Continuing Education Activity

Lymphoproliferative disorders (LPD) comprise a heterogeneous group of diseases characterized by uncontrolled production of lymphocytes that cause monoclonal lymphocytosis, lymphadenopathy and bone marrow infiltration. These diseases often occur in immunocompromised individuals. There are two subsets of lymphocytes: T and B cells that regenerate uncontrollably to produce immunoproliferative disorders, which are prone to immunodeficiency, a dysfunctional immune system, and lymphocyte dysregulation. Several gene mutations have been described as causes of LPD that can be iatrogenic or acquired. Describe the roles of various interprofessional team members in caring for patients with LPD and how the team can improve chances for survival and recovery.

Objectives:

• Describe the signs and symptoms of lymphoproliferative disorders.
• Review the diagnostic evaluation of LPD.
• Explain treatment considerations for patients with LPD.
• identify the roles of various interprofessional team members in caring for patients with LPD and improving chances for survival and recovery.

Introduction

Lymphoproliferative disorders (LPD)[1][2] comprise a heterogeneous group of diseases characterized by uncontrolled production of lymphocytes that cause monoclonal lymphocytosis, lymphadenopathy and bone marrow infiltration. These diseases often occur in immunocompromised individuals. There are two subsets of lymphocytes: T and B cells that regenerate uncontrollably to produce immunoproliferative disorders, which are prone to immunodeficiency, a dysfunctional immune system, and lymphocyte dysregulation. Several gene mutations have been described as causes of LPD that can be iatrogenic or acquired.

The X-linked LPD is characterized by a mutation in the X chromosome that predisposes to natural killer cell LPD and T-cell LPD. Autoimmune lymphoproliferative syndrome (ALPS) is a type of LPD caused by a mutation in the gene that encodes for a Fas protein which is located in the long arm of chromosome 10. Males with X-linked immunodeficiency syndrome are susceptible to LPD and at risk for acquiring EBV and further development of lymphoma.

Individuals with common variable immunodeficiency (CVID), severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, ataxia-telangiectasia, Chediak–Higashi syndrome and viral infections including HIV, are also prone to LPD. Others at risk include patients undergoing tissue transplantation and the use of immunosuppressive drugs such as cyclosporin, sirolimus, and tacrolimus. Invasive fungal infections have also been linked to this pathology.[3]

Chronic lymphoproliferative disorders are immuno-morphologically and clinically heterogeneous. Common features of these processes include various immunophenotypes (T, B, and NK cells) and terminal deoxynucleotidyl transferase negativity. The B-cell lymphocytic disorders include B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, non-Hodgkin lymphoma (including mantle cell lymphoma) in leukemic phase, hairy cell leukemia and splenic lymphoma with villous lymphocytes. The T-cell chronic lymphoproliferative disorders include Sezary syndrome, T-cell prolymphocytic leukemia, adult T-cell leukemia-lymphoma, and large granulated lymphocyte leukemia.[4]

Etiology

X-linked LPD can present as X-LPD-1 where there is a mutation on the X-chromosome associated with a T- and NK-cell lymphoproliferative disease. The mutation is on the long arm of the X chromosome, at position 25 (Xq25), where there is a deletion in the SH2D1A gene, which encodes for an SH2 domain on SLAM-associated protein (SAP).

Recipients of solid organs or allogeneic hematopoietic stem cells are at increased risk of developing lymphoma, which can be secondary to immunosuppression caused by Epstein-Barr virus (EBV).[5]

Epidemiology

LPD is a disease caused by cells of the lymphatic system that grow excessively. B-cell neoplasms are much more common than T-cell neoplasms in the United States and Europe.

Epstein-Barr virus (EBV) is an etiological factor for most lymphoproliferative disorders. EBV infects 90% of people during their lives. It presumably spreads by saliva or droplets. It has an incubation period of 4 to 5 weeks. In early childhood, it causes few symptoms, but in adolescents and young adults, it may cause infectious mononucleosis. 

Pathophysiology

Lymphoproliferative disorders originate when physiological mechanisms of control of proliferation of both T and B cells break down, resulting in the uncontrolled and autonomous increase of immune cells leading to lymphocytosis and lymphadenopathy, and often involvement of extranodal sites, e.g., bone marrow.

In immunocompromised patients, EBV can cause a mild disease. However, in immune-suppressed transplant patients, immunosurveillance may be compromised by the lack of T cells, leading to a proliferation of EBV-infected B-lymphocytes and post-transplant lymphoproliferative disorder (PTLD). Polyclonal PTLD can form tumor masses and presents with symptoms of a mass effect. Monoclonal forms of PTLD can manifest as a disseminated malignant lymphoma.

Histopathology

Analysis of blood samples frequently reveals large quantities of immature lymphocytes that are usually oligoclonal. One may see monoclonal cell populations in primary malignant tumors other than in LPD. Cytogenetic alterations are uncommon in LPD. Prolymphocytic leukemia is an uncommon variant of chronic lymphocytic leukemia (CLL). It differs from small cell CLL in that the leukemic cells are larger with more cytoplasm, and a prominent nucleolus. Approximately two-thirds have the phenotype of B cells. 

Post-transplant lymphoproliferative disorder (PTLD) is a B-lymphocyte growth caused by therapeutic immunosuppression common after organ transplantation. Patients can develop polyclonal B-cell hyperplasia.

The presence of Reed-Sternberg cells can differentiate Hodgkin lymphoma from non-Hodgkin lymphomas.

Toxicokinetics

Generation of T-cell depletion by use of anti-T lymphocyte antibodies in the prevention/treatment of graft rejection can further increase the risk of developing post-transplant lymphoproliferative disorder (PTLD). Such antibodies include anti-lymphocyte globulin (ALG), muromonab-CD3 (OKT3), and anti-thymocyte globulin (ATG).

History and Physical

The X-linked lymphoproliferative syndrome is characterized by an inappropriate immune response to EBV and leads to death from infectious mononucleosis, a dysgammaglobulinemia, or a B-cell lymphoproliferative disorder. However, the link between X-linked lymphoproliferative disorder and EBV is unknown.

ALPS presents with an increased size of lymphoid organs including lymph nodes and spleen in up to 90% of patients. The liver may be enlarged in up to 40% of patients. Autoimmune cytopenia is common including autoimmune hemolytic anemia, neutropenia, and thrombocytopenia. Symptoms that resemble systemic lupus erythematosus may be present. ALPS is associated with other autoimmune disorders like autoimmune cerebellar ataxia, transverse myelitis, Guillain–Barre syndrome, and autoimmune glomerulonephritis.

Clinical features of chronic hematological malignancies (chronic leukemias and lymphomas) include:

• Males are more affected than women
• Asthenia 
• Anemia
• Thrombocytopenia
• Granulocytopenia
• Loss of weight
• Lymphadenopathy (for example, peripheral, mesenteric, and retroperitoneal).
• Splenomegaly
• Hepatomegaly
• Metastatic disease affecting several organs including jaw, liver, ovaries, central nervous system (CNS), and gastrointestinal (GI) tract
• Recurrent infections
• Skin rash

Evaluation

The new criteria required for the diagnosis of an autoimmune lymphoproliferative syndrome (ALPS)[6] include chronic non-malignant lymphoproliferation (lymphadenopathy or splenomegaly over six months of evolution) and elevated peripheral blood double-negative T cells (DNTs). The first accessory in diagnosis is a somatic or a germ-line mutation in ALPS causative gene (FASL, CASP10, FAS) and defective in vitro Fas-mediated apoptosis. Secondary diagnostic criteria are elevated biomarkers (plasma sFASL over 200 pg/ml, plasma or serum vitamin B12 greater than 1500 ng/L, plasma IL-10 greater than 20 pg/ml, and plasma IL-18 greater than 500pg/ml) and immunohistochemical findings on biopsy consistent with ALPS. Other diagnostic signs are polyclonal hypergammaglobulinemia, autoimmune cytopenia and a family history of ALPS or non-malignant lymphoproliferation.

Treatment / Management

Epstein–Barr virus (EBV)-associated T-cell and/or NK-cell (EBV T/NK-cell) lymphoproliferative disorders can be cured in most cases with allogeneic hematopoietic stem cell transplantation (HSCT). Primary-EBV infection-associated hemophagocytic lymphohistiocytosis that is an EBV T/NK-cell lymphoproliferation may be managed with the use of steroids, cyclosporine A, and etoposide. Remission is known to occur in some patients but may require multi-drug block chemotherapy.[2]

In autoimmune lymphoproliferative syndrome, one should treat the underlying autoimmune disease. First-line therapy includes the use of corticosteroids and intravenous immunoglobulins. Second-line treatment includes mycophenolate mofetil. Sirolimus, which is a mammalian target of rapamycin (mTOR) can lead to near-complete resolution of the autoimmune disease.[7]

PTLD can spontaneously regress with cessation or reduction of immunosuppressant therapy and can additionally be treated with antiviral therapy. One can also treat hematological malignancies with multiple-agent chemotherapy, including cyclophosphamide and prednisone in combination with vincristine and doxorubicin.

Rituximab has been used to treat CD20-positive hematological malignancies since 1997 and now can be replaced by anti-CD20 biosimilar that is more effective.[8]

Differential Diagnosis

• EBV is associated with various cancers including lymphoma and infectious mononucleosis that can mimic lymphoproliferative syndrome/disorders.
• Multiple myelomas are a monoclonal proliferation of a clone of plasma cells. The clinical syndrome of multiple myeloma is characterized by hypergammaglobulinemia, hypercalcemia, susceptibility to infections, and pathological fractures.

Radiation Oncology

Radiation therapy can be used in the treatment of Hodgkin lymphoma as it plays a vital role in localized disease. It is beneficial when combined with chemotherapy in high-grade lymphoma and may be the choice of treatment for low-grade lymphomas.[9][10]

Pertinent Studies and Ongoing Trials

A study (phase 2) of adoptively transferred EBV-specific T lymphocytes showed high efficacy with minimal toxicity in patients with EBV-positive post-transplantation lymphoproliferative disease.[11]

Prognosis

Overall, the disorder has a poor outcome, but myeloablative hematopoietic stem cell transplantation (SCT) may be beneficial in some patients.[12]

Complications

Lymphoproliferative disease (LPD) is a recognized complication of immune dysregulation syndromes and primary immunodeficiency (PID). The recurrent lymphoproliferative disease is a post-transfusional complication.[12] PTLD may sometimes progress to non-Hodgkin lymphoma that can often be fatal.

Enhancing Healthcare Team Outcomes

An interprofessional team should educate and manage the patient with LPD. Since this condition may often be life-threatening, the health care providers should advise the patient or parents entirely about all other treatment options including the use of immunosuppressant therapy, in an already immunocompromised host, and also provide psychological support.