Lymphoproliferative Disorders – Symptoms, Treatment

Last updated: February 8, 2026Reviewed date: February 8, 2026Reading time: 12 min read
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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...

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Article Summary

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...

Key Takeaways

  • This article explains Types of Lymphoproliferative Disorders in simple medical language.
  • This article explains Pathophysiology in simple medical language.
  • This article explains Causes of Lymphoproliferative Disorders in simple medical language.
  • This article explains Symptoms of Lymphoproliferative Disorders in simple medical language.
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Definition

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.

Lymphoproliferative disorders (LPDs) refer to a specific class of diagnoses, comprising a group of several conditions, in which, lymphocytes are produced in excessive quantities. These disorders primarily present in patients who have a compromised immune system. Due to this factor, there are instances of these conditions being equated with “immunoproliferative disorders”; although, in terms of nomenclature, lymphoproliferative disorders are a subclass of immunoproliferative disorders—along with hypergammaglobulinemia and paraproteinemias.

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.

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.

Synonyms of X linked Lymphoproliferative Syndrome

  • Duncan Disease
  • EBV Susceptibility (EBVS)
  • Epstein-Barr Virus-Induced Lymphoproliferative Disease in Males
  • Immunodeficiency-5 (IMD5)
  • Purtilo Syndrome
  • X-Linked Progressive Combined Variable Immunodeficiency
  • XLP

Types of Lymphoproliferative Disorders

Lymphoproliferative disorders 

  • Follicular lymphoma
  • Chronic lymphocytic leukemia
  • Acute lymphoblastic leukemia
  • hairy cell leukemia
  • Hemophagocytic lymphohistiocytosis (HLH)’
  • B-cell lymphomas
  • T-cell lymphomas
  • multiple myeloma
  • Waldenström’s macroglobulinemia
  • Wiskott–Aldrich syndrome
  • Langerhans cell histiocytosis (LCH)
  • Lymphocyte-variant hypereosinophilia
  • Pityriasis Lichenoides (PL, PLC, PLVA)
  • post-transplant lymphoproliferative disorder
  • autoimmune lymphoproliferative syndrome (ALPS)
  • Lymphoid interstitial pneumonia”[1]
  • Epstein–Barr virus-associated lymphoproliferative disease
  • Castleman disease
  • X-linked lymphoproliferative disease

Lymphoproliferative disorders are a set of disorders characterized by the abnormal proliferation of lymphocytes into a monoclonal lymphocytosis. The two major types of lymphocytes are B cells and T cells, which are derived from pluripotent hematopoietic stem cells in the bone marrow. Individuals who have some sort of dysfunction with their immune system are susceptible to develop a lymphoproliferative disorder because when any of the numerous control points of the immune system become dysfunctional, immunodeficiency or deregulation of lymphocytes is more likely to occur. There are several inherited gene mutations that have been identified to cause lymphoproliferative disorders; however, there are also acquired and iatrogenic causes.[rx]

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.

Causes of Lymphoproliferative Disorders

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).

X-linked Lymphoproliferative disorder

A mutation on the X chromosome is associated with a T cell and natural killer cell lymphoproliferative disorder.

Autoimmune lymphoproliferative disorder

Some children with autoimmune lymphoproliferative disorders are heterozygous for a mutation in the gene that codes for the Fas receptor, which is located on the long arm of chromosome 10 at position 24.1, denoted 10q24.1.[rx] This gene is member 6 of the TNF-receptor superfamily (TNFRSF6). The Fas receptor contains a death domain and has been shown to play a central role in the physiological regulation of programmed cell death. Normally, stimulation of recently activated T cells by antigen leads to coexpression of Fas and Fas receptor on the T cell surface. The engagement of Fas by Fas receptor results in apoptosis of the cell and is important for eliminating T cells that are repeatedly stimulated by antigens.[rx] As a result of the mutation in the Fas receptor gene, there is no recognition of Fas by Fas receptor, leading to a primitive population of T cells that proliferates in an uncontrolled manner.[rx]

Other inherited causes

Boys with X-linked immunodeficiency syndrome are at a higher risk of mortality associated with Epstein–Barr virus infections, and are predisposed to develop a lymphoproliferative disorder or lymphoma.

Children with common variable immunodeficiency (CVID) are also at a higher risk of developing a lymphoproliferative disorder.

Some disorders that predispose a person to lymphoproliferative disorders are severe combined immunodeficiency (SCID), Chédiak–Higashi syndrome, Wiskott–Aldrich syndrome (an X-linked recessive disorder), and ataxia–telangiectasia.

Even though ataxia telangiectasia is an autosomal recessive disorder, people who are heterozygotes for this still have an increased risk of developing a lymphoproliferative disorder.[rx]

Acquired causes

Viral infection is a very common cause of lymphoproliferative disorders. In children, the most common is believed to be congenital HIV infection because it is highly associated with acquired immunodeficiency, which often leads to lymphoproliferative disorders.[rx]

Iatrogenic causes

There are many lymphoproliferative disorders that are associated with organ transplantation and immunosuppressant therapies. In most reported cases, these cause B cell lymphoproliferative disorders; however, some T cell variations have been described.[rx] The T cell variations are usually caused by the prolonged use of T cell suppressant drugs, such as sirolimus, tacrolimus, or ciclosporin.[rx] The Epstein-Barr virus, which infects >90% of the world population, is also a common cause of these disorders, being responsible for a wide range of non-malignant, pre-malignant, and malignant Epstein-Barr virus-associated lymphoproliferative diseases.[rx]

Symptoms of Lymphoproliferative Disorders

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

Males are more affected than women
  • Asthenia
  • Anemia
  • platelet count, which can increase bleeding risk. সহজ বাংলা: প্লাটিলেট কম।" data-rx-term="thrombocytopenia" data-rx-definition="Thrombocytopenia means low platelet count, which can increase bleeding risk. সহজ বাংলা: প্লাটিলেট কম।">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

X-linked lymphoproliferative syndrome (XLP), an extremely rare inherited disorder, is characterized by a range of symptoms and findings that occur due to a defective immune system response to infection with the Epstein-Barr virus (EBV). This virus is common among the general population and usually infects “silently,” causing no apparent symptoms (asymptomatic). In some other cases, particularly during adolescence, EBV infection may cause infectious mononucleosis (IM), usually with no long-lasting effects (benign, self-limited IM). However, males with XLP who are exposed to Epstein-Barr virus may develop severe, life-threatening hepatic (liver) form infectious mononucleosis and hepatitis, abnormally low levels of antibodies or immunoglobulins (hypogammaglobulinemia) in the blood and body secretions, malignancies of certain types of lymphoid tissue (B-cell lymphomas), or other abnormalities.

Approximately half of individuals with X-linked lymphoproliferative syndrome experience severe, life-threatening mononucleosis characterized by fever, infection, or irritation, often causing pain, swelling, heat, or redness. সহজ বাংলা: শরীরের প্রদাহ; ব্যথা, ফোলা বা লালভাব হতে পারে।" data-rx-term="inflammation" data-rx-definition="Inflammation is the body’s response to injury, infection, or irritation, often causing pain, swelling, heat, or redness. সহজ বাংলা: শরীরের প্রদাহ; ব্যথা, ফোলা বা লালভাব হতে পারে।">inflammation and soreness of the throat (pharyngitis), swollen lymph glands, enlargement of the spleen (splenomegaly), enlargement of the liver (hepatomegaly), and/or abnormal functioning of the liver, resulting in yellowing of the skin, mucous membranes, and whites of the eyes (jaundice or icterus). In some cases, individuals who experience life-threatening mononucleosis infection may subsequently have an abnormal increase (i.e., proliferation) of certain white blood cells (lymphocytes and histiocytes) in particular organs, severe liver damage and/or failure, damage to the blood-cell generating bone marrow (hematopoietic marrow cells) that may result in aplastic anemia, and/or other symptoms that may result in life-threatening complications in affected children or adults. Aplastic anemia is characterized by a marked deficiency of all types of blood cells (pancytopenia) including low levels of red blood cells, certain white blood cells, and platelets, specialized red blood cells that function to assist appropriate blood clotting. In individuals with XLP, a decrease in platelets (platelet count, which can increase bleeding risk. সহজ বাংলা: প্লাটিলেট কম।" data-rx-term="thrombocytopenia" data-rx-definition="Thrombocytopenia means low platelet count, which can increase bleeding risk. সহজ বাংলা: প্লাটিলেট কম।">thrombocytopenia) results in increased susceptibility to bruising and excessive bleeding (hemorrhaging). Because X-linked lymphoproliferative syndrome is inherited as an X-linked recessive genetic trait, the disorder is usually fully expressed in males only.

X-linked lymphoproliferative syndrome is considered a rare primary immunodeficiency disorder; one of a group of disorders characterized by irregularities in the cell development and/or cell maturation process of the immune system. The immune system is divided into several components, the combined actions of which are responsible for defending against different infectious agents (i.e., invading microscopic life-forms). The T-cell system (cell-mediated immune response) is responsible for fighting yeast and fungi, several viruses, and some bacteria. The B-cell system (humoral immune response) fights infection caused by other viruses and bacteria by secreting immune factors called antibodies or immunoglobulins into the blood and body secretions (e.g., saliva). Antibodies can kill microorganisms or “coat” them so they are more easily destroyed by certain white blood cells. White blood cells (leukocytes) are part of the body’s immune system, playing an essential role in protecting against infection as well as fighting infection once it occurs. In addition, antibodies are produced following vaccination, providing protection from infectious diseases like polio, measles, and tetanus. The immune deficiency in XLP affects both T-cell and B-cell immune responses and therefore is classified as a “combined immunodeficiency.”

According to the medical literature, either directly after EBV exposure or following infectious mononucleosis, approximately one third of males with XLP may begin to exhibit abnormally low levels of antibodies (immunoglobulins) in the blood and body secretions (acquired hypogammaglobulinemia). As with bone marrow suppression, low levels of protective antibodies in the blood and body secretions may result in an increased susceptibility to various “opportunistic” infections.

In addition, approximately one fourth of males with XLP may develop malignancies of certain types of lymphoid tissue (B-cell lymphomas) subsequent to EBV exposure or development of infectious mononucleosis. Such lymphomas are characterized by malignant transformation of abnormally proliferating B cells. Burkitt’s Lymphoma involving the area where the small intestine joins the large intestine (ileocecal area) is the most commonly reported B-cell lymphoma among affected males. Symptoms and findings associated with Burkitt’s Lymphoma involving the intestines may include abdominal swelling (distention) and discomfort, impaired absorption of nutrients by the gastrointestinal (GI) tract (malabsorption), nausea, vomiting, changes in bowel habits, weakness, and/or weight loss.

Diagnosis of Lymphoproliferative Disorders

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.

Evaluation

The new criteria required for the diagnosis of an autoimmune lymphoproliferative syndrome (ALPS) 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 of Lymphoproliferative Disorders

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.

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.

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.

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.

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. PTLD may sometimes progress to non-Hodgkin lymphoma that can often be fatal.

References

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Care roadmap for: Lymphoproliferative Disorders – Symptoms, Treatment

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Doctor / service to discuss: Qualified healthcare provider; specialist depends on symptoms and examination.
  1. Step 1

    Check danger signs first

    If danger signs are present, seek emergency care and do not wait for online information.

  2. Step 2

    Record the symptom story

    Write when symptoms started, severity, medicines already taken, allergies, pregnancy status, and test results.

  3. Step 3

    Visit a qualified clinician

    A doctor, nurse, or qualified healthcare provider can examine you and decide which tests or treatment are needed.

  4. Step 4

    Do only useful tests

    Do tests after clinical assessment. Avoid unnecessary tests, random antibiotics, or repeated medicines without diagnosis.

  5. Step 5

    Follow up and return early if worse

    If symptoms worsen, new warning signs appear, or treatment is not helping, return for review quickly.

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