Lymphoproliferative Disorders Clinical Presentation

  • Author: Donna A Wall, MD; Chief Editor: Robert J Arceci, MD, PhD   more...
 
Updated: Mar 12, 2012
 

Physical

  • 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.
Next

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[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.
    • 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,[12] 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.
Previous
Proceed to Differential Diagnoses
 
 
Contributor Information and Disclosures
Author

Donna A Wall, MD  Professor of Pediatrics and Child Health, University of Manitoba; Director, Manitoba Blood and Marrow Transplant Program, Director, Cellular Therapy Laboratory, CancerCare Manitoba

Donna A Wall, MD is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Association of Immunologists, American Medical Association, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society of Hematology, and American Society of Pediatric Hematology/Oncology

Disclosure: Nothing to disclose.

Specialty Editor Board

Kathleen M Sakamoto, MD, PhD  Professor and Chief, Division of Hematology-Oncology, Vice-Chair of Research, Mattel Children's Hospital at UCLA; Co-Associate Program Director of the Signal Transduction Program Area, Jonsson Comprehensive Cancer Center, California Nanosystems Institute and Molecular Biology Institute, University of California, Los Angeles, David Geffen School of Medicine

Kathleen M Sakamoto, MD, PhD is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology, International Society for Experimental Hematology, Society for Pediatric Research, and Western Society for Pediatric Research

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Timothy P Cripe, MD, PhD  Professor of Pediatrics, Division of Hematology/Oncology, Cincinnati Children's Hospital Medical Center; Clinical Director, Musculoskeletal Tumor Program, Co-Medical Director, Office for Clinical and Translational Research, Cincinnati Children's Hospital Medical Center; Director of Pilot and Collaborative Clinical and Translational Studies Core, Center for Clinical and Translational Science and Training, University of Cincinnati College of Medicine

Timothy P Cripe, MD, PhD is a member of the following medical societies: American Association for the Advancement of Science, American Pediatric Society, American Society of Hematology, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Samuel Gross, MD  Professor Emeritus, Department of Pediatrics, University of Florida; Clinical Professor, Department of Pediatrics, University of North Carolina; Adjunct Professor, Department of Pediatrics, Duke University

Samuel Gross, MD is a member of the following medical societies: American Association for Cancer Research, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society of Hematology, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Chief Editor

Robert J Arceci, MD, PhD  King Fahd Professor of Pediatric Oncology, Professor of Pediatrics, Oncology and the Cellular and Molecular Medicine Graduate Program, Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine

Robert J Arceci, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Pediatric Society, American Society of Hematology, and American Society of Pediatric Hematology/Oncology

Disclosure: Nothing to disclose.

References

  1. Spector BD, Perry GS III, Kersey JH. Genetically determined immunodeficiency diseases (GDID) and malignancy: report from the immunodeficiency--cancer registry. Clin Immunol Immunopathol. Sep 1978;11(1):12-29. [Medline].

  2. Dronca RS, Jevremovic D, Hanson CA, Rabe KG, Shanafelt TD, Morice WG, et al. CD5-positive chronic B-cell lymphoproliferative disorders: diagnosis and prognosis of a heterogeneous disease entity. Cytometry B Clin Cytom. 2010;78 Suppl 1:S35-41. [Medline]. [Full Text].

  3. Sciallis AP, Law ME, Inwards DJ, McClure RF, Macon WR, Kurtin PJ, et al. Mucosal CD30-positive T-cell lymphoproliferations of the head and neck show a clinicopathologic spectrum similar to cutaneous CD30-positive T-cell lymphoproliferative disorders. Mod Pathol. Mar 2 2012;[Medline].

  4. Engel P, Eck MJ, Terhorst C. The SAP and SLAM families in immune responses and X-linked lymphoproliferative disease. Nat Rev Immunol. Oct 2003;3(10):813-21. [Medline].

  5. Latour S. Natural killer T cells and X-linked lymphoproliferative syndrome. Curr Opin Allergy Clin Immunol. Dec 2007;7(6):510-4. [Medline].

  6. Worth A, Thrasher AJ, Gaspar HB. Autoimmune lymphoproliferative syndrome: molecular basis of disease and clinical phenotype. Br J Haematol. Apr 2006;133(2):124-40. [Medline].

  7. Kaplan J, De Domenico I, Ward DM. Chediak-Higashi syndrome. Curr Opin Hematol. Jan 2008;15(1):22-9. [Medline].

  8. Notarangelo LD, Miao CH, Ochs HD. Wiskott-Aldrich syndrome. Curr Opin Hematol. Jan 2008;15(1):30-6. [Medline].

  9. Boztug K, Schmidt M, Schwarzer A, Banerjee PP, Díez IA, Dewey RA, et al. Stem-cell gene therapy for the Wiskott-Aldrich syndrome. N Engl J Med. Nov 11 2010;363(20):1918-27. [Medline]. [Full Text].

  10. Ishihara D, Dovas A, Park H, Isaac BM, Cox D. The chemotactic defect in wiskott-Aldrich syndrome macrophages is due to the reduced persistence of directional protrusions. PLoS One. 2012;7(1):e30033. [Medline]. [Full Text].

  11. Houshmand M, Kasraie S, Etemad Ahari S, Moin M, Bahar M, Zamani A. Investigation of tRNA and ATPase 6/8 gene mutations in Iranian ataxia telangiectasia patients. Arch Med Sci. Jun 2011;7(3):523-7. [Medline]. [Full Text].

  12. Ohta H, Fukushima N, Ozono K. Pediatric post-transplant lymphoproliferative disorder after cardiac transplantation. Int J Hematol. Sep 2009;90(2):127-36. [Medline].

  13. Baehner RL. Lymphocytes. In: Miller DR, Baehner RL, eds. Blood Diseases in Infancy and Childhood. St. Louis, MO: CV Mosby; 1990:578-603.

  14. Bird AG, Britton S. The relationship between Epstein-Barr virus and lymphoma. Semin Hematol. Oct 1982;19(4):285-300. [Medline].

  15. Brusamolino E, Pagnucco G, Bernasconi C. Secondary lymphomas: a review on lymphoproliferative diseases arising in immunocompromised hosts: prevalence, clinical features and pathogenetic mechanisms. Haematologica. Nov-Dec 1989;74(6):605-22. [Medline].

  16. Certain S, Barrat F, Pastural E, et al. Protein truncation test of LYST reveals heterogenous mutations in patients with Chediak-Higashi syndrome. Blood. Feb 1 2000;95(3):979-83. [Medline].

  17. Craig FE, Gulley ML, Banks PM. Posttransplantation lymphoproliferative disorders. Am J Clin Pathol. Mar 1993;99(3):265-76. [Medline].

  18. Fiorilli M, Carbonari M, Crescenzi M, et al. T-cell receptor genes and ataxia telangiectasia. Nature. Jan 17-23 1985;313(5999):186. [Medline].

  19. Kempf W. CD30+ lymphoproliferative disorders: histopathology, differential diagnosis, new variants, and simulators. J Cutan Pathol. Feb 2006;33 Suppl 1:58-70. [Medline].

  20. Locker J, Nalesnik M. Molecular genetic analysis of lymphoid tumors arising after organ transplantation. Am J Pathol. Dec 1989;135(6):977-87. [Medline].

  21. Loughrey M, Trivett M, Lade S, et al. Diagnostic application of Epstein-Barr virus-encoded RNA in situ hybridisation. Pathology. Aug 2004;36(4):301-8. [Medline].

  22. Lundell R, Elenitoba-Johnson KS, Lim MS. T-cell posttransplant lymphoproliferative disorder occurring in a pediatric solid-organ transplant patient. Am J Surg Pathol. Jul 2004;28(7):967-73. [Medline].

  23. Marti GE, Rawstron AC, Ghia P, et al. Diagnostic criteria for monoclonal B-cell lymphocytosis. Br J Haematol. Aug 2005;130(3):325-32. [Medline].

  24. Nichols KE. X-linked lymphoproliferative disease: genetics and biochemistry. Rev Immunogenet. 2000;2(2):256-66. [Medline].

  25. Rigaud S, Fondaneche MC, Lambert N, et al. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature. Nov 2 2006;444(7115):110-4. [Medline].

  26. Sanal O, Wei S, Foroud T, et al. Further mapping of an ataxia-telangiectasia locus to the chromosome 11q23 region. Am J Hum Genet. Nov 1990;47(5):860-6. [Medline].

  27. Sander CA, Medeiros LJ, Weiss LM, et al. Lymphoproliferative lesions in patients with common variable immunodeficiency syndrome. Am J Surg Pathol. Dec 1992;16(12):1170-82. [Medline].

  28. Snyder MJ, Stenzel TT, Buckley PJ, et al. Posttransplant lymphoproliferative disorder following nonmyeloablative allogeneic stem cell transplantation. Am J Surg Pathol. Jun 2004;28(6):794-800. [Medline].

  29. Straus SE, Sneller M, Lenardo MJ, et al. An inherited disorder of lymphocyte apoptosis: the autoimmune lymphoproliferative syndrome. Ann Intern Med. Apr 6 1999;130(7):591-601. [Medline].

  30. Su HC, Lenardo MJ. Genetic defects of apoptosis and primary immunodeficiency. Immunol Allergy Clin North Am. May 2008;28(2):329-51, ix. [Medline].

  31. Uzel G. The range of defects associated with nuclear factor kappaB essential modulator. Curr Opin Allergy Clin Immunol. Dec 2005;5(6):513-8. [Medline].

  32. Vetrie D, Vorechovsky I, Sideras P, et al. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature. Jan 21 1993;361(6409):226-33. [Medline].

 
Previous
Next
 
Parenchymal nodularities.
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2012 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.