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Lymphoma and Plasma Cell Neoplasms


Lymphoproliferative diseases associated with primary immune disorders

Reviewer: Dragos Luca, M.D. (see Reviewers page)
Revised: 12 January 2012, last major update January 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.


● 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 x 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)


● 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


● Dependent on the underlying disease
● Most commonly extranodal: GI tract, lung, CNS

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: see table below
● 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)


Treatment and prognosis

● 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

Micro 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

Non-neoplastic lesions:
● Fatal infectious monoucleosisis - primarily in XLP and SCID, systemic, both lymphoid and non-lymphoid (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)

Micro Images



ALPS - spleen

ALPS - associated lymphomas


Non-neoplastic 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

Genetics & molecular

● 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

Additional references

Medeiros, Diagnostic Pathology: Lymph Nodes and Spleen with Extranodal Lymphomas, 2011
J Clin Pathol 2000;53:60, J Allergy Clin Immunol 2007;120:776, Hematology Am Soc Hematol Educ Program 2005:260
Am J Pathol 1998;153:1541,, Blood 1997;89:1341, Blood 1998;92:3018
Arch Dis Child 2000;82:400, Neth J Med 2006;64:136, Blood 1996;87:423, Blood 2001;98:194

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