NORD gratefully acknowledges Thomas M. Habermann, MD, Division of Hematology, Department of Medicine, Mayo Clinic, for assistance in the preparation of this report.
Post-transplant lymphoproliferative disease (PTLD) is a rare, but well-known complication of solid organ transplants and hematopoietic stem cell transplantation. PTLD is related to the Epstein-Barr virus and immunosuppression therapy. People who receive these transplants are treated with drugs that suppress the activity of the immune system. Doctors must suppress the immune system to help the body accept the transplant and avoid rejection. Individuals receive these drugs at the time of the transplant (induction therapy) and must remain on these drugs for the rest of their lives (maintenance therapy). Immunosuppressive therapy leaves patients at a greater risk of developing infections and, in some people, of developing post-transplant lymphoproliferative disease. Early diagnosis and prompt treatment of these disorders are extremely important.
PTLD is characterized by the overproduction and spread of too many white blood cells (lymphocytes). This can cause complications ranging from a benign (noncancerous) enlargement of an organ or tissue because of the overproduction of these cells (hyperplasia) to the development of a malignant (cancerous) form of lymphoma. In most instances, PTLD is associated with the Epstein-Barr virus, a common virus that does not usually cause problems in people with normal-functioning immune systems. The abnormal white blood cells that grow out of control, usually a type of lymphocyte called a B-cell, may be infected by the Epstein-Barr virus. After a transplant, the dormant Epstein-Barr virus is reactivated, or the transplant recipient becomes infected with the virus for the first time.
PTLD is classified as a lymphoma, a group of related cancers that affect the lymphatic system. The lymphatic system functions as part of the immune system and helps to protect the body against infection and disease. It consists of a network of tubular channels (lymph vessels) that drain a thin watery fluid known as lymph from different areas of the body into the bloodstream. Lymph accumulates in the tiny spaces between tissue cells and contains proteins, fats, and certain white blood cells known as lymphocytes. As lymph moves through the lymphatic system, it is filtered by a network of small structures known as lymph nodes that help to remove microorganisms (e.g., viruses, bacteria, etc.) and other foreign bodies. Groups of lymph nodes are located throughout the body, including, but not limited to, the neck, under the arms (axillae), at the elbows, and in the chest, abdomen, and groin. Lymphocytes are stored within lymph nodes and may also be found in other lymphatic tissues. In addition to the lymph nodes, the lymphatic system includes the spleen, which filters worn-out red blood cells and produces lymphocytes, and bone marrow, which is the spongy tissue inside the cavities of bones that manufactures blood cells. Lymphatic tissue or circulating lymphocytes may also be located in other regions of the body.
There are two main types of lymphocytes: B-lymphocytes (B-cells), which may produce specific antibodies to “neutralize” certain invading microorganisms, and T-lymphocytes (T-cells), which may directly destroy microorganisms or assist in the activities of other lymphocytes. Some T-cells are cytotoxic lymphocytes and they function by eliminating other cells that are damaged, stressed, or infected. In most people with PTLD, there are too many B-cells being produced, but T-cell PTLD is also possible.
The specific symptoms and severity of PTLD can vary greatly from one person to another. Some affected individuals develop a mild, noncancerous overgrowth of affected tissue, while other people can develop a cancerous, life-threatening form of lymphoma. The mild, benign form of PTLD can resemble reactive hyperplasia, the normal process in which lymph nodes become enlarged in response to an infection or inflammation. PTLD can be localized, which means the disease only affects a specific area of the body, or widespread (disseminated), which means it affects several different areas of the body. They can also cause severe, life-threatening complications. In addition, PTLD may affect the transplanted organ, and these disorders commonly involve extranodal tissue.
It is important to remember that every person is an individual and how these disorders will affect one person as compared to another person can be very different. This report is a general overview of these disorders and details the most common ways PTLD affects people.
The 2017 World Health Organization (WHO) classification breaks down PTLD into six subclasses. Three forms are classified as non-destructive PTLD and are called plasmacytic hyperplasia, infectious mononucleosis-like PTLD, and florid follicular hyperplasia. Three other forms are classified as destructive PTLD and are called polymorphic PTLD, monomorphic PTLD, and classic Hodgkin lymphoma-like PTLD. The three non-destructive forms are almost much more commonly associated with Epstein-Barr virus infection. The symptoms are usually on the milder end of the spectrum, which is sometimes called “early” disease. Early lesions can act similar to how the body reacts to an infection such as infectious mononucleosis, in which there is an increase in B-cell production, but no signs of tumor formation or cancerous cells. This is called reactive hyperplasia and is a noncancerous (benign) condition. In individuals who are taking immunosuppressive drugs, these lesions may go away when the drugs are stopped or reduced. Early lesions can potentially progress to more serious complications, but that does not necessarily occur. Polymorphic PTLD is characterized by the overproduction of both B-cells and T-cells and can have some features of cancer (malignancy), but fail to meet the criteria for lymphoma. The clinical symptoms associated with the polymorphic form are variable. Many cases of polymorphic cases are Epstein-Barr virus positive. Monomorphic PTLD is the most common form and is characterized by the development of malignant lymphoma, usually diffuse large B-cell lymphoma (this is the most common type of non-Hodgkin lymphoma in the United States). The signs and symptoms of the monomorphic form can range from early lesions described above to more severe “late” disease such as organ failure. About 50% of cases are Epstein-Barr virus positive. Classic Hodgkin-like PTLD is when PTLD fulfills the criteria for Hodgkin lymphoma, a form of cancer that arises from white blood cells, and are often are Epstein-Barr virus positive.
Specific signs and symptoms depend on several factors including the areas of the body affected and the type of PTLD. Affected individuals often develop symptoms that are vague and can be nonspecific, which means that the symptoms are common to many different disorders or conditions. When dealing with lymphoma, these symptoms may come and go and are sometimes referred to as ‘B symptoms.’ These symptoms can include a persistent, chronic fever; unintended weight loss, and excessive sweating, especially at night (night sweats). Some individuals develop abnormal enlargement of the lymph nodes (lymphadenopathy), fatigue, or a general feeling of poor health (malaise).
PTLD can often have a rapid and severe development (fulminant course). Disease may be widespread throughout the body and frequently there is involvement of organs and tissue beyond the lymph nodes (extranodal involvement). The exact organs involved can vary, but often include the gastrointestinal tract, the transplanted organ (allograft), and the central nervous system. Specific signs and symptoms will depend on the organ system(s) involved. For example, central nervous system involvement can be associated with seizures and neuropsychiatric symptoms. Headaches, nausea, vomiting, and vision problems can occur because of an increase in pressure within the skull (intracranial pressure).
PTLD may also be referred to as early onset or late onset. Early onset means that a lymphoproliferative disorder develops shortly after the transplant, usually within twelve months. Late onset means that a lymphoproliferative disorder develops after twelve months. In about half the patients, PTLD occurs within the first year following the transplant. Early onset PTLD is more likely to be characterized by the presence of Epstein-Barr virus in affected B-cells, and may include involvement of the donated organ or extranodal sites. Late onset PTLD is more likely to have disease spread outside of the lymphatic system (extranodal), and often results in the development of malignant lymphoma.
Post-transplant lymphoproliferative disease may be associated with infection with the Epstein-Barr virus (EBV). This is a common virus that, generally, does not cause any problems in people after an active phase. This virus infects B-cells. After the active phase, the virus remains in the body, where it lies dormant or “silent” in these cells (latent phase). Most people are first infected with the Epstein-Barr virus in childhood and only develop mild symptoms or no symptoms. If infection first occurs in the teen-aged years or adulthood, affected individuals may develop fever, sore throat, and enlarged lymph nodes. The Epstein-Barr virus is one of the most common causes of infectious mononucleosis or “mono.” As many as 90-95% of people will be infected with the Epstein-Barr virus at some point during their lives. EBV negative recipients are at higher risk of PTLD.
When patients who have undergone a solid organ or hematopoietic stem cell transplant receive drugs to suppress their immune systems, this can lead to reactivation of Epstein-Barr-infected B-cells, which demonstrate uncontrolled growth and accumulation. This most likely occurs because of a lack of T-cells due to immunosuppression. Some T-cells called cytotoxic T-cells function by eliminating other cells that are damaged, stressed, or infected. Because cytotoxic T-cells levels are low, Epstein-Barr-infected B-cells are allowed to grow and spread.
Sometimes, PTLD occurs because of reactivation and uncontrolled growth of Epstein-Barr-infected B-cells that come from the donor organ. This is most common in people who receive a hematopoietic stem cell transplant. When an organ or stem cells are donated, other cells are also donated, including B-cells. If the person who donates the organ or stem cells has had Epstein-Barr infection in the past, these dormant, infected cells will be passed onto the recipient. This is most common with solid organ transplants. PTLD can also occur if a person who received a transplant becomes infected with the Epstein-Barr virus for the first time.
PTLD only occurs in a small percentage of people who receive a transplant, regardless if they have had Epstein-Barr infection. As an example, the long-term risk in renal transplantation is 2%, but it is higher in other solid organ transplant patients. Because of this, researchers believe that there are additional factors necessary for the development of these disorders. Although the Epstein-Barr virus is associated with the majority of affected individuals, some people do not have any evidence of this infection. Researchers are not sure what causes PTLD in people with the Epstein-Barr-negative version of PTLD.
There are several risk factors that have been identified for PTLD. These risk factors can differ based on the type of transplant. For solid organ transplants, risk factors include EBV serostatus of the donor and recipient and what organ is being transplanted (see Affected Populations below). For hematopoietic stem cell transplants, the source of the stem cells affects the degree of risk. Stem cells donated from unrelated individuals or that are mismatched based on tissue type increase the risk. The use of antibodies preparations containing antithymocyte globulin or anti-CD3 antibodies also increases the risk. Being over the age of 50 is also a risk factor for PTLD following a hematopoietic stem cell transplant. Chronic graft-versus-host disease, in which immune system cells from the donated stem cells attack healthy cells in the recipient, is a major risk factor for the development of late onset PTLD.
Risk factors for both types of transplants include the degree of immunosuppression and types of drugs used, specifically in how low the levels of cytotoxic T-cells drop (T-cell depletion); the serostatus of the Epstein-Barr virus in the transplant recipient, which determines whether antibodies against the Epstein-Barr virus are detectable in the blood; fewer human leukocyte antigen matches between the cells of the donor and recipient (HLAs are used by the immune system to recognize cells of the body so they are not destroyed); a history of cancer (malignancy) before the transplant in the recipient; and younger age.
PTLD occurs in solid organ transplants and hematopoietic stem cell transplants. Solid organ transplants are when surgeons remove a solid organ like the heart, lungs, liver or kidneys because the organs are no longer functioning sufficiently and cannot be improved. The organ is replaced by a healthy, functioning organ from a donor.
A hematopoietic stem cell transplant is a type of bone marrow transplant. Hematopoietic stem cells are special cells found in bone marrow that manufacture different types of blood cells (e.g., red blood cells, white blood cells, platelets). In allogeneic stem cell transplantation, stem cells are donated from another person, usually from a closely matched family member. Allogeneic stem cell transplants can be used for different conditions but often are used to treat blood cancers. Generally, this therapy is reserved for people who do not respond to other treatment options and younger patients who meet specific criteria.
The incidence and prevalence of post-transplant lymphoproliferative disease varies based on the type of transplant and affects about 1%-2% of people who have received a kidney (renal) transplant. Rates are higher in heart and lung transplants. PTLD occurs most often with gastrointestinal and multiorgan transplants. PTLD is the most common cancer affecting people who receive solid organ transplants after squamous cell carcinoma of the skin. In a retrospective multicenter study, the overall incidence of PTLD in people who had hematopoietic stem-cell transplants was reported to be 3.2%
A diagnosis of a post-transplant lymphoproliferative disease is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests, including a complete blood count (CBC), chemical panel, specialized imaging (x-ray) techniques, an evaluation for the Epstein-Barr virus, and a tissue biopsy.
Clinical Testing and Workup
A doctor may remove a small sample of an area identified on scans or physical examination that will be studied under a microscope (biopsy). The sample is studied by a pathologist, who is a specialist trained in examining tissues and cells to find disease and determine what disease is present. Immunohistochemistry is routinely performed.
This examination involves using antibodies to diagnosis and differentiate cancer. Antibodies are specialized proteins of the immune system that work to help protect the body from foreign substances. Different antibodies react to specific substances, which are collectively called antigens. When doing immunohistochemistry, antibodies are linked to an enzyme or fluorescent dye and exposed to the tissue sample. Specific antibodies will bind to specific antigens and the enzyme or dye will allow physicians to see this under a microscope. Immunohistochemistry can diagnose cancer as well as differentiate different types of cancer.
Tissue samples may also be studied for the presence of genomic changes that can indicate PTLD. These are changes in the DNA within the cells that are often associated with the development of cancer. At this time, genomic studies are not routinely performed.
Additional tests can be done to support a diagnosis of PTLD or can help determine the extent and spread of the disease. A complete blood count will measure the levels of the three main blood cells: red cells, white cells and platelets, which can be low in people with PTLD. A chemical (metabolic) panel is a group of blood tests that measure the levels of certain substances in the body. A chemical panel can help to assess how well certain organs are functioning. Some affected individuals will undergo a blood test to assess the levels of lactate dehydrogenase (LDH). LDH is a chemical that is released from cells that are damaged. High levels of LDH in the blood indicate that cell damage is present. This can occur in cancer, and is a sign of tumor lysis.
A test called an Epstein-Barr virus viral load will be conducted to determine the status of Epstein-Barr infection in both the transplant recipient and the donor. Most people scheduled to receive a transplant have this test done before the transplant is to take place, but not all donors do. During a viral load test, a sample of blood is studied to detect the DNA of the Epstein-Barr virus. A test called polymerase chain reaction (PCR) is usually used. PCR, which has been described as a form of “photocopying,” enables doctors to enlarge, analyze, and copy sequences of DNA and can be used to identify the DNA of the Epstein-Barr virus. A positive result on Epstein-Barr virus viral load test is not necessary for a diagnosis of PTLD as there are people who develop this condition without evidence of EBV infection.
Specialized imaging techniques may include computerized tomography (CT) scanning, PET scanning, and magnetic resonance imaging (MRI) can be used to determine the extent of the disease. During CT and PET scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. Imaging scans of the neck, chest, abdomen, pelvis, and head are commonly conducted to look for signs of cancer spread such as enlarged lymph nodes or the presence of a tumor.
A highly sensitive imaging test called combined positron emission tomography (PET) and computerized tomography (CT) scan known as a PET/CT scan can also be recommended. During a PET scan, three-dimensional images are produced to evaluate how healthy and functional certain tissues and organs are. This exam involves the use of a radioactive drug called a tracer that is combined with sugar (glucose). This radioactive sugar is injected into the body. This sugar will collect in areas of the body where there is a higher demand for energy. Cancer requires a lot of energy to keep growing and spreading, and will soak up the radioactive sugar. These areas will show up on the PET scan as brighter than the surrounding areas. A CT scan can show enlarged organs or lymph nodes. A PET/CT allows physicians to assess the metabolic and structural (anatomic) in one session and can return a more accurate image or picture of cancer than either test can by itself.
If doctors suspect that the central nervous system is involved, they may order a lumbar puncture, which is also called a spinal tap. During a lumbar puncture, a needle is inserted into the spinal canal in the lower back to retrieve a sample of cerebrospinal fluid (CSF). CSF is the fluid that surrounds the brain and spinal cord. The fluid is examined to detect malignant cells.
The treatment of post-transplant lymphoproliferative disease is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists, including physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), disorders of the blood and blood-forming tissues (hematologists), the use of radiation to treat cancers (radiation oncologists); transplant specialists; surgeons; oncology nurses; dietitians; and other healthcare professionals may need to systematically and comprehensively plan treatment. Psychosocial support for the entire family is essential as well.
The primary goal of treatment is to cure the PTLD, while preserving the function and health of the transplant. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as transplant type; disease stage; specific lymphoma subtype; tumor size; the organ systems involved; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.
The reduction (tapering) of immunosuppressive drugs may be recommended and may be sufficient for people with early PTLD. Such reduction can allow the immune system to recover and fight off the Epstein-Barr infection. However, sufficiently reducing the dosage of immunosuppression is not always possible because tapering these drugs can increase the risk of post-transplant complications including graft-versus-host disease or organ rejection.
If PTLD is localized to one specific area of the body, surgery may be recommended to remove the tumor and/or surrounding lymph nodes.
Sometimes, a drug called rituximab (Rituxan®) may be recommended. This drug can destroy Epstein-Barr-infected B-cells and can be used alone as a single agent (monotherapy) or as part of a drug regimen (immunochemotherapy) that includes other drugs. Rituximab is classified as a monoclonal antibody or biologic therapy – medications that act like antibodies, but are artificially created in a lab. Rituximab is recommended for CD20+ PTLD. CD20 is a substance found on the surface of B-cells that can be targeted by rituximab. PTLD can recur after successful treatment with this drug. Rituximab is also a type of immunotherapy because it aims to enhance the body’s innate ability to fight cancer cells using the immune system.
Sometimes, doctors may recommend anti-cancer drugs (chemotherapy). Chemotherapy is often given along with rituximab in patients with CD20+ disease (immunochemotherapy). In patients without CD20+ disease, different combinations of chemotherapy drugs, called regimens, will be recommended. When chemotherapy is given, the specific chemotherapy regimen used can vary. There are no standard regimens identified for PTLD. Different medical centers may have their own preferences as to the best way to approach treatment and what chemotherapeutic regimen is best for each individual.
Sometimes, the use of radiation to kill cancer cells (radiation therapy) is recommended. This is usually recommended for individuals whose disease is localized to one area of the body, or in individuals with involvement of the central nervous system.
Antiviral therapy, which is the use of drugs that are effective against viruses, has been tried in people with PTLD. These drugs, which include acyclovir, ganciclovir, and foscarnet, are usually used in conjunction with reducing the dosage of immunosuppression. These drugs have not been effective in treating PTLD when used by themselves, and the overall effectiveness as a treatment for PTLD remains unproven.
Some individuals may be treated by adoptive immunotherapy. This is also called T-cell immunotherapy. This procedure is a therapeutic process in which doctors collect cytotoxic T-cells from a healthy donor. The specific T-cells collected target Epstein-Barr-infected B-cells. The donated T-cells are infused into the patient where they identify and destroy Epstein-Barr-infected B-cells while sparing other cells and tissues of the body. This process makes up for the patient’s lack of cytotoxic T-cells due to immunosuppression. In the United States, adoptive immunotherapy is not readily available and is only offered at a handful of medical centers.
A medication known as tabelecleucel (tab-cel™) is being studied in clinical trials as a treatment for individuals with PTLD that are associated with the Epstein-Barr virus following either a solid organ transplant or a hematopoietic stem cell transplant. Initial studies have shown positive results and was well-tolerated by patients. The medication is a T-cell immunotherapy that contains cytotoxic T-cells that act against cells infected with the Epstein-Barr virus.
Initial research into the use of antiviral medications along with viral thymidine kinase-inducing agents have shown promise as a combined therapy for PTLD. However, more research is necessary to determine the long-term safety and effectiveness of this combination therapy.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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