What is Lymphoproliferative Disorders?
Lymphoproliferative disorders (LPD) are a diverse group of diseases that result from the uncontrolled production of lymphocytes, which are a type of white blood cell. This overproduction can cause an excess of lymphocytes in the blood (monoclonal lymphocytosis), swollen lymph nodes (lymphadenopathy), and the spread of these cells into the bone marrow. LPDs are often seen in people whose immune systems are compromised.
There are two main kinds of lymphocytes: T and B cells. In LPDs, these cells multiply uncontrollably and can cause problems with the immune system, leading to immune disorders, as well as unusual behavior of the lymphocyte cells. Certain gene mutations, which can either be caused by medical treatment (iatrogenic) or naturally acquired, have been identified as causes of LPD.
One type of LPD, X-linked LPD, is caused by a mutation in the X chromosome and can lead to overproduction of natural killer cells and T-cell lymphocytes. Another type, called autoimmune lymphoproliferative syndrome (ALPS), is caused by a mutation in the gene that makes a protein called Fas, located on chromosome 10. Males with X-linked immunodeficiency syndrome are more susceptible to LPD and are at risk for contracting the Epstein-Barr virus (EBV), which could lead to lymphoma.
People with certain immune disorders, such as common variable immunodeficiency (CVID), severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, ataxia-telangiectasia, and Chediak–Higashi syndrome, as well as viral infections including HIV, are also at a higher risk of developing LPD. Other risk factors include undergoing tissue transplantation and the use of immunosuppressive drugs such as cyclosporin, sirolimus, and tacrolimus. Certain invasive fungal infections have also been associated with LPD.
Chronic LPDs vary widely in terms of their clinical appearance and how they affect the immune system. They often involve various types of lymphocytes (T, B, and NK cells) and lack an enzyme called terminal deoxynucleotidyl transferase. B-cell disorders include types of leukemia and non-Hodgkin lymphoma, while T-cell disorders include conditions like Sezary syndrome, different types of leukemia, and large granulated lymphocyte leukemia.
What Causes Lymphoproliferative Disorders?
X-linked LPD is a condition where there is a change, or mutation, on the X chromosome linked with an overgrowth of certain types of white blood cells (T- and NK-cells). This mutation happens on a specific location of the X chromosome, at a section known as Xq25. Here, there’s a deletion in a gene known as SH2D1A. This gene is responsible for creating a part of a protein called SLAM-associated protein (SAP).
Patients who have received transplants, like solid organs or specific stem cells, are at a greater risk of developing a type of cancer called lymphoma. This increased risk can be due to weakening of the immune system caused by a virus known as the Epstein-Barr virus (EBV).
Risk Factors and Frequency for Lymphoproliferative Disorders
Lymphoproliferative disorder (LPD) is a condition where the body’s lymphatic system cells grow more than they should. In the United States and Europe, a type of LPD called B-cell neoplasms is far more prevalent than another type called T-cell neoplasms.
The Epstein-Barr virus (EBV) is often responsible for causing most LPDs. This virus infects most people at some point in their lives, probably through saliva or droplets. It typically takes about 4 to 5 weeks for symptoms to show up after infection. While EBV doesn’t cause many symptoms in young children, it can lead to a condition called infectious mononucleosis in teens and young adults.
Signs and Symptoms of Lymphoproliferative Disorders
X-linked lymphoproliferative syndrome is a condition where the body’s immune system reacts improperly to the Epstein-Barr Virus (EBV). It can result in death due to severe glandular fever, antibody disorders, or excessive growth of B cells. However, the exact connection between this disorder and the EBV remains unclear.
Autoimmune lymphoproliferative syndrome (ALPS) typically leads to an increase in the size of the lymph nodes and spleen in around 90% of patients. In the case of 40% of patients, the liver may also be larger than usual. ALPS often comes with autoimmune cytopenia, which includes conditions such as autoimmune hemolytic anemia, neutropenia, and thrombocytopenia. Some patients may experience symptoms similar to systemic lupus erythematosus. ALPS can also be associated with other autoimmune disorders like autoimmune cerebellar ataxia, transverse myelitis, Guillain-Barre syndrome, and autoimmune kidney inflammation.
Chronic blood cancers (such as chronic leukemias and lymphomas) present with the following clinical features:
- More common in men than women
- Weakness and fatigue
- Anemia
- Thrombocytopenia (low platelet count)
- Granulocytopenia (low white blood cell count)
- Weight loss
- Swelling of the lymph nodes in different areas (for example, peripheral, mesenteric, and retroperitoneal)
- Enlarged spleen
- Enlarged liver
- Metastatic disease affecting several organs including jaw, liver, ovaries, the central nervous system, and the digestive tract
- Frequent infections
- Skin rash
Testing for Lymphoproliferative Disorders
Autoimmune Lymphoproliferative Syndrome, or ALPS, is a condition which affects the immune system. The new standard for diagnosing ALPS involves several factors. First, evidence of prolonged non-cancerous lymph tissue growth, like enlarged lymph nodes or spleen over six months. Second, there is a high presence of a certain type of immune cell, called double-negative T cells, in the patient’s blood.
Your doctor may then look for changes (mutations) in certain genes linked to ALPS, like FASL, CASP10, FAS. They also perform a specific medical test to check how well your cells are induced to die in response to signals – a process known as ‘Fas-mediated apoptosis’. Issues with this process can further indicate you may have ALPS.
Additional factors that support the diagnosis include high levels of certain substances in your blood, i.e., sFASL greater than 200 pg/ml, vitamin B12 greater than 1500 ng/L, IL-10 greater than 20 pg/ml, and IL-18 greater than 500pg/ml. The ALPS diagnosis can also be supported by certain signs in tissue samples from a biopsy.
Extra indicators for ALPS can include high levels of antibodies (hypergammaglobulinemia), a decrease in the number of red or white blood cells (autoimmune cytopenia), or a family history of ALPS or harmless lymph tissue growth.
Treatment Options for Lymphoproliferative Disorders
Epstein-Barr virus (EBV), commonly associated with T-cell and NK-cell disorders, can generally be treated via an transplant technique called allogeneic hematopoietic stem cell transplantation (HSCT). This is where a donor’s stem cells are used to replace the patient’s unhealthy blood-forming cells. Conditions that arise from an initial infection of EBV, known as hemophagocytic lymphohistiocytosis, can often be managed with the use of steroids, a medication called cyclosporine A, and etoposide, a type of chemotherapy. Although some people respond well to these treatments, others might require more intensive drug therapy.
In the case of a condition known as autoimmune lymphoproliferative syndrome, treatment is focused on managing the underlying autoimmune disease. This can involve the use of corticosteroids and intravenous immunoglobulins, which are a type of injection that boost the immune system. If these treatments are inefficient, it might be necessary to progress to the second-line treatment, which includes a medication called mycophenolate mofetil. Sirolimus, a type of drug that helps regulate the immune system, can often bring about a great improvement in the autoimmune disease.
Post-transplant lymphoproliferative disorder (PTLD) can sometimes improve by simply adjusting or halting the patient’s treatment with immunosuppressant drugs. Antiviral therapy can also be beneficial for patients with PTLD. Scientists have found that effective treatment options in the fight against blood cancers could include chemotherapy, specifically with medications such as cyclophosphamide, prednisone, vincristine, and doxorubicin.
Rituximab, a type of chemotherapy, has been used since 1997 to treat blood disorders that test positively for a marker known as CD20. Nowadays, similar but more effective treatments called anti-CD20 biosimilars are often used as a substitute.
What else can Lymphoproliferative Disorders be?
The Epstein-Barr Virus (EBV) is linked with different types of cancers such as lymphoma, and it can also lead to infectious mononucleosis. Interestingly, these conditions can mimic lymphoproliferative syndrome/disorders, a group of diseases in which the body produces too many lymphocytes (a type of white blood cells).
On the other hand, Multiple Myelomas are a condition where one type of white blood cells, known as plasma cells, multiplies uncontrollably. This leads to a condition characterized by:
- High levels of antibodies in the blood (hypergammaglobulinemia)
- Raised levels of calcium in the blood (hypercalcemia)
- Increased susceptibility to infections
- The occurrence of fractures that happen more easily than normal (pathological fractures)
What to expect with Lymphoproliferative Disorders
In general, this condition doesn’t have a good prognosis. However, a type of treatment known as myeloablative hematopoietic stem cell transplantation (SCT), which involves the replacement of damaged blood cells with healthy ones, may be helpful for some patients.
Possible Complications When Diagnosed with Lymphoproliferative Disorders
Lymphoproliferative disease (LPD) is a problem often seen in individuals with immune system disorders and primary immunodeficiency (PID), a condition where your immune system doesn’t function properly. This issue, where the body creates an excess of lymphocytes (a type of white blood cell), can recur after a blood transfusion. In some cases, lymphoproliferative disease can advance into a type of cancer called non-Hodgkin lymphoma, which can often be deadly.
Definition and Potential Risks:
- Lymphoproliferative disease (LPD): a common issue in people with immune system disorders
- Primary immunodeficiency (PID): a condition where the immune system doesn’t work properly
- Recurrent lymphoproliferative disease: recurring after a blood transfusion
- Potential development into non-Hodgkin lymphoma: a potentially deadly type of cancer
