Overview of Lymphoproliferative Disorders Associated with Primary Immune Deficiency Disorders



Overview of Lymphoproliferative Disorders Associated with Primary Immune Deficiency Disorders


Keyur Patel, MD, PhD








Chronic granulomatous inflammation involving lymph node in a patient with common variable immunodeficiency (CVID).






B-cell lymphoma with polymorphous features in a patient with ataxia-telangiectasia (AT).


TERMINOLOGY


Definitions



  • Lymphomas and lymphoma-like lesions arising in clinical setting of primary immunodeficiency



    • Primary immunodeficiency disorders are a heterogeneous group of genetic diseases that result in an immunocompromised state


Abbreviations



  • Primary immunodeficiency disorders (PID)


Synonyms



  • Primary immune disorders


  • Congenital immunodeficiency diseases (disorders)


EPIDEMIOLOGY


Incidence



  • Variable incidence of clinically evident PID in USA



    • Cumulative incidence: 1 in 10,000


    • Incidence likely higher but some diseases are not evident clinically


  • Lymphoproliferative disorders (LPDs) associated with PID



    • LPDs are most common neoplasms in patients with PID



      • Up to 75% of all neoplasms in a given PID


    • Risk of developing LPD varies by type of PID, ranging 0.7-15% (accurate estimation is difficult due to low incidence)


Age Range



  • PIDs are more common in pediatric age group



    • Exception: Common variable immunodeficiency disease (CVID) occurs in adults


  • Median age of LPD onset: 7.1 years (per Immunodeficiency-Cancer Registry)



    • Recent increase in LPDs at older ages due to better survival of PID patients


Gender



  • More common in males; true for X-linked as well as for autosomal recessive disorders


ETIOLOGY/PATHOGENESIS


Etiology



  • Gene mutations account for many PIDs



    • X-linked hyper-IgM syndrome (XHIGM): CD40 or CD40 ligand (CD40LG)


    • Autoimmune lymphoproliferative syndrome (ALPS): FAS or FAS ligand (FASLG)


    • Ataxia-telangiectasia (AT): ATM


    • Nijmegen breakage syndrome (NBS): NBS1 (nibrin)


  • Complex abnormalities account for other PIDs



    • Wiskott-Aldrich syndrome exhibits defective function of T cells, B cells, neutrophils, and macrophages


Pathogenesis



  • Basis for increased risk of hematologic neoplasms is poorly understood; likely multifactorial



    • Epstein-Barr virus infection drives subset of LPDs in PID settings


    • Defective DNA mismatch repair involved in AT and NBS


    • Possible underlying immune defect against cancer cells


CLINICAL IMPLICATIONS


Clinical Presentation



  • Patients with PID often present with recurrent infection



    • Fever, fatigue, infectious-mononucleosis-like syndrome



  • Lymphadenopathy &/or hepatosplenomegaly occur in ALPS and X-linked lymphoproliferative syndrome (XLP)



    • In XLP, fulminant infectious mononucleosis (FIM) can occur, which is marked by fever, rash, generalized lymphadenopathy, and hepatomegaly


Site



  • LPDs in PID often present in extranodal sites


Treatment



  • Reduced risk of LPD after allogeneic stem cell transplant in PIDs


  • Limited data due to rarity of PIDs and lack of randomized trials


  • Recommendation is to treat with histologic subtype-specific protocol


  • Possible role for immunoregulatory therapy (e.g., interferon-α 2b)


Prognosis



  • Related to both underlying PID and type of LPD



    • Most LPDs in PID patients are clinically aggressive


    • Self limited, ALPS; clinically indolent, common variable immunodeficiency (CVID)


  • Newer antimicrobial therapies that allow more aggressive treatments have improved prognosis


  • Fatal hemophagocytic syndrome can occur in EBV-driven infectious mononucleosis



    • Occurs in XLP and severe combined immunodeficiency (SCID)


MICROSCOPIC FINDINGS


Nonneoplastic Lesions in Lymph Nodes



  • Spectrum of morphologic abnormalities


  • Subtle alterations may require immunophenotyping


  • Common findings



    • Lymphoid depletion


    • Atrophic follicles with progressive depletion of germinal centers


    • Depletion of small lymphocytes in paracortical region with increase in histiocytes and plasma cells


    • Similar findings observed in spleen and tonsils at autopsy


  • Secondary changes



    • Chronic granulomatous inflammation secondary to infections


    • Florid reactive hyperplasia


    • Atypical hyperplasia


  • Fatal infectious mononucleosis (FIM) resulting from EBV infection (XLP, SCID)



    • Extreme atypical hyperplasia


    • Polymorphous lymphoid cells with plasmacytoid and immunoblastic differentiation


    • Systemic uncontrolled proliferation of abnormal B cells


    • Frequent hemophagocytic syndrome, most readily identified on bone marrow aspirates


  • Waxing and waning lymphoproliferations (CVID)



    • Variable morphology showing follicular hyperplasia and paracortical expansion with many EBV(+) cells


    • Characteristic nodular lymphoid hyperplasia in gastrointestinal tract


  • Autoimmune lymphoproliferative syndrome



    • Expansion of CD4(-), CD8(-) T cells (so-called double negative cells)


    • Increased CD5(+) polyclonal B cells


    • Prominent follicular hyperplasia


  • X-linked hyper-IgM syndrome



    • Extensive accumulation of IgM-producing plasma cells in extranodal sites without malignant transformation


    • Peripheral blood B-cells express only IgM and IgD


Precursor Lesions



  • Broad morphologic spectrum


  • Increasingly dominant clonal population, from polyclonal, to oligoclonal, to monoclonal


  • Monoclonal expansions may or may not progress to major persistent lesions


Neoplastic Lesions



  • Increased risk of developing leukemias, lymphomas and nonhematopoietic tumors (lymphoma > leukemia)


  • In general, morphology and immunophenotype similar to lymphomas in immunocompetent hosts


  • Polymorphous cytologic features commonly seen


  • Non-Hodgkin lymphoma



    • Overall, B-cell more common than T-cell lymphomas



      • Exception: In ataxia-telangiectasia, T-cell lymphoma/leukemia is common


    • Diffuse large B-cell lymphoma (DLBCL) is most common NHL in PID patients



      • Immunophenotype similar to DLBCLs in immunocompetent patients


      • If EBV(+): Focal expression or absence of CD20 and CD79a; aberrant CD30(+)


    • Many cases are polymorphous with plasmacytoid differentiation


    • Frequently EBV(+)


    • Burkitt lymphoma is more common in XLP than in other PIDs


  • Hodgkin lymphoma (HL)



    • 2nd most common LPD per Immunodeficiency Cancer Registry



      • ˜ 10% of all lymphomas in PID patients


    • Classical HL most common in PID patients



      • Lymphocyte depleted and mixed cellularity types more common due to feeble immune response


      • HRS cells: CD15(+/-), CD30(+), pax-5(+, dim), CD45/LCA(-)


    • NLPHL relatively uncommon except in patients with ALPS


CLASSIFICATION


Immunodeficiencies



  • Combined T- and B-cell immunodeficiencies



    • Severe combined immunodeficiency (SCID)


    • X-linked hyper-IgM syndrome


  • Predominantly antibody deficiencies




    • Common variable immunodeficiency (CVID)


  • Other well-defined immunodeficiency syndromes



    • Ataxia-telangiectasia (AT)


    • Nijmegen breakage syndrome (NBS)


    • Wiskott-Aldrich syndrome (WAS)


  • Diseases of immune dysregulation



    • Autoimmune lymphoproliferative syndrome (ALPS)


    • X-linked lymphoproliferative disorder (XLP)


  • Congenital defects of phagocyte number, function, or both


  • Defects in innate immunity


  • Autoinflammatory disorders


  • Complement deficiencies


DIAGNOSTIC TESTS


Laboratory Tests to Diagnose PID

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Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Overview of Lymphoproliferative Disorders Associated with Primary Immune Deficiency Disorders

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