Lymphoma & related disorders
Other immunosuppression related
Associated with primary immune disorders

Topic Completed: 1 January 2012

Minor changes: 5 July 2020

Copyright: 2002-2020,, Inc.

PubMed Search: Lymphoproliferative disease [title] primary immune disorders

Dragos C. Luca, M.D.
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Cite this page: Luca D. Associated with primary immune disorders. website. Accessed August 10th, 2020.
Definition / general
  • Lymphoproliferative diseases associated with primary immune disorders (PID / LPD) are lymphoid proliferations that arise as a result of immune deficiency due to a primary immunodeficiency or immunoregulatory disorder (WHO)
  • Usually extranodal
  • Varies from polymorphous proliferation of lymphoid cells to diverse lymphomas
  • Usually humoral (B cell) types but also cellular (T cell) types
  • Usually EBV+
  • Primary immune disorders are rare, therefore low overall occurrence of PID / LPD
  • Primary immune disorders primarily occur in children (except CVID); median age of onset: 7.1 years; more common in males (mostly due to several being X-linked: XLP, SCID, hyper IgM syndrome)
  • Overall risk for malignancy in patients with PID is 4% (range: 0.7 - 15%), 10,000 × greater than normal
  • Over 60 different primary immune disorders with heterogeneous pathology and pathogenesis cause highly variable LPD

Primary immune disorders most frequently associated with LPD:
  • Ataxia-telangiectasia (AT)
  • Wiskott-Aldrich syndrome (WAS)
  • Common variable immunodeficiency (CVID)
  • Severe combine immunodeficiency (SCID)
  • X-linked lymphoproliferative disorder (XLP, Duncan syndrome)
  • Nijmegen breakage syndrome (NBS)
  • Hyper IgM syndrome
  • Autoimmune lymphoproliferative syndrome (ALPS, Canale-Smith syndrome)
  • Dependent on the underlying disease
  • Most commonly extranodal: GI tract, lung, CNS
  • Cause of the LPD is related to the underlying immune defect
  • EBV involved in most cases (defective T cell immune surveillance; if complete – fatal infectious mononucleosis [FIM], if partial – LPD)
  • WAS: complex immune disorder with defects in function of T cells (tends to increase in severity during the course of disease), B cells, neutrophils and macrophages
  • Hyper IgM syndrome: mutations in the CD40 or CD40 ligand genes, defective interaction between T cells and B cells, impairment of differentiation into plasma cells
  • ALPS: mutations in the FAS or FASL genes, impairment of apoptosis, accumulation of CD4 / CD8 double negative T cells in peripheral blood or lymph nodes, severity of apoptotic defect directly correlated with the risk of LPD
  • AT: mutations in the ATM gene, abnormal DNA repair, peripheral blood has non-leukemic T cell clones demonstrating TCR gene translocations similar to those in overt leukemias
  • NBS: mutations in the NBS1 gene, defects in DNA repair, chromosomal breaks and translocations
  • CVID: marked lymphoid hyperplasia in the lung or GI tract, often with LPD or overt lymphoma
  • XLP: mutations in the SAP / SLAM gene
Clinical features
  • Fever, fatigue, infectious mononucleosis-like syndrome
  • The lymphoid proliferation may be the first sign of the primary disorder (ALPS, XLP) but diagnosis of primary immune disorders already established in most cases due to other manifestations
  • WAS: triad of eczema, thrombocytopenia and severe recurrent infections
  • AT: progressive cerebellar ataxia, mucocutaneous telangiectasia, sinopulmonary infections
  • ALPS, XLP: lymphadenopathy, hepatosplenomegaly
  • Hematologic neoplasms are associated with various PID
  • Nonhematologic neoplasms: renal & pulmonary leiomyomata (SCID), epithelial tumors of bladder, breast, cervix, stomach & vulva (CVID), cerebellar astrocytoma, Kaposi sarcoma, muscle tumors (WAS), epithelial tumors (AT), brain tumors (NBS)
  • Age specific mortality rates for all neoplasms in patients with primary immune disorders are 10 - 200 times the expected rates for the general population
  • Prognosis dependent both on the underlying PID and the type of LPD
  • Lymphoid proliferations in ALPS are often self limiting
  • Lymphoid hyperplasia in CVID may be indolent
  • Most other LPD in patients with PID are aggressive
  • In EBV driven infectious mononucleosis, a hemophagocytic syndrome may cause death
  • In general, less aggressive therapy than in patients without PID
  • Allogeneic BMT has been used in WAS, SCID and hyper IgM syndrome
  • The EBV driven B cell expansion in LYG may respond to immunomodulation with interferon α-2b
Microscopic (histologic) description
  • Reactive hyperplasia, polymorphous lymphoid infiltrates, or frank lymphoma similar to those seen in immunocompetent hosts
  • Castleman disease-like features may be seen in children: atrophic follicles, hyalinized germinal centers, marked vascular proliferation
  • Different types and frequencies of each lesion based on the PID

Nonneoplastic lesions:
  • Fatal infectious monoucleosisis - primarily in XLP and SCID, systemic, both lymphoid and nonlymphoid (most commonly terminal ileum), frequent hemophagocytosis (bone marrow)
  • CVID – lymph nodes and extranodal, waxing / waning, follicular hyperplasia, paracortical expansion, many EBV positive cells, nodular lymphoid hyperplasia of the GI tract
  • ALPS – prominent follicular hyperplasia, progressive transformation of germinal centers, expansion of CD4 / CD8 double negative T cells in peirpheral blood, lymph nodes, spleen
  • Hyper IgM syndrome – circulating IgM and IgD only B cells, absent germinal centers, accumulation of IgM plasma cells in GI tract, gallbladder and liver

  • Generally similar in morphology to immunocompetent host counterparts
  • Lymphomatoid granulomatosis (LYG) – EBV-driven B cell proliferation, marked T cell infiltration, frequently in WAS, usually lung, skin, brain, kidney
  • Diffuse large B cell lymphoma – the most common PID associated lymphoma; also Hodgkin and Burkitt
  • Peripheral T cell lymphoma – more common than B cell neoplasms in AT and NBS; also rarely in ALPS
  • T lymphoblastic leukemia/lymphoma and T cell prolymphocytic leukemia also reported
  • Hodgkin lymphoma: reported in WAS and AT (resemble those post methotrexate therapy); also, NLPHL, CHL and T cell rich B cell lymphoma described in ALPS
  • Precursor lesions: represented by the underlying primary immune disorders with a wide morphological spectrum, from clearly polyclonal to oligoclonal to monoclonal (monoclonal expansions, especially if minor, may not necessarily progress)
Microscopic (histologic) images

Images hosted on other servers:



ALPS - spleen

ALPS - associated lymphomas

Nonneoplastic proliferations:
  • ALPS: CD3+, CD4-, CD8-, CD45RA+, CD45RO-, CD25-, +/-CD57, may have an increase in CD5+ B cells
  • Hyper IgM syndrome: IgM and IgD only B cells in peripheral blood

  • Neoplasms: most are B cell, EBV may downregulate CD19, CD20 and CD79a also leading to CD30 expression, LMP1 may be positive, may have monotypic Ig in cases with plasmacytoid features
Molecular / cytogenetics description
  • Polyclonal, oligoclonal or monoclonal
  • FIM – generally polyclonal; overt lymphomas show Ig heavy and light chain gene rearrangements
  • TCR genes on chromosomes 7 and 14 often involved in AT, including TCL1
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