This category includes includes:

• LPDs Associated with inborn errors of immunity
• Post-transplant lymphoproliferative disorders
• Iatrogenic immunodeficiency associated lymphoproliferative disorders
• HIV associated lymphomas

Lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation include: (Common to all)

• Hyperplasias arising in immune deficiency/dysregulation (Most of them are EBV related)
  • Follicular proliferations:
    • Follicular hyperplasia
    • Follicle lysis/ involution
    • Lymphoid/ lymph node depletion
    • Progressive transformation of germinal center
    • Castleman disease like changes
  • Interfollicular and paracortical proliferations
    • Infectious mononucleosis-like hyperplasia
    • Plasmacytic hyperplasia
  • Other types of hyperplasias and involutions
    • EBV reactivation
    • Immune reconstitution inflammatory syndrome
  • T cell and histiocytic proliferations
    • Hemophagocytic lymphohistiocytosis
    • Extranodal T cell proliferation/ expanstion especially ALPS
    • Chronic active EBV disease
• Polymorphic lymphoproliferative disorders arising in immune deficiency / dysregulation
  • Polymorphic lymphoproliferative disorder
  • EBV+ mucocutaneous ulcer
  • KSHV/HHV8-positive germinotropic lymphoproliferative disorder
• Lymphomas arising in immune deficiency / dysregulation
  • Small (low grade) B cell lymphomas
  • Diffuse large B-cell lymphoma
  • Burkitt lymphoma
  • Classical Hodgkin lymphoma
  • KSHV/HHV8+ diffuse large B-cell lymphoma, NOS
  • Primary effusion lymphoma
  • Plasmablastic lymphoma
  • Plasma cell neoplasms
  • T- and NK- cell lymphomas

3 part nomenclature used for LPDs associated with immune deficiency and dysregulation:

Name of diagnosis must include: Name of lesion, virus status, type of immunodeficiency

Examples: 

• Follicular hyperplasia, EBV+, HIV setting
• Burkitt lymphoma, EBV-, posttransplant setting
• Classic Hodgkin lymphoma, EBV+, HIV setting
• Extranodal marginal zone lymphoma, EBV-, hyper-IgM syndrome

LPDs associated with inborn errors of immunity

Introduction:

• As IEIs are heterogeneous, LPDs are also highly variable
• Most common type of LPD in IEI is diffuse large B-cell lymphoma
• IEIs most commonly associated with LPDs
  • Ataxia telangiectasia
  • Wiskott Aldrich syndrome
  • Common variable immunodeficiency
  • Severe combined immunodeficiency
  • X-linked immunoproliferative disorders
  • Nijmegen breakage syndrome
  • Hyper IgM syndrome
  • Autoimmune lymphoproliferative disorder

Risk Factor: EBV Infection

Classification:

• B-cell neoplasms
  • Diffuse Large B-cell Lymphoma 
  • Lymphomatoidgranulomatosis
  • Burkitt lymphoma
• T-cell Neoplasms 
  • Precursor T lymphoblastic lymphoma / leukemia
  • T-cell prolymphocyticleukemia
• Hodgkin’s Lymphoma

Prognosis: Depends on type of LPD and underlying IEI

Treatment: 

• Lymphoma specific chemotherapy: Generally less aggressive therapy, than patients without IEI is needed.
• Radiotherapy should be avoided in patients with DNA repair defects
• Allo SCT may be curative, both for lymphoma and IEI

Post-transplant Lymphoproliferative Disorder

Categories of post-transplant lymphoproliferative disease (PTLD)

• Non-destructive/Early lesions
  • Infectious mononucleosis like- Paracortical expansion and numerous immunoblasts in background of small lymphocytes
  • Reactive plasmacytic hyperplasia- Polytypic light chain staining
• Polymorphic PTLD- Destructive lesions composed of immunoblasts, plasma cells, and intermediate sized lymphoid cells that efface lymph node architecture or form destructive extra nodal masses
• Monomorphic PTLD
  • B-cell neoplasms
    • Diffuse large B-cell lymphoma (immunoblastic, centroblastic, anaplastic)
    • Burkitt / Burkitt-like lymphoma
    • Plasma cell myeloma
    • Plasmacytoma like lesions
  • T-Cell neoplasms
    • Peripheral T-cell lymphoma, not otherwise specified
    • Other types of NK, T cell lymphomas

Risk

• Bone marrow transplant- <1% 
• Renal transplant - <1%
• Hepatic, cardiac – 1-2%
• Heart lung, liver, bowel – 5 %
• Immunosuppression for GVHD – 20%

Etiology:

• EBV
• Use of Azathioprine / Cyclosporin / Tacrolimus
• Risk factors in stem cell transplant
  • T cell depletion allograft
  • Unrelated or HLA mismatched grafts
  • Anti T cell therapy for GVHD
  • Higher recipient age
• Risk factors in solid organ transplant:
  • Type of organ transplant: High risk with bowel and lung
  • CMV/EBV positive donor
  • HLA mismatch
  • Anti T cell therapy

Clinical Features:

• Lymphadenopathy
• Hepatomegaly/ splenomegaly
• Extranodal involvement is common with solid organ transplants
• B symptoms

Investigations:

• Histopathology
• Immunophenotyping by IHC
• Imaging for staging
• EBER in situ hybridization

Prognosis:

• Overall mortality- 50%
• Poor prognostic markers
  • Poor performance score
  • EBV negative tumor
  • Graft organ involvement
  • Monomorphic pathology

Pretreatment Work-up:

• History
  • B-Symptoms
  • Immunosuppression 
• Examination
  • LN:
  • Spleen:
• WHO P. S.
• BSA
• IHC
• BMA and Bx
• CT (CAP)/ PET
• Stage
• Hemoglobin
• TLC, DLC
• Platelet count
• LFT: Bili- T/D    SGPT:     SGOT:     Albumin:      Globulin:
• Creatinine
• Electrolytes: Na:      K:     Ca:   Mg:      PO4:   
• Uric acid:
• LDH
• HIV: 
• HBsAg:
• HCV:
• EBV PCR
• CMV PCR
• UPT
• ECHO  (If anthracyclines planned) LVEF-               %
• Chemotherapy consent after informing about disease, prognosis, cost of therapy, side effects, hygiene, food and contraception
• Fertility preservation
• PICC line insertion and Chest X ray after line insertion
• Tumor board meeting and decision
• Attach supportive care drug sheet
• Inform primary care physician

Treatment Plan:

Reduction in immunosuppression:

• Response to RI is variable
• It should be co-ordinated with transplant team
• Reduce calcineurin inhibitor to about 50% (Cyclosporine and tacrolimus)
• Discontinueantimetabolic agents (Azathioprine and MMF)
• For critically ill, all non-glucocorticoidimmunosuppression must be stopped.
• Stopping immunosuppression completely is feasible only if
  • Alternate support is available- Ex: Dialysis for renal transplant
  • Transplanted organ is resistant to rejection. Ex: Liver
• Response to RIS is assessed by
  • Assessing change in tumour size
  • Reduction in LDH
  • Resolution of constitutional symptoms
• Response is often seen in 2-4 weeks.
• If there is graft rejection, retransplantation can be done after PTLD has been treated. There are good results with retransplantation. Retransplantation should be done 1 year after control of PTLD.

Iatrogenic Immunodeficiency Associated Lymphoproliferative Disorders

• They include lymphomas that arise in patients treated with immunosuppressive drugs for autoimmune diseases or conditions other than the allograft/ autograft transplant setting.
• They include
  • Polymorphic lesions that are seen in post transplant LPDs
  • DLBCL
  • T/NK cell lymphoma
  • Classical Hodgkin's lymphoma
• Etiology: Methotrexate, Infliximab, Adalimumab, Etanercept
• EBV is seen in 40% of cases.
• Survival depends on type of LPD.
• Many show at least partial regression after stopping drug.
• Others need chemotherapy

HIV Associated Lymphoma

• Lymphomas seen in HIV patients include
  • DLBCL
  • Burkitt’s lymphoma
  • MALT lymphoma
  • Plasmablastic lymphoma of oral cavity
  • Primary effusion lymphoma
  • Hodgkin’s lymphoma
  • Peripheral T cell lymphoma
  • KSHV/HHV8+ multicentric castleman disease
  • Primary CNS lymphoma
• Incidence of lymphoma in HIV patients is 60-200 times more than general population
• Causes:
  • Infection with EBV 
  • Infection with Kaposi’s sarcoma human virus
  • Chronic antigenic stimulation
  • Genetic abnormalities
  • Cytokine dysregulation due to increased serum levels of IL6 & IL10
  • Abnormalities involving MYC and BCL-6 oncogenes
• Pathogenesis:

1.

HIV Infection

Ongoing infections

↓

Macrophage activation with release of cytokines

Chronic antigenic stimulation

↓

Proliferation of B lymphocytes

↓

Recombinase error

↓

Abnormal DNA rearrangements

↓

Chromosomal abnormalities

↓

Mutations in critical oncogenes or tumor suppressor genes

↓

Clonal selection

↓

Development of lymphoma

2.

Compromised cellular immunity

↓

Decreased immune surveillance of EBV and KSHV infected B cells

↓

Viral lymphomagenesis

• Prognosis:
  • Outcome of therapy is same as non-HIV cases, when chemotherapy is combined with HAART therapy
  • Poor prognostic markers
    • CD4 count of <200/cmm
    • Age prognostic markers
    • IV drug use
    • Stage III/IV disease
  • Plasmablastic lymphoma has aggressive disease with survival of <1 year
• Pretreatment workup
  • History including B-Symptoms
  • Examination
    • LN:
    • Spleen:
    • WHO P. S.
    • BSA
  • IHC
  • Subtype
  • BMA and Bx(Can avoid if PET Negative)
  • CT (CAP)/ PET
  • Stage
  • Hemoglobin
  • TLC, DLC
  • Platelet count
  • LFT: Bili- T/D  SGPT:          SGOT:    Albumin:      Globulin:
  • Creatinine
  • Electrolytes
  • Uric acid:
  • LDH
  • Beta 2 Microglobulin
  • CD4 count
  • HIV Viral Load
  • LP (Except for early DLBCL and Primary Effusion Lymphoma)
  • HBsAg:
  • HCV:
  • UPT
  • ECHO(If anthracyclines planned)- LVEF
• Treatment 
  • ART has to be initiated/ continued during the chemotherapy as well. Avoid using zidovudine, cobicistat and ritonavir, as they tend to increase drug toxicity.
  • All must receive PCP and other prophylaxis
  • If CD4 count <50/cmm, maximise supportive care and monitor closely for cytopenias and infections
  • If CD4 count <100, avoid Rituximab
  • Give G-CSF for all patients
  • Give CNS prophylaxis for all category of patients (By intrathecal therapy)
  • Treatment is similar to immunocompetent patients
  • For DLBCL, HHV-8 positive DLBCL, Primary effusion lymphoma- R-EPOCH is preferred over R-CHOP.
  • For plasmablastic lymphoma- R-CHOP is not adequate therapy. Give EPOCH or CODOX-M/IVAC or Hyper-CVAD followed by HDT and ASCR in CR1.
  • For non-Burkitt lymphomas, when EPOCH is being used following adjustments must be made:
    • Etoposide, Vincristine and Doxorubicin must be infused over 96 hrs
    • Dose of Day 5 Cyclophosphamide is reduced to 187.5mg/m2, if CD4 count is <50/cmm

Recent advaces:

Outcomes of HIV-Associated High-Grade B-Cell Non-Hodgkin Lymphoma (NHL) Treated with Dose Adjusted EPOCH (+/−R) Regimen

In a retrospective analysis of treatment-naïve HIV-associated high-grade B-cell non-Hodgkin lymphoma (NHL) patients aged 18 and above treated with the DA-EPOCH(+/-R) regimen from 2011 to 2015, a cohort of 40 patients was studied. The cohort included diffuse large B-cell lymphoma (DLBCL), Burkitt’s lymphoma, high-grade B-cell lymphoma-unclassifiable, and plasmablastic lymphoma. The median CD4+ T cell count was 202/mm3, and CNS prophylaxis was administered to 90% of patients. With a median follow-up of 72 months, the estimated 5-year overall survival (OS) was 82.5%, and 5-year progression-free survival (PFS) was 77.5%. At least 4 cycles of chemotherapy were administered to 93% of patients. Grade 3–4 toxicities were observed in 83% of patients, with febrile neutropenia being the most common. 

https://doi.org/10.1007/s12288-023-01652-3