What is lymphoproliferative disease?

The term lymphoproliferative disease (LPD) describes a group of conditions in which lymphocytes—a type of white blood cell that helps fight infections—grow or multiply beyond normal levels.

Lymphocytes include B cells, T cells, and natural killer (NK) cells. These cells normally protect the body by recognizing and destroying viruses, bacteria, and abnormal cells. In a lymphoproliferative disease, one group of lymphocytes divides too quickly or lives too long, leading to an abnormal build-up of cells in the lymph nodes, blood, bone marrow, or other organs.

Some lymphoproliferative diseases are non-cancerous (benign), while others are cancers, such as lymphoma or leukemia.

What causes lymphoproliferative disease?

There are many possible causes of lymphoproliferative disease. In some people, the condition develops spontaneously, while in others it arises due to a weakened or overactivated immune system.

Common causes and risk factors include:

• Chronic infections, such as Epstein–Barr virus (EBV) or human herpesvirus 8 (HHV-8), can trigger ongoing lymphocyte stimulation.

• Immunosuppression from organ transplantation or long-term medications that lower immune activity.

• Autoimmune diseases can lead to continuous lymphocyte activation.

• Genetic changes or inherited conditions: In some people, small changes in specific genes can make lymphocytes less able to regulate their own growth or “shut off” at the right time. Rare inherited immune disorders may also allow abnormal lymphocyte clones to expand more readily.

• Age-related changes in the immune system can allow one abnormal group of lymphocytes to dominate.

Because there are so many potential causes, additional tests are usually needed to identify the underlying trigger and determine whether the process is reactive (non-cancerous) or clonal (cancerous).

Is lymphoproliferative disease the same as lymphoma?

Not always. Lymphoma is one type of lymphoproliferative disease, but not all lymphoproliferative diseases are lymphomas.

• Reactive (non-cancerous) lymphoproliferations occur when lymphocytes multiply in response to an infection, inflammation, or immune suppression. The process often returns to normal once the underlying problem resolves.

• Clonal (neoplastic) lymphoproliferations arise from a single abnormal lymphocyte that divides uncontrollably. A neoplasm is a mass or overgrowth of cells that occurs because of abnormal or unregulated cell division. When lymphoid cells form a neoplasm, it is usually called lymphoma or leukemia, depending on where it develops.

Your pathology report and supporting laboratory studies will clarify which type you have.

How is the diagnosis made?

The diagnosis of lymphoproliferative disease is based on a combination of clinical information, laboratory findings, and pathologic examination.

• Biopsy: A small piece of tissue, usually from a lymph node, bone marrow, or another affected site, is examined under the microscope. The pathologist looks for an increased number of lymphocytes and assesses whether they are typically arranged or exhibit abnormal growth patterns.

• Immunohistochemistry (IHC): This test uses specific antibodies to detect specific proteins in cells. It helps determine whether the lymphocytes are B cells, T cells, or NK cells, and whether they look reactive or abnormal. For example, normal B cells produce proteins such as CD20, while T cells express CD3. IHC can also identify abnormal patterns, such as loss or overexpression of specific proteins, which can support a diagnosis of lymphoma or another specific subtype of lymphoproliferative disease.

• Flow cytometry: a laboratory technique that analyzes individual cells as they pass through a laser beam in a stream of fluid. The test uses fluorescent antibodies to identify cell surface markers that define B cells, T cells, or NK cells. It can also detect whether all cells are identical (clonal) or diverse (polyclonal). Finding a clonal population of B cells or T cells supports a diagnosis of a lymphoid neoplasm.

• Molecular tests: Additional tests such as polymerase chain reaction (PCR) or fluorescence in situ hybridization (FISH) may be used to detect genetic changes or chromosomal rearrangements that confirm a specific diagnosis.

Together, these studies determine whether the condition is reactive, clonal, or malignant and help classify the specific type of lymphoproliferative disease.

What are the most common types of lymphoproliferative diseases?

Lymphoproliferative diseases include a wide range of disorders. Some are reactive (non-cancerous) and others are clonal (cancerous).

The most common types include:

• Post-transplant lymphoproliferative disorder (PTLD): This condition can develop in people who take medications to prevent organ rejection. Because the immune system is suppressed, abnormal B cells—often infected with the Epstein–Barr virus—can grow uncontrollably. PTLD can range from a benign overgrowth of lymphocytes to an aggressive lymphoma.
• Autoimmune lymphoproliferative syndrome (ALPS): A rare inherited disorder where lymphocytes do not undergo normal cell death when they are no longer needed. This leads to enlarged lymph nodes and spleen and an increased risk of developing lymphoma.
• Chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL/SLL): A slow-growing cancer caused by the abnormal proliferation of mature B cells. CLL affects the blood and bone marrow, while SLL affects lymph nodes and tissues.
• Peripheral T-cell lymphoma: A group of cancers that develop from mature T cells. They often behave more aggressively and may require more intensive treatment.
• Reactive lymphoid hyperplasia: A non-cancerous overgrowth of lymphocytes in response to infection or inflammation. The appearance may resemble lymphoma under the microscope, so additional tests are used to distinguish between the two.

Your pathology report will specify which type you have once all testing is complete.

Is lymphoproliferative disease severe?

The seriousness of a lymphoproliferative disease depends on its cause and type.

• Reactive forms (for example, due to infection or immune suppression) may resolve once the underlying trigger is treated or removed.

• Clonal or cancerous forms require further evaluation and may be treated with chemotherapy, immunotherapy, targeted therapy, or stem cell transplant, depending on the exact subtype.

Your healthcare team will explain the specific diagnosis, its severity, and the recommended treatment or monitoring.

Questions to ask your doctor

• What type of lymphoproliferative disease do I have—reactive or clonal?

• Is this considered a neoplasm (cancer) or a non-cancerous condition?

• What tests were performed to confirm the diagnosis?

• Were any genetic changes found in the lymphocytes?

• Is there a known infection or immune problem that caused this?

• What are the treatment options or next steps for monitoring my condition?