively more common with age.

Clinical

Physical

• Physical findings most commonly include adenopathy, splenomegaly, or symptoms attributable to organ infiltration by an expanding lymphoid clone.
• Because the GI tract or lungs may be affected preferentially 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 a variety of lymphoid organs, and that have the distinct ability to undergo malignant transformation into true lymphoid malignancies.
  • Indeed, the risk of mortality from cancer is 10- to 300-fold 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.
• Inherited molecular causes of LPDs
  • X-linked LPDs
    • In boys with X-linked LPD, an overwhelming T-cell–mediated response to the Epstein-Barr virus (EBV) often leads to death from marrow failure, irreversible hepatitis, and malignant lymphoma.
    • The 3 phenotypes associated with the diagnosis of X-linked LPD are severe and mostly fatal infectious mononucleosis (58%), LPDs of B-cell origin (30%), and/or dysgammaglobulinemia (31%).
    • Mutations in the SH2-domain on band Xq25, which contains gene 1A (SH2D1A), result in X-linked LPD. This gene, also known as DSHP, or SAP, encodes a protein primarily expressed in T and NK cells. The protein functions as an intracellular adapter that transduces T- and NK-cell activation. SAP protein is expressed in T cells, natural killer (NK) cells, and NK T cells, on which it binds to the cytoplasmic domain of the surface receptor SLAM (CD150) and the related receptors, 2B4 (CD244), CD84, Ly9 (CD229), NK-T-B-antigen, and CD2-like receptor-activating cytotoxic T cells. SH2D1A elicits cellular activation by means of SLAM, a T-cell costimulatory molecule, or by means of 2B4, an NK-cell activator receptor.
    • Experimental data suggest that these molecules regulate important aspects of lymphocyte function, such as proliferation, cytokine secretion, cytotoxicity, and antibody production. These signaling abnormalities likely contribute to the phenotypes of X-linked LPD, which include fulminant infectious mononucleosis, lymphoma, and hypogammaglobulinemia.
    • Approximately 55% of EBV-negative patients eventually develop dysgammaglobulinemia or LPDs later in life. This finding suggests that the initial EBV infection is merely a powerful trigger for the immunologic abnormalities observed in X-linked LPD. The characterization of genetic abnormalities in SH2D1A enables the identification of affected male and female carriers.
  • Autosomal LPDs
    • Some children with autoimmune lymphoproliferative syndrome have heterozygous mutations in the Fas receptor (CD95), a key component of a major apoptotic pathway. As a consequence of these mutations, a primitive population of T cells proliferates in an uncontrolled manner, leading to the clinical sequelae of lymphoid infiltration, autoantibodies, and autoimmune disease.
    • Both of these models demonstrate the importance of the regulatory balance that must exist between T cells and B cells and other components of the immune system and which, when dysregulated, can lead to uncontrolled proliferation in cell populations that are immunologically active.
• Other inherited causes
  • Most LPDs 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 they are predisposed to develop LPDs 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 LPDs commonly occur in children with SCID. Of interest, immunoreconstitution with bone marrow transplantation in children with SCID can prevent LPDs and other sequelae of extreme immunodysfunction.
  • Chédiak-Higashi syndrome is transmitted as an autosomal recessive disorder characterized by giant lysosomes in neutrophils and other leukocytes. Patients also have incomplete oculocutaneous albinism, photophobia, and severe recurrent infections. Approximately 85% eventually enter an accelerated lymphomatous phase in which lymphoid and histiocytic cells infiltrate visceral tissue and in which they are likely to develop opportunistic infections. In addition, lymphadenopathy, hepatosplenomegaly, and pancytopenia frequently occur, possibly as the result of chronic EBV infection. The LYST gene is mutated in patients with Chédiak-Higashi syndrome. This gene is located at a 1q locus, but screening for mutations in this gene is difficult because of its large size.
  • Wiskott-Aldrich syndrome is an X-linked recessive disorder characterized by a triad of recurrent pyogenic infections, thrombocytopenia, and severe atopic dermatitis. The dermatitis can be associated with painful vasculitis and predispose to severe skin infections. As the child ages, T-cell function declines, with LPDs occurring in approximately 15% of patients. Extranodal and brain involvement with LPDs are commonplace. Again, chronic EBV infections are thought to play an important role in the development of this disorder.
  • 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 LPDs 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.
  • Of interest, unlike other disorders related to mutations of DNA damage repair genes, even heterozygotes for ataxia telangiectasia have an increased risk of developing cancer, while the risk of homozygotes to develop leukemia or lymphoma may be as high as 40% over a lifetime.
• 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.
• Iatrogenic causes
  • LPDs associated with organ transplantation and concomitant immunosuppressive therapy are increasingly common. Posttransplantation LPDs 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 LPD is of B-cell origin; however, in rare cases, T-cell LPDs are described.
  • Most posttransplantation LPDs occur in the setting of a solid organ transplantation, especially cardiac transplantation. In these cases, posttransplantation LPD is likely the consequence of prolonged therapy with sirolimus, tacrolimus, cyclosporine A, or other profound inhibitors of T-cell function.
  • LPDs have been described as posttransplant complications when alemtuzumab (antiCD52 monoclonal antibody) is included in the preparative regimen.

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