Lymphoma & related disorders

Lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation

Polymorphic lymphoproliferative disorders arising in immune deficiency / dysregulation



Last author update: 27 April 2023
Last staff update: 15 May 2023

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PubMed Search: Polymorphic lymphoproliferative disorders in immune deficiency

Miguel Gonzalez-Mancera, M.D.
Sumire Kitahara, M.D.
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Cite this page: Gonzalez-Mancera M, Kitahara S. Polymorphic lymphoproliferative disorders arising in immune deficiency / dysregulation. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomapolymorphicimmunedeficiency.html. Accessed April 14th, 2024.
Definition / general
  • Lymphoproliferative disorders (LPDs) arising in patients with immune deficiency or dysregulation are usually Epstein-Barr virus (EBV) driven and composed of a heterogeneous lymphoid cell infiltrate with a variable number of B cells that efface the architecture of involved tissues
  • New standardized nomenclature for reporting this histological diagnosis is based on an integrated approach and consists of 3 parts
    • Histological diagnosis (polymorphic lymphoproliferative disorder)
    • Viral association
    • Immune deficiency / dysregulation setting
Essential features
  • Polymorphous lymphoproliferative disorder arising in any immune deficiency / dysregulation setting
  • Typically associated with EBV infection
  • Histologically, there is effacement of the architecture of the involved tissue by a mixed inflammatory process and absence of sheets of monotonous cells
Terminology
  • Encompasses the previous polymorphic posttransplant lymphoproliferative disorders, other iatrogenic immunodeficiency associated lymphoproliferative disorders, among others such as lymphomatoid granulomatosis (LYG) grade 1 and 2 in IDD settings (except immunosenescence) and lymphoid proliferations in the HIV setting (although usage of these terms is not recommended)
  • Not recommended: polymorphic lymphoma
ICD coding
  • ICD-O:
    • 9971/1 - posttransplant lymphoproliferative disorder, NOS
    • 9971/3 - polymorphic posttransplant lymphoproliferative disorder, NOS
  • ICD-10: D47.Z1 - posttransplant lymphoproliferative disorder (PTLD)
  • ICD-11: 2B32.3 - polymorphic posttransplant lymphoproliferative disorder
Epidemiology
Sites
Pathophysiology
  • First step in the development of polymorphic LPDs is a disruption in T cell immune surveillance that results from an immunodeficient status
  • In the setting of EBV positive LPDs, associated proteins promote cellular proliferation and immune evasion
    • EBV is transmitted by oral transfer; EBV shedding can also be detected in cervical secretions of the gynecologic tract
    • EBV latent membrane proteins LMP2A (that mimics the B cell receptor signaling) and LMP1 (that mimics CD40 signaling) activate NFκB, inducing cell proliferation (N Engl J Med 1998;338:1413, N Engl J Med 2004;350:1328)
    • EBV nuclear antigen (EBNA1) plays a role in DNA regulation, transcription and immune evasion, while EBNA2 regulates viral and cellular genes
    • EBV can present as multiple latency patterns depending on which proteins are expressed
      • Latency patterns II (LMP1+ / EBNA2-) and III (LMP1+ / EBNA2+) are the most common patterns associated with immune deficiency / dysregulation associated LPDs
  • In the setting of EBV negative LPDs, multiple theories have been proposed
Etiology
  • Any immunodeficiency setting, typically associated with EBV infection
Diagrams / tables

Images hosted on other servers:
Relationship between immunodeficiency-associated lymphoproliferative disorders  in 4th edition and 5th edition of the WHO

Immunodeficiency
associated LPDs
in WHO-HAEM4R
and WHO-HAEM5

3 part nomenclature for immunodeficiency-associated LPDs

3 part nomenclature
for immunodeficiency
associated LPDs

Clinical features
Diagnosis
Laboratory
  • Elevated lactate dehydrogenase (LDH) levels have been associated with a poor response to treatment and overall survival (Blood 2006;107:3053, Am J Transplant 2006;6:569)
  • EBV serology (Am J Transplant 2009;9:S87)
    • Its most important role in the posttransplant setting is the determination of pretransplant donor and recipient EBV serostatus for posttransplant lymphoproliferative disorder risk assessment
    • In immunocompromised patients, serology is an unreliable diagnostic tool due to delayed or absent humoral response
      • If these patients are receiving blood products, the passive transfer of antibodies is another important drawback to consider
  • EBV viral load can be used to monitor therapeutic response (Am J Transplant 2008;8:1016, Transplantation 1998;66:1641, Transplantation 2002;74:656)
Radiology description
  • Depending on the involved site, imaging studies may show localized or diffuse lymphadenopathy, organomegaly or a mass lesion
Prognostic factors
  • There are no well defined histopathologic, immunophenotypic or molecular prognostic / predictive factors within the group of polymorphic LPDs
  • Staging with PET / CT imaging should be done following the Lugano staging system (J Clin Oncol 2014;32:3059)
  • Lymphadenopathy resolves in up to 20% of cases with no therapy
  • Clinical progression has been reported in 38% of patients, with 10% progressing to DLBCL (Blood 2011;117:4726)
  • Improvement may be seen upon discontinuation of immunosuppression in the posttransplant setting or in therapy related immunodeficiency (Med Oncol 2009;26:1)
  • In the posttransplant setting, factors that have been associated with lack of response to decreased immunosuppression include elevated LDH levels, organ dysfunction, multiorgan involvement, advanced age, bulky disease and older age of presentation (Am J Transplant 2011;11:336, Transplantation 2001;71:1076)
Case reports
  • 26 year old woman presented with pharyngeal foreign body sensation after peripheral blood stem cell transplant (PBSCT) (Int J Clin Exp Med 2014;7:1904)
  • 36 year old HIV infected man presented with acute abdominal pain (EJHaem 2021;2:562)
  • 67 year old man status post-renal transplant presented with multiple allograft parenchymal cystic lesions (Am J Transplant 2012;12:245)
Treatment
Gross description
  • Lesions can present as a mass with ulceration or necrosis
Microscopic (histologic) description
  • Histologic features include architectural destruction and a mixed infiltrate of cells, including B cells at different stages of maturation such as immunoblasts, small lymphoid cells, plasmacytoid cells, plasma cells (Am J Clin Pathol 2017;147:129, Blood 2011;117:4726)
  • Intermixed T cells and histiocytes are commonly seen
  • Immunoblasts may show Hodgkin / Reed-Sternberg (HRS)-like morphology
  • Sheets of monotonous cells are not present
  • Necrosis may be seen and angiocentric / angiodestructive polymorphous infiltrate may be seen in lymphomatoid granulomatosis type lesions
Microscopic (histologic) images

Contributed by Miguel Gonzalez-Mancera, M.D.

Heterogeneous infiltrate

Heterogeneous infiltrate

Gastrointestinal biopsy


CD3

CD20

CD68

MUM1

Kappa light chain


Lambda light chain

EBV EBER

EBV EBER

EBV EBER

LMP1

Positive stains
Negative stains
  • Not relevant to the diagnosis
Flow cytometry description
  • Not essential for diagnosis; mixed lymphoid population expected to be seen
Molecular / cytogenetics description
Sample pathology report
  • Rectum, biopsy:
    • Polymorphic lymphoproliferative disorder, EBV+, in the setting of HIV infection (see comment)
    • Comment: The patient's history of HIV / AIDS with proctitis and lymphadenopathy is noted. The current specimen shows a polymorphic lymphoid infiltrate composed of small cells, plasma cells, immunoblasts and large, atypical cells. Occasional Reed-Sternberg-like cells are seen. EBV EBER is positive in many cells and plasma cells are polytypic. Immunoglobulin heavy chain and kappa light chain gene rearrangement studies are negative.
Differential diagnosis
Board review style question #1

An excisional lymph node biopsy from a patient with rheumatoid arthritis on methotrexate shows the histologic findings seen in the image above. EBV EBER is positive in many cells of varying sizes. What is the most appropriate diagnostic interpretation?

  1. Diffuse large B cell lymphoma, EBV+, iatrogenic methotrexate related
  2. Infectious mononucleosis
  3. Polymorphic lymphoproliferative disorder, EBV+, iatrogenic methotrexate related
  4. Reactive follicular hyperplasia
Board review style answer #1
C. Polymorphic lymphoproliferative disorder, EBV+, iatrogenic methotrexate related. These findings are consistent with polymorphic lymphoproliferative disorder (LPD) arising in immune deficiency / dysregulation. Polymorphic LPDs in the posttransplant setting are among the most commonly seen.

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Reference: Polymorphic lymphoproliferative disorders arising in immune deficiency / dysregulation
Board review style question #2
A 40 year old woman post-renal transplant presents with iliac lymphadenopathy. Excisional biopsy is consistent with polymorphous posttransplant lymphoproliferative disorder. Which of the following histologic features is characteristic of this entity?

  1. Florid reactive follicles with prominent germinal centers
  2. Mixed population of plasma cells, histiocytes, variably sized lymphocytes and immunoblasts effacing normal lymphoid architecture
  3. Necrotizing granulomatous lymphadenitis with palisading histiocytes
  4. Sheets of immunoblasts diffusely replacing normal architecture
Board review style answer #2
B. Mixed population of plasma cells, histiocytes, variably sized lymphocytes and immunoblasts effacing normal lymphoid architecture. In polymorphic LPDs, these are the usual histologic findings.

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Reference: Polymorphic lymphoproliferative disorders arising in immune deficiency / dysregulation
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