Lymphoproliferative Disorders

Updated: Mar 02, 2023
  • Author: Lianna Marks, MD; Chief Editor: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK)  more...
  • Print

Practice Essentials

Lymphoproliferative disorders (LPDs) in children represent a heterogeneous group of conditions characterized by the expansion of monoclonal or polyclonal lymphoid cells in the setting of immune dysfunction. The risk of true malignancy in immunocompromised 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.


Pathophysiology and Etiology


Lymphoproliferative disorders occur when physiological mechanisms that control proliferation of lymphocytes break down, resulting in uncontrolled proliferation of immune cells leading to lymphocytosis and lymphadenopathy.


Childhood immunodeficiency syndromes

Although the clinical features are somewhat similar among patients, the predisposing abnormalities of lymphocyte-mediated immune function stem 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 50% of the tumors identified in patients in the Immunodeficiency Disease Registry are lymphoid neoplasms. Patients with immunodeficiencies are almost 10 times more likely to develop lymphoma than the age-matched general population. [1]

Inherited causes of lymphoproliferative disorders [2, 3]

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%). [4]

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. [5]  XLP-1 is caused by mutations in the gene SH2D1A  which encodes SLAM-associated protein (SAP) 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. [6]

Other inherited causes

X-linked agammaglobulinemia 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. [7]

Common variable immune deficiency (CVID) encompasses a group of hypogammaglobulinemia syndromes in which patients have reduced serum concentrations of immunoglobulin G (IgG), IgA, and usually IgM, together with loss of protective antibodies and an increased incidence of lymphoreticular malignancies. Approximately 30% of children with CVID have splenomegaly, diffuse adenopathy, and even extranodal infiltration into intestinal tissue that mimics lymphoma. [8, 9]

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. [10]

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. [11, 12, 13]

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. [14]

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.

Post-transplant lymphoproliferative disorder (PTLD)

Lymphoproliferative disorders associated with transplantation and concomitant immunosuppressive therapy are increasingly common. PTLDs are varied and risk depends 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. [15]

Most PTLDs occur in the setting of a solid organ transplantation. The primary risk factor is EBV seronegativity at time of transplant, which is more common in children than in adults. 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, [16]  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.

Weintraub et al conducted a retrospective chart review of pediatric solid-organ transplant recipients (aged 0 to 21 years) at a single institution between 2001 and 2009 to identify risk factors for the development of posttransplant lymphoproliferative disease (PTLD). [17]  A total of 350 pediatric patients received a solid organ transplant during the study period. Of those patients, 90 (25.7%) developed Epstein-Barr virus (EBV) viremia. Of those, 28 (31%) developed PTLD. The median age at time of transplant was 11.5 months in the PTLD group and 21.5 months in the EBV viremia–only group. All patients who developed PTLD had one or more clinical symptoms. Younger age at transplant, increased immunosuppression before the development of EBV viremia, higher peak EBV level, and the presence of clinical symptoms were found to be predictive of the development of PTLD in solid-organ transplant recipients who had EBV viremia. [17]



United States statistics

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

Race-, sex-, and age-related demographics

Overall, no significant racial predilection has been reported.

The majority of disorders are autosomal recessive and affect both sexes equally with a male-to-female ratio of 1:1. A small but distinct population suffer from X-linked immunodeficiency syndromes, which almost exclusively affect male individuals; but may affect females if mutations in the gene that encodes NFkappaB essential modifier (NEMO) are involved, which is inherited in autosomal dominant fashion.

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



Lymphoproliferative disorders of low-grade histologic features tend to remit with a reduction of immunosuppression, whereas higher-grade lymphoproliferative disorders require a more aggressive, response-based therapeutic approach.


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