Splenic marginal zone lymphoma is a rare type of blood cancer that primarily affects the spleen, causing it to enlarge significantly while typically progressing slowly over time.

Splenic marginal zone lymphoma, often called SMZL, is a particular form of cancer that originates in the immune system. It belongs to a broader category known as non-Hodgkin lymphomas, which are cancers affecting white blood cells that normally protect the body from infections. What makes SMZL distinct is where it begins and how it behaves. This cancer develops in special immune cells called B lymphocytes or B cells, which are found in a specific area of the spleen called the marginal zone.^[1]

The disease is classified as a low-grade or slow-growing lymphoma, meaning it tends to develop gradually rather than aggressively. Unlike many cancers that spread widely through the body, SMZL has a particular pattern. It primarily involves the spleen, often causing it to become massively enlarged. The cancer can also affect the bone marrow, where blood cells are produced, and sometimes appears in the blood itself as circulating cancer cells. The lymph nodes near the spleen may be involved, but involvement of other distant lymph nodes or organs outside the lymphatic system is rare.^[4]

Epidemiology

Splenic marginal zone lymphoma is quite rare in the general population. It represents the second most common type within the marginal zone lymphoma group, accounting for roughly 20 percent of all marginal zone lymphomas.^[4] When looking at all non-Hodgkin lymphomas diagnosed worldwide, SMZL makes up only about 1 to 2 percent of cases, making it an uncommon disease that many people have never heard of.^[6]

The condition tends to affect certain groups more than others. Most people diagnosed with SMZL are older adults, typically around 60 years of age or older.^[5] The disease shows a slight preference for men over women, though both sexes can develop it. Because SMZL is so rare, much of what doctors know about the disease comes from small studies at individual medical centers rather than large international trials, which has made it challenging to establish standardized treatment approaches.^[4]

Causes

The exact cause of splenic marginal zone lymphoma remains not fully understood, but researchers have identified several important connections. The disease is thought to arise from B cells that have already passed through a stage of development in structures called germinal centers, though the precise degree of cell maturation is unknown.^[9]

A significant link exists between SMZL and hepatitis C virus (HCV) infection. Approximately one in five people with SMZL also have an active HCV infection.^[6] This connection is strong enough that doctors now routinely test SMZL patients for hepatitis C, because treating the viral infection first can sometimes reduce lymphoma symptoms and may even eliminate the need for cancer treatment in some cases.^[7]

The body’s own immune system may also play a role in disease development. The cancer cells originate from immune cells that normally help fight infections, and something appears to cause these cells to multiply out of control. Scientists believe that chronic stimulation of the immune system, whether from ongoing infections or from the body mistakenly attacking itself in autoimmune conditions, might contribute to the development of SMZL.

Risk Factors

Several factors appear to increase a person’s likelihood of developing splenic marginal zone lymphoma, though having these risk factors does not mean someone will definitely develop the disease. Family history plays a notable role, as people with relatives who have had lymphoma face higher risks of developing various types of lymphoma themselves, including SMZL.^[5]

Infection with hepatitis C virus stands out as one of the most significant risk factors specifically for SMZL. About 20 percent of SMZL patients have HCV infection, a rate much higher than in the general population.^[6] However, it’s important to note that most people with hepatitis C will never develop SMZL, showing that other factors must also be involved.

Autoimmune diseases, conditions where the immune system mistakenly attacks the body’s own tissues, also increase risk. These disorders create an environment of chronic immune system activation that may, over time, contribute to abnormal growth of immune cells. Common autoimmune conditions linked to increased lymphoma risk include rheumatoid arthritis, systemic lupus erythematosus, and Sjögren’s syndrome.^[5]

Symptoms

One of the remarkable features of splenic marginal zone lymphoma is that many people have no symptoms at all when first diagnosed. Studies show that about one in four people with SMZL are asymptomatic, meaning the disease is discovered accidentally during medical tests for other reasons.^[4] This is possible because the lymphoma grows slowly and may take considerable time before causing noticeable problems.

When symptoms do appear, the most common issue is an enlarged spleen, called splenomegaly. This happens in nearly all people with SMZL eventually. The spleen, an organ located in the upper left side of the abdomen just beneath the rib cage, can grow to many times its normal size. A normal spleen is about the size of a fist, but in SMZL it can reach 25 centimeters or more, becoming so large it is easily felt through the abdominal wall.^[6]

An enlarged spleen causes several uncomfortable symptoms. People may feel fullness or pressure in the upper left abdomen or even pain in that area or in the left shoulder. The enlarged spleen takes up space normally occupied by the stomach, so people often feel full after eating only small amounts of food. This can lead to unintended weight loss. The spleen may become so large it presses on other organs, causing additional discomfort.^[6]

When the lymphoma spreads to the bone marrow, it can interfere with normal blood cell production, leading to low blood cell counts or cytopenias. About one quarter of people with SMZL develop cytopenias.^[4] Low red blood cell counts cause anemia, which leads to extreme tiredness, shortness of breath, rapid heartbeat, and pale skin. Low platelet counts, called thrombocytopenia, can result in easy bruising and bleeding problems. Some people notice they bleed longer than normal from minor cuts or develop small red spots on their skin.

Another characteristic feature is the presence of abnormal lymphocytes circulating in the blood. These cancer cells, when viewed under a microscope, have a distinctive appearance with short projections on their surface, earning them the name “villous lymphocytes.”^[4] Although these cells can be seen in blood tests, they don’t usually cause symptoms directly.

Some people with SMZL experience what doctors call B symptoms, a specific group of symptoms that includes unexplained fever, drenching night sweats that require changing clothes or bedding, and unintentional weight loss of more than 10 percent of body weight over six months. However, B symptoms and elevated levels of lactate dehydrogenase (LDH), an enzyme that increases with tissue damage, are less common in SMZL than in more aggressive lymphomas.^[4]

Interestingly, about 20 percent of people with SMZL develop autoimmune disorders, where the body’s immune system begins attacking its own cells. The most common is autoimmune hemolytic anemia, where antibodies destroy red blood cells faster than the body can replace them. Other autoimmune complications can include problems with blood clotting or even rare conditions affecting various organs.^[4]

Prevention

Unfortunately, there are no known specific measures to prevent splenic marginal zone lymphoma from developing. Because the exact causes of the disease are not fully understood and seem to involve a combination of genetic factors, infections, and immune system changes, there are no vaccines or lifestyle modifications proven to reduce risk.

However, managing known risk factors may be beneficial. For people with hepatitis C infection, receiving appropriate antiviral treatment can clear the virus from the body and may reduce the risk of developing SMZL. Regular medical care for autoimmune diseases and prompt treatment of infections when they occur may also be prudent, though direct evidence that these measures prevent lymphoma is limited.

For individuals with a strong family history of lymphoma, staying alert to potential symptoms and maintaining regular contact with healthcare providers is important. While this does not prevent the disease, early detection when symptoms first appear may allow for prompt diagnosis and treatment planning.

Pathophysiology

The development of splenic marginal zone lymphoma involves complex changes at the cellular and molecular level that transform normal B lymphocytes into cancer cells. These B cells normally reside in the marginal zone of the spleen’s white pulp, a region rich in immune cells that helps filter blood and fight infections. In SMZL, something triggers these cells to begin multiplying uncontrollably.

The cancer cells typically include both small lymphocytes and larger, more immature-looking cells called lymphoblasts. These abnormal cells gradually invade different areas of the spleen, first affecting structures called follicles in the white pulp, then spreading to erode the marginal zone itself, and eventually infiltrating the red pulp of the spleen where old blood cells are normally removed.^[9]

At the genetic level, scientists have identified several abnormalities that may drive the disease. Many people with SMZL have changes in their immunoglobulin genes, which provide instructions for making antibodies. A deletion of genetic material on chromosome 7 (specifically the region 7q21-32) appears in about 40 percent of patients with SMZL.^[9] These genetic changes disrupt normal cell growth control mechanisms, allowing cancer cells to survive and multiply when they should not.

The cancer cells in SMZL have characteristic markers on their surface that help doctors identify the disease. They express certain proteins like CD20 and CD79a, which are typical of B cells, but they lack other markers like CD5, CD10, and CD23 that are found in different types of lymphoma. This specific pattern of protein expression helps doctors distinguish SMZL from other similar-looking blood cancers.^[9]

About one-third of people with SMZL develop small amounts of a monoclonal protein in their blood, usually a type of antibody called immunoglobulin M (IgM) kappa. This protein is produced by the cancer cells but typically does not reach levels high enough to cause blood thickening or other serious problems.^[4]

The bone marrow involvement in SMZL shows a distinctive pattern when examined under the microscope, with cancer cells forming nodules similar to those seen in lymph nodes near the spleen. However, the enlarged spleen shows the most dramatic changes, with its normal architecture being replaced by sheets of cancer cells.^[4]

The low blood cell counts that develop in some patients have several causes. The enlarged spleen can trap and destroy blood cells in a process called hypersplenism, which is responsible for cytopenias in many cases. Other times, the bone marrow becomes so packed with cancer cells that there is insufficient room for normal blood cell production. Occasionally, autoimmune antibodies attack blood cells directly, adding to the problem.^[4]