Lymphoproliferative Disorders 

Updated: Apr 18, 2019
Author: Donna A Wall, MD; Chief Editor: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP 

Overview

Background

Lymphoproliferative disorders (LPDs) in children represent a heterogeneous group of expanding, monoclonal or oligoclonal, lymphoid cells 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.

Epidemiology

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 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.

Age

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

 

Presentation

Physical

See the list below:

  • Physical findings of lymphoproliferative disorders (LPDs) most commonly include adenopathy, splenomegaly, or symptoms attributable to organ infiltration by the abnormal lymphoid cells.

  • Because the GI tract or lungs may be preferentially affected in certain subtypes, abdominal bloating or pulmonary findings may dominate the physical examination.

Causes

See the list below:

  • 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[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 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.[6]

  • 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 following 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.[7]

    • 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.[8, 9, 10]

    • 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.[11]

  • 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.[12]

    • 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,[13] 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).[14] 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 1 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.[14]

 

DDx

Differential Diagnoses

 

Workup

Laboratory Studies

See the list below:

  • General tests in lymphoproliferative disorders (LPDs)

    • Clinical findings indicate local or distant adenopathy and hepatosplenomegaly.

    • In certain conditions, the GI tract or lung tissue may also be affected.

  • Biochemical panel

    • Perform serologic tests for cytomegalovirus and Epstein-Barr virus (EBV).

    • Measure the erythrocyte sedimentation rate.

    • Evaluate electrolyte, BUN, creatinine, phosphate, calcium, and uric acid levels to rule out tumor lysis syndrome.

    • Assess lactate dehydrogenase levels to assess the neoplastic burden.

Imaging Studies

See the list below:

  • Radiography

    • CT scans obtained with intravenous or oral contrast material can help in determining the true extent of abdominal adenopathy, infiltration of the bowel wall, and the accurate sizes of tumorous masses. This information is important for staging and assessing therapeutic response. For example, the CT scan in the image below reveals parenchymal nodularities.

      Parenchymal nodularities. Parenchymal nodularities.
    • MRI studies of soft-tissue infiltrative processes can refine the clinician's understanding of the tumor burden and the potential that vital structures might be compromised.

    • Chest radiography is performed in patients with pulmonary lesions to follow the progression or regression of disease. In some patients, pulmonary functional tests can provide further objective evidence of disease progression or a therapeutic response.

  • Bone scanning

  • Ultrasonography: Ultrasonography is sometimes helpful.

  • Small bowel follow-through study: In children with GI lesions, this test helps in diagnosing ileal disease.

Other Tests

See the list below:

  • As with all neoplastic processes, "the tissue is the issue." In rapidly growing tumors, areas of necrotic tissue may complicate morphologic use of fine-needle aspirates.

  • EBV detection by means of Southern blot hybridization or polymerase chain reaction (PCR) can be helpful. The in situ hybridization of the EBV-encoded RNA (EBER) test has become a useful adjunct in the diagnosis of EBV-related lymphoproliferative disorders.

Procedures

See the list below:

  • Examination of the bone marrow may help in differentiating metastatic disease from other diseases.

  • Diagnostic spinal tap is used in children with primary tumors involving the head or neck region to exclude spread to the neuraxis.

  • Surgical resection does not play an important role in the control of lymphoproliferative disorders. Most lymphoproliferative tumors are not easily resectable and, given the underlying nature of the affected cell type, rapid lymphatic spread to distant sites is common.

Histologic Findings

See the list below:

  • Important histologic findings often include an amorphous oligoclonal or monoclonal population of immature-appearing lymphocytes. Histologic samples tend to show either polymorphic or monomorphic infiltrates of lymphocytes.

  • In most cases, flow cytometric and cytogenetic analyses show polyclonal populations of B cells or T cells without cytogenetic abnormalities. These features can distinguish lymphoproliferative disorders from true malignancies, which frequently show monoclonal cell populations and acquired cytogenetic abnormalities. However, the cell morphology occasionally mimics specific malignant lymphomas, such as Hodgkin disease or Burkitt lymphoma.

 

Treatment

Medical Care

See the list below:

  • Children with inherited immunodeficiency syndromes

    • Truly malignant neoplasms are sometimes difficult to differentiate from nonmalignant lymphoproliferative disorders (LPDs) with aggressive features. When the underlying immunodeficiency manifested to only a minor degree and when the histologic features are marked nuclear atypia and other features of a high-grade neoplasm, standard chemotherapeutic regimens are usually recommended. These regimens include cyclophosphamide, prednisone, vincristine, and doxorubicin.

    • In other cases, local control of the lymphoproliferative disorder by using surgical resection or irradiation with adjunctive interleukin-2 or monoclonal antibody therapy may prove beneficial.

    • Boys with X-linked immunodeficiency syndrome appear to benefit from immunoglobulin therapy.

    • If cytotoxic therapy is chosen in child with an underlying immunodeficiency syndrome, myelosuppressive therapy may worsen their immunocompromise beyond what is ordinarily expected. Therefore, care should be taken to begin support for febrile neutropenia and other infections in a timely fashion. As described above, bone marrow reconstitution with an immunocompetent donor appears to be the best method to prevent lymphoproliferative disorders in children with severe inherited immunodeficiency syndromes.

  • Patients with posttransplant lymphoproliferative disorder (PTLD)

    • PTLDs are varied and somewhat depend on the nature of the allograft and on the immunosuppressive agents used to prevent graft (or host) rejection. The histologic grades of lymphoproliferative disorders can vary widely in this setting and range from a benign oligoclonal expansion of lymphoid cells to a high-grade neoplastic process. Low-grade tumors usually respond favorably to a reduction in immunosuppression, whereas high-grade tumors may require chemotherapy, irradiation, and/or surgery.

    • Cyclosporin A and antithymocyte globulin are associated with the development of lymphoproliferative disorders within months of transplantation, often in the GI tract. In many instances, Epstein-Barr virus (EBV) DNA transcripts can be identified with Southern blotting, anti-EBV-encoded RNA (EBER) staining, or polymerase chain reaction (PCR), but results of serologic tests are frequently nonreactive. The lymphocytic infiltration into transplanted organs can often mimic organ rejection.

    • In contrast to the lymphoproliferative disorders observed in primary immunodeficiency syndromes, a sometimes successful treatment after transplantation is to decrease or discontinue immunosuppressive drug therapy.

Surgical Care

See the list below:

  • Surgical resection can sometimes play an important role in managing lymphoproliferative disorders.

  • Circumstances are limited to obtaining enough tissue to make a diagnosis and to debulking large tumors that compromise surrounding vital structures. However, in most cases, the primary means to control lymphoproliferative disorders is medical management.

Consultations

See the list below:

  • In children with a suspected lymphoproliferative disorders, consultation with a physician familiar with the underlying immunodeficiency syndrome is indicated, in addition to consultation with a pediatric oncologist.

  • Consider an infectious process with appropriate consultation with a pediatric infectious disease specialist.

Diet

See the list below:

  • In children, diet does not appear to play a role in the pathogenesis or treatment of lymphoproliferative disorders.

Activity

See the list below:

  • Activity does not appear to play a role in the treatment or pathogenesis of lymphoproliferative disorders.

 

Medication

Antineoplastic agents

Class Summary

Prescribe chemotherapeutic agents only to children with the help of clinicians who are experienced with the doses and toxicities of these drugs. The drugs detailed below are those used in standard CHOP regimen and include cyclophosphamide, hydroxydaunomycin (doxorubicin), vincristine (Oncovin), and prednisone.

Doxorubicin (Adriamycin)

Alkylating agent with several mechanisms of action (eg, DNA intercalation, topoisomerase-mediated DNA strand breaks, oxidative damage by producing free radicals).

Cyclophosphamide (Cytoxan)

Exerts cytotoxic effect by alkylation of DNA, leading to interstrand and intrastrand DNA crosslinks, DNA-protein crosslinks and inhibition of DNA replication.

Vincristine (Oncovin)

Plant-derived vinca alkaloid. Inhibits mitosis by binding tubulin. Inhibits microtubule formation in mitotic spindle, arresting metaphase.

Prednisone (Deltasone, Meticorten, Orasone, Sterapred)

Combines ubiquitous uses and likely to downregulate inflammatory proteins by directly signaling with intrachromosomal binding sites.

Antiemetic agents

Class Summary

Antineoplastic-induced vomiting is stimulated through the chemoreceptor trigger zone, which then stimulates the vomiting center in the brain. Increased activity of central neurotransmitters, dopamine in the chemoreceptor trigger zone or acetylcholine in the vomiting center appears to be major mediators for inducing vomiting. After the administration of antineoplastic agents, serotonin (5-HT) is released from enterochromaffin cells in the GI tract. With release of 5-HT and its subsequent binding to 5-HT3-receptors, vagal neurons are stimulated and transmit signals to the vomiting center, resulting in nausea and vomiting.

Antineoplastic agents may cause nausea and vomiting so intolerable that patients may refuse further treatment. Some antineoplastic agents are more emetogenic than others. Prophylaxis with antiemetic agents before and after cancer treatment is often essential to ensure administration of the entire chemotherapy regimen.

Ondansetron (Zofran)

Selective 5-HT3–receptor antagonist that blocks 5-HT peripherally and centrally. Ameliorates chemotherapy-induced nausea and vomiting.

Uroprotective antidote

Class Summary

Mesna is a prophylactic detoxifying agent used to inhibit hemorrhagic cystitis caused by ifosfamide and cyclophosphamide.

In the kidney, mesna disulfide is reduced to free mesna. Free mesna has thiol groups that react with acrolein, which is the ifosfamide and cyclophosphamide metabolite considered responsible for urotoxicity.

Mesna (Mesnex)

Inactivates acrolein and prevents urothelial toxicity without affecting cytostatic activity.

 

Follow-up

Further Inpatient Care

See the list below:

  • Follow-up care of a child with lymphoproliferative disorder (LPD) can range from simple (eg, watchful observation) to very complex (bone marrow transplantation).

  • Coordinate with a team of subspecialists familiar with immunodeficiency disorders and the management of potentially toxic drug therapy.

Inpatient & Outpatient Medications

See the list below:

  • Inpatient and outpatient drugs depend on the nature of the underlying immunodeficiency syndrome.

Deterrence/Prevention

See the list below:

  • The best preventive measure is to correct the underlying immunodeficiency syndrome.

  • Children who have had a bone marrow transplant with an immunocompetent graft are unlikely to develop problems with a lymphoproliferative disorder.

Prognosis

See the list below:

  • Lymphoproliferative disorders prognoses are determined by the prevalence of immunodeficiency in the patient.

  • Ordinarily, a favorable response in a relatively immunocompetent patient is a good prognostic factor for long-term survival. Lymphoproliferative disorders of low-grade histological features tend to remit with a reduction of immunosuppression, whereas higher-grade lymphoproliferative disorders require a more aggressive therapeutic approach and often require several cycles of CHOP therapy with close follow-up.