Stage 4 Lymphoma

Treatment of stage 4 lymphoma depends on the lymphoma type and may involve a combination of therapies, including chemotherapy, radiation therapy, stem cell transplantation, targeted therapy, immunotherapy, and surgery. Prognosis for stage 4 lymphoma also depends on the cancer type — along with patient age, overall health, and response to treatment.

• Hodgkin lymphoma (formerly known as Hodgkin disease), which involves an abnormal type of lymphocyte called Reed-Sternberg cells
• Non-Hodgkin lymphoma, which does not contain Reed-Sternberg cells

Both Hodgkin and non-Hodgkin lymphomas have a number of subtypes, which differ depending on the cells and tissues the cancer affects and how quickly they grow.

Hodgkin Lymphoma

• Nodular Sclerosing Hodgkin Lymphoma This is the most common subtype of classic Hodgkin lymphoma, and it affects the lymph nodes in the central part of the chest.
• Mixed Cellularity Hodgkin Lymphoma This subtype is marked by lymph nodes carrying a mix of cell types, including many Reed-Sternberg cells.
• Lymphocyte-Rich Classic Hodgkin Lymphoma About 6 percent of Hodgkin lymphomas are of this subtype, which is characterized by a higher number of normal lymphocytes along with Reed-Sternberg cells.
• Lymphocyte-Depleted Hodgkin Lymphoma About 1 percent of people with Hodgkin lymphoma have this subtype, which is characterized by many abnormal lymphocytes in place of normal lymphocytes.

The slow-growing nodular lymphocyte-predominant Hodgkin lymphoma makes up the other 5 percent of Hodgkin cases. This type grows more slowly and is more common in people in their twenties.

Non-Hodgkin Lymphoma

• Diffuse large B-cell lymphoma, the most common type of non-Hodgkin lymphoma, which grows quickly in lymph nodes and often in other organs
• Follicular lymphoma, a slower-growing form that is characterized by enlarged lymph nodes and large cancel cells that may appear U-shaped

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• Mantle cell lymphoma, a rare and aggressive form that often affects the lymph nodes, bone marrow, spleen, and gastrointestinal tract
• Burkitt lymphoma, a highly aggressive form that primarily affects children and young adults
• Peripheral T-cell lymphomas, a diverse group of aggressive lymphomas that arise from mature T-cells in the thymus gland and travels to the lymph nodes, bone marrow, or spleen
• Small lymphocytic lymphoma, a slow-growing cancer that’s closely related to chronic lymphocytic leukemia and primarily involves the lymph nodes and spleen

Lymphoma Staging

• Enlarged lymph nodes in the neck, under the arm, or in the groin
• Persistent fatigue
• Unexplained weight loss
• Drenching night sweats
• Itchy skin
• Fever without an infection

• Abdominal pain and swelling, loss of appetite, or feeling full after a small meal, if the cancer involves organs in the abdominal cavity
• Breathing difficulties, including coughing and chest pain, if lymphoma affects the mediastinum (the area between the lungs)
• Gastrointestinal issues such as nausea, vomiting, abdominal pain, or changes in bowel habits if the lymphoma affects the stomach or intestines
• Neurological symptoms such as headaches, trouble thinking, changes in vision, personality changes, seizures, facial numbness, or trouble speaking if lymphoma affects the central nervous system

• Medical History and Physical Examination Your healthcare provider will thoroughly review your medical history, including symptoms, previous illnesses, possible risk factors, and family history to understand the likelihood of you having lymphoma. They will then perform a physical exam to check for signs of lymphoma, such as swollen lymph nodes, enlarged spleen or liver, and other abnormalities.
• Biopsy To confirm suspected lymphoma, your provider will perform a biopsy by taking a sample of a lymph node or, in some cases, an entire lymph node, for examination. Though unlikely, your provider may perform a less invasive procedure, such as a core needle biopsy or fine-needle aspiration, which involves using a thin needle to extract a small sample of tissue from a suspicious lymph node. Biopsies can often determine the type of lymphoma you have, but additional lab tests on the samples, such as immunochemistry, may be needed.
• Blood Tests After confirming you have cancer, your provider may order certain blood tests to determine how advanced the lymphoma is, evaluate your overall health, and assess the function of various organs, such as the liver and kidneys. Your provider may also order a complete blood count to check for abnormalities in blood cell counts.
• Imaging Tests Along with the blood tests, your provider may also order imaging tests to understand where lymphoma is occurring in your body. These include CT (computerized tomography) and PET (positron emission tomography) scans to visualize enlarged lymph nodes and other organs to see if they contain cancerous cells.

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   MRI scans aren’t used as often for lymphoma, but they can help determine if lymphoma is affecting the spinal cord or brain.

• Bone marrow aspiration and biopsy to see if the lymphoma affects your bone marrow
• Lumbar puncture (spinal tap) to see if lymphoma has spread to your central nervous system
• Pleural or peritoneal fluid sampling to see if lymphoma is in your chest or abdomen and causing a buildup of fluid

Treatment for stage 4 lymphoma often involves a combination of therapies, including chemotherapy, radiation therapy, stem cell transplantation, and more.

Chemotherapy

Chemotherapy is the use of powerful drugs to kill or inhibit the growth of cancer cells throughout the body. These medicines are usually given as an IV infusion or in pill form.

• ABVD, made up of doxorubicin hydrochloride (Adriamycin), bleomycin, vinblastine sulfate, and dacarbazine

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• BEACOPP, made up of bleomycin, etoposide phosphate, doxorubicin hydrochloride (Adriamycin), cyclophosphamide, vincristine sulfate (Oncovin), procarbazine hydrochloride, and prednisone

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• EPOCH, made up of etoposide phosphate, prednisone, vincristine sulfate (Oncovin), cyclophosphamide, and doxorubicin hydrochloride (hydroxydaunomycin)

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Researchers are still learning more about which chemotherapy regimens are most effective for specific types of lymphoma.

• Anemia
• Breathlessness
• Bruising, bleeding gums, or nosebleeds
• Chills
• Constipation
• Diarrhea
• Hair loss
• Fatigue
• Fever
• Increased risk of infection
• Loss of appetite
• Mouth sores
• Nausea
• Risk of blood clots
• Skin problems, such as a rash or blistering, thickening, or itching of the skin.
• Weight gain or loss
• Heart, liver, or lung changes

Radiation Therapy

• Redness, blistering, or peeling of the skin where radiation is given
• Fatigue
• Nausea
• Dizziness

• Lung or heart damage from radiation to the chest
• Thyroid problems from radiation to the neck
• Headache, memory loss, and personality changes from radiation to the brain
• Formation of other cancers

Targeted Therapy

Targeted therapy fights cancer by specifically targeting certain molecules involved in cancer growth. Some types of targeted therapies include the following:

• Monoclonal Antibodies These are immune system proteins made in the laboratory to target and kill cancer cells, block their growth, or keep them from spreading. Sometimes a monoclonal antibody is linked to a chemotherapy drug (called an antibody-drug conjugate), allowing the drug to be delivered directly to the cancer cell.

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• Proteasome Inhibitors These medications block the activity of proteins called proteasomes that remove proteins in cells that are no longer needed. Blocking proteasomes allows proteins to build up in cells, potentially killing cancer cells.
• Kinase Inhibitors These drugs block certain enzymes that control cell growth, helping to keep lymphoma cells from growing.

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• brentuximab vedotin (Adcetris)
• copanlisib (Aliqopa)
• crizotinib (Xalkori)
• ibrutinib (Imbruvica)
• idelalisib (Zydelig)
• mogamulizumab (Poteligeo)
• polatuzumab vedotin (Polivy)
• rituximab (Rituxan)

• Cough
• Diarrhea or constipation
• Flu-like symptoms such as fever and chills
• Fatigue
• Headache
• Heart problems
• Infection
• Kidney problems
• Liver problems
• Loss of appetite and weight loss
• Low blood cell counts
• Nausea and vomiting
• Nerve damage
• Joint pain
• Skin rashes, redness, itching, or dryness
• Allergic reaction to the medication

Immunotherapy

Immunotherapy aims to enhance the body's immune system to recognize and attack cancer cells. Types of immunotherapy used to treat stage 4 lymphoma include:

• CAR T-Cell Therapy This is a type of immunotherapy where your doctor will remove some of your T cells, add special receptors to their surfaces in a laboratory, and then return the modified cells back to your body to bind to and kill cancer cells.

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   Researchers are getting better at determining which lymphoma patients will respond well to CAR T-cell therapy before beginning treatment.

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• Checkpoint Inhibitors PD-1 is a type of checkpoint protein on cell surfaces that helps prevent the body’s immune system from attacking normal, healthy cells. Some cancer cells also have these proteins and can therefore “hide” from the immune system. PD-1 inhibitors such as nivolumab (Opdivo) and pembrolizumab (Keytruda) block this checkpoint protein and allow the body’s immune system to better attack cancer cells.

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• Immunomodulating Drugs Medications such as thalidomide (Thalomid) and lenalidomide (Revlimid) are a type of immunotherapy called immunomodulating drugs. They are given to patients with lymphoma who have not responded to other treatments. It’s not yet clear to researchers exactly how these drugs work, but they are thought to work against cancer by affecting parts of the immune system.

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Stem Cell Transplantation

Surgery

Clinical Trials

The prognosis for stage 4 lymphoma varies based on factors such as lymphoma type, age, overall health, and response to treatment. Advances in medical research and treatment options have significantly improved survival rates in recent years.

• Lymphoma Subtype Patients with indolent or slow-growing subtypes such as follicular lymphoma may live with the disease for many years. Some subtypes such as diffuse large B-cell lymphoma may respond better to treatment.
• Age, Sex, and General Health Patients who are healthy, under 60 years old, and female have a better prognosis.
• Lactate Dehydrogenase (LDH) Levels Higher LDH levels in the blood indicate poorer survival.
• Extent of the Disease Survival is reduced at higher stages with more widespread disease and more organs affected.

• A weakened immune system
• Infertility
• Heart disease
• Lung disease
• Stroke
• Thyroid problems
• A second cancer

The Takeaway

• Stage 4 lymphoma is the most advanced stage of the disease, characterized by its spread to other areas of the body like the lungs or liver.
• Many advanced treatment options are available to manage stage 4 lymphoma and improve survival, although the response to treatment depends on a variety of factors, including the type of lymphoma, age, and overall health.
• It's important for individuals with symptoms that may suggest stage 4 lymphoma — such as unexplained weight loss, persistent fatigue, fever without an infection, or swollen lymph nodes — to seek immediate evaluation from a healthcare professional for accurate diagnosis and prompt treatment.