Introduction: Who Should Seek Diagnostics and When

If you have previously been treated for diffuse large B-cell lymphoma and achieved remission, understanding when to seek diagnostic testing is crucial for your ongoing health. Recurrent DLBCL refers to lymphoma that reappears or grows again after a period of remission following initial treatment. This is often called relapsed disease. Sometimes, DLBCL does not respond well to the first treatment, or the response does not last very long. This situation is known as refractory disease.^[2]

You should contact your healthcare provider if you notice any new lumps or swelling, especially in areas where you previously had symptoms. Pay attention to changes in your body that persist for several weeks rather than days. Around 40 percent of patients with DLBCL experience either refractory disease or relapse after their first line of treatment.^[5] Understanding this risk can help you stay alert to symptoms without becoming overly anxious.

Most people who experience a relapse notice symptoms similar to those they had before their initial diagnosis. Research shows that about two-thirds of people experiencing a DLBCL relapse have noticeable symptoms when the cancer returns.^[4] These symptoms might appear gradually or develop quickly, depending on how fast the cancer is growing.

Common symptoms that should prompt you to seek diagnostic evaluation include swollen or enlarged lymph nodes that you can feel under your skin. These lumps most commonly appear in the neck, armpits, or groin area, and they typically do not cause pain, although they can sometimes be tender. Unlike swollen lymph nodes from a common cold or infection, these lumps continue growing over several weeks and do not go away on their own.^[18]

Some people experience what doctors call “B symptoms,” which include fevers above 103 degrees Fahrenheit that come and go without an obvious cause, unexplained weight loss of more than 10 percent of your body weight over six months, and intense night sweats that are severe enough to drench your bed sheets.^[1] If you develop these symptoms, especially in combination with swollen lymph nodes, contact your oncologist promptly.

Abdominal pain can also signal a DLBCL relapse, particularly if lymph nodes deeper inside your body become swollen. This type of swelling can cause pain in your stomach area, often on the lower right side, though it may spread to other areas as well. Because abdominal pain has many possible causes, it is important to describe all your symptoms to your doctor so they can determine whether further testing is needed.^[18]

Diagnostic Methods for Identifying Recurrent DLBCL

When you present with symptoms that suggest your DLBCL may have returned, your healthcare team will conduct several tests to confirm whether cancer is present and to understand its extent. The diagnostic process for recurrent DLBCL involves multiple steps and different types of examinations.

Biopsy: The Gold Standard for Confirmation

Before starting a second line of treatment, doctors recommend repeating a tumor biopsy. This is a procedure where a doctor removes a sample of tissue from a suspicious lump or swollen lymph node to examine it under a microscope. A biopsy is essential because it provides definitive proof that cancer has returned rather than another condition that might cause similar symptoms.^[5]

The biopsy serves several important purposes beyond simply confirming relapse. First, it can help exclude other diseases that might mimic lymphoma symptoms, such as tuberculosis, sarcoidosis, fungal infections, or even other types of cancer. Second, the biopsy can reveal whether the lymphoma cells have changed since your initial diagnosis. Sometimes the characteristics of cancer cells evolve over time or in response to treatment, and understanding these changes helps your doctors choose the most effective treatment plan.^[5]

There are different types of biopsies depending on where the suspicious tissue is located. A lymph node biopsy involves removing part or all of a swollen lymph node. Sometimes doctors can perform this with a needle, which is less invasive, but other times they need to surgically remove the entire node to get enough tissue for thorough examination.^[6]

Imaging Tests: Seeing Inside Your Body

Imaging tests create pictures of the inside of your body and help doctors see where cancer might be growing. Several types of imaging tests are commonly used when evaluating suspected DLBCL relapse.

A PET scan, which stands for positron emission tomography, is particularly valuable in lymphoma diagnosis and monitoring. This test involves injecting a small amount of radioactive material into your bloodstream. Cancer cells, which are growing rapidly, absorb more of this material than normal cells. A special camera then creates images showing areas where this material has concentrated, revealing potential cancer locations throughout your body.^[6]

However, PET scans are not perfect. They can sometimes show activity in areas that are inflamed or infected but not cancerous, giving what doctors call “false-positive” results. This is one reason why biopsies remain so important—they provide certainty that PET scans cannot always offer. If you did not achieve complete metabolic remission after your first treatment (meaning PET scans still showed some activity), doctors may recommend repeating the PET scan six to twelve weeks later or proceeding directly to biopsy to determine whether active cancer is present.^[5]

CT scans, or computed tomography scans, use X-rays taken from multiple angles to create detailed cross-sectional images of your body. These scans can reveal enlarged lymph nodes and assess how cancer might be affecting various organs. CT scans provide more detailed information than standard X-rays and help doctors understand the size and location of tumors.^[6]

MRI scans, which stands for magnetic resonance imaging, use powerful magnets and radio waves rather than radiation to create detailed images of soft tissues in your body. MRI may be particularly helpful if doctors suspect lymphoma has spread to your brain, spinal cord, or other areas where soft tissue detail is especially important.^[6]

Blood Tests: Looking for Clues in Your Bloodstream

Blood tests provide valuable information about your overall health and can sometimes reveal indirect signs that cancer has returned. While blood tests alone cannot diagnose DLBCL relapse, they help build a complete picture of what is happening in your body.

Standard blood tests check your counts of different blood cells. DLBCL can affect your bone marrow, where blood cells are made, potentially causing abnormal numbers of white blood cells, red blood cells, or platelets. Blood tests also evaluate how well your organs, particularly your liver and kidneys, are functioning. This information helps doctors understand whether cancer might be affecting these organs and also helps them plan safe treatment if cancer is confirmed.^[6]

Bone Marrow Tests: Examining Where Blood Cells Are Made

A bone marrow test involves taking a small sample of the spongy tissue inside your bones where blood cells are produced. This test helps determine whether lymphoma cells have spread to your bone marrow. The procedure typically involves inserting a needle into a large bone, often in your hip, to remove a small amount of marrow for examination under a microscope.^[6]

Bone marrow testing is not always necessary for every patient with suspected relapse, but it provides important staging information. Staging refers to determining how widespread the cancer is in your body, which significantly influences treatment decisions.

Lumbar Puncture: Checking Spinal Fluid

In some cases, particularly if you have symptoms suggesting lymphoma might have spread to your central nervous system (brain and spinal cord), doctors may recommend a lumbar puncture. This procedure, also called a spinal tap, involves inserting a thin needle between the bones in your lower back to collect a small sample of the fluid that surrounds your brain and spinal cord. Laboratory specialists then examine this fluid under a microscope looking for lymphoma cells.^[6]

Diagnostics for Clinical Trial Qualification

If standard treatment options for recurrent DLBCL have not been successful or if you are interested in exploring newer therapies, you and your doctor might consider enrolling in a clinical trial. Clinical trials test new treatments to determine whether they are safe and effective. However, participating in a clinical trial requires meeting specific eligibility criteria, and certain diagnostic tests are used to determine whether you qualify.

Confirming Relapsed or Refractory Disease

Clinical trials for recurrent DLBCL typically require documented evidence that your lymphoma has either relapsed after achieving remission or is refractory to treatment. This confirmation almost always requires a biopsy showing active lymphoma cells. Imaging tests alone, such as PET or CT scans, generally are not sufficient for trial enrollment because they can produce false-positive results.^[5]

Some clinical trials have specific definitions for what qualifies as relapsed or refractory disease. For example, the SCHOLAR-1 study, which established a benchmark for comparing new treatments for recurrent DLBCL, defined refractory disease as having stable or progressive disease as the best response to treatment, or experiencing relapse within 12 months after an autologous stem cell transplant.^[12]

Performance Status Assessment

Clinical trials typically have requirements about your overall health and ability to perform daily activities. Doctors assess this using what is called performance status, which is a standardized way of describing how cancer affects your daily functioning. To qualify for most trials, you need to be well enough to tolerate the experimental treatment and to provide meaningful information about whether it is working.

Organ Function Tests

Before enrolling in a clinical trial, you will undergo tests to evaluate how well your major organs are functioning. These tests typically include blood tests to check your liver and kidney function, as well as heart tests such as an electrocardiogram (ECG) that records your heart’s electrical activity. Many experimental treatments can stress the body’s organs, so doctors need to ensure your organs are healthy enough to handle the treatment safely.

Prior Treatment Documentation

Clinical trials for relapsed or refractory DLBCL require detailed documentation of all previous treatments you have received. This includes which drugs were used, how many cycles you received, how your cancer responded, and how long any remissions lasted. Trials often specify that participants must have tried and not benefited from certain standard treatments before being eligible for experimental therapies.

Disease Measurement and Monitoring

Clinical trials require precise ways to measure whether a treatment is working. This typically involves baseline imaging tests—meaning scans performed before treatment starts—that clearly show where cancer is located and how large tumors are. These baseline scans are then compared to scans taken during and after treatment to determine whether the experimental therapy is causing tumors to shrink, remain stable, or continue growing.

Most trials use standardized criteria for evaluating treatment response. These criteria define what counts as a complete response (no detectable cancer), partial response (cancer has shrunk but is still present), stable disease (cancer is neither growing nor shrinking significantly), or progressive disease (cancer is growing or spreading). Precise measurements from imaging tests provide the objective data needed to make these determinations.