Non-Hodgkin Lymphoma

What is Non-Hodgkin Lymphoma?

Non-Hodgkin lymphoma (NHL) is a type of cancer that starts in the lymphoid tissues, which are a part of our immune system. It can start from different types of cells like immature or mature B cells, or T cells.

Non-Hodgkin lymphoma comes in different types, each with its own set of characteristics, causes, appearance under a microscope, genetic make-up, clinical symptoms, and reaction to treatments. It can also be categorized into two groups — ‘indolent’ and ‘aggressive,’ depending upon the outlook of the disease.

The most common types of NHL that start from mature B cells are Follicular lymphoma, Burkitt lymphoma, and Diffuse large B cell lymphoma, among others. The ones that start from mature T cells include Adult T cell lymphoma and Mycosis fungoides.

How NHL is treated varies a lot. It can depend on the stage and grade of the tumor, the specific type of lymphoma, and the patient’s individual factors like symptoms, age, and overall health.

Different types of NHL behave differently. Indolent lymphomas can quietly grow over several years, whereas aggressive lymphomas can cause serious symptoms like weight loss, night sweats, fever, and even lead to death within a few weeks if left untreated.

Most people with NHL experience swelling in lymph nodes, which can be anywhere on the body. Other symptoms can include skin rashes, allergic reactions to insect bites, extreme tiredness, itchy skin, fever of unknown origin, build-up of fluid in the abdomen, and many more. About half of the patients will have the disease spread outside of the lymph nodes (secondary extranodal disease) over time, and around 10 to 35 percent already have NHL outside of the lymph nodes (primary extranodal lymphoma) when they are diagnosed. Specific symptoms can depend upon where the cancer is located. For instance, lymphoma in the digestive tract can cause feelings of nausea, vomiting, loss of appetite, weight loss, feelings of fullness in the stomach and others. If the disease is in the brain, it can cause headaches, fatigue, paralysis, seizures, and other neurological symptoms.

What Causes Non-Hodgkin Lymphoma?

Non-Hodgkin lymphomas, also referred to as NHL, could be linked to various factors such as infections, environmental elements, weakened immune systems, and ongoing inflammation.

Some infectious agents have been connected to different types of NHL:

• The Epstein-Barr virus, a type of DNA virus, is linked with certain types of NHL, including a specific variation of Burkitt lymphoma.
• Human T-cell leukemia virus type 1 (HTLV-1) leads to a form of lymphoma, known as adult T-cell lymphoma. This virus results in chronic antigen stimulation and cytokine dysregulation, causing uncontrolled stimulation and growth of B- or T-cells.
• Hepatitis C virus (HCV) contributes to the growth of certain B-cells. Specific types of NHL, like splenic marginal zone lymphoma and diffuse large B cell lymphoma, can be linked to this virus.
• Human herpesvirus 8 has been associated with primary effusion lymphoma (PEL), which is a rare and aggressive type of B-cell non-Hodgkin lymphoma often associated with Kaposi sarcoma, a type of skin cancer.

Infections from a bacterium called Helicobacter pylori increases the risk of developing a primary gastrointestinal lymphoma known as gastric mucosa-associated lymphoid tissue (MALT) lymphomas.

Furthermore, exposure to certain drugs such as phenytoin, digoxin, and TNF antagonist; organic chemicals; pesticides; phenoxy-herbicides; wood preservatives; dust; hair dye; solvents; and radiation from chemotherapy have been associated with the development of NHL.

Certain immune deficiency disorders, like Wiskott-Aldrich syndrome, severe combined immunodeficiency disease (SCID), and induced immune deficiency states – such as those caused by immunosuppressant medications – have been linked with an increased risk of developing NHL. People who have AIDS can develop primary CNS lymphoma, a type of brain lymphoma.

Additionally, autoimmune disorders, which are conditions in which the body’s immune system attacks its own cells, such as Sjögren syndrome, rheumatoid arthritis, and Hashimoto thyroiditis, are associated with a higher risk of NHL. People with Hashimoto’s thyroiditis, a condition which can cause underactive thyroid, are at risk of developing primary thyroid lymphomas. Celiac disease, an autoimmune disorder triggered by consuming gluten, has also been linked with an increased risk of non-Hodgkin lymphoma.

Risk Factors and Frequency for Non-Hodgkin Lymphoma

Different types of lymphomas are more common in certain parts of the world. For example, follicular lymphoma often occurs in Western countries, while T cell lymphoma is more common in Asia.

• Non-Hodgkin lymphoma often affects people between the ages of 65 and 74, with the average age of diagnosis being 67.
• Epstein-Barr virus-related Burkitt lymphoma tends to be found in Africa and New Guinea, and affects children between the ages of four and seven more than others. There are about 50 times more cases in Africa than in the U.S., and it affects more boys than girls. There is also a different variant of Burkitt lymphoma that is seen more in the U.S. and Western Europe. This version is more common among white people, and it predominantly affects males.
• Mantle Cell Lymphoma, which accounts for about 7% of adult non-Hodgkin lymphomas in the U.S. and Europe, affects mostly men and white people. About 4 to 8 cases are diagnosed per million people each year, and the average age of diagnosis is 68.
• Non-Hodgkin lymphoma ranks as the fifth most common cancer in children under the age of 15, and it represents about 7% of childhood cancers in developed countries. Each year, about 800 cases are diagnosed in U.S. children. The types of lymphoma that often affect children and young adults are high-grade lymphomas like lymphoblastic and small noncleaved lymphomas.
• Lymphomas rarely occur in infants. They represent about 4% of tumors in children aged 1 to 4, 14% in children aged 5 to 9, 22% in children aged 10 to 14, and 25% in teens aged 15 to 19. They are more often seen in boys and in white children compared to African American children.

Signs and Symptoms of Non-Hodgkin Lymphoma

Non-Hodgkin lymphoma patients often report symptoms like fever, weight loss, or night sweats. Painless swelling in the lymph nodes is common among more than two-thirds of patients, and they might often experience it come and go. Symptoms can vary depending on the affected area and the type of lymphoma.

Some specific types of non-Hodgkin lymphomas are:

• Burkitt Lymphoma: Patients typically show rapidly growing tumors and may have a drastic increase in cellular waste products in the blood, a condition known as tumor lysis syndrome. In African populations, it can often present as tumors in facial bones. However, these types of tumors are less common in the abdomen. The tumors can spread to other parts of the body, like the connective tissues in the abdomen, ovaries, testicles, kidneys, breasts, and brain linings. The non-African variant often affects the abdomen and may present with bloating, a large amount of fluid in the abdomen, and symptoms associated with intestinal obstruction or bleeding.
• Mantle cell Lymphoma: Most patients are diagnosed at advanced stages, and roughly three-fourths initially present with lymphadenopathy, swelling in the lymph nodes. The disease may also primarily present in the spleen, bone marrow, Waldeyer’s ring, blood, and other organs. Other symptoms include fever, night sweats, and unintentional weight loss.
• Gastrointestinal Lymphoma: This type commonly presents with nonspecific symptoms like stomach pain or discomfort, loss of appetite, weight loss, nausea, vomiting, hidden gastrointestinal bleeding, and an early feeling of fullness after eating.
• Primary Central Nervous System (CNS) Lymphoma: These patients may show symptoms such as headaches, tiredness, specific neurological deficits, seizures, paralysis, spinal cord compression, or brain inflammation resulting from lymphoma.

Important areas to examine in patients suspected of lymphoma include the tonsils, base of the tongue, nasopharynx, lymph nodes in various locations, liver, and spleen. A proper examination of the head and neck, checking for any enlargement of preauricular nodes or tonsillar asymmetry, is crucial as it might indicate the involvement of the head and neck. The eyelid, eye muscles, tear ducts, and the conjunctiva should also be checked, as they can be involved in certain types of lymphomas. Symptoms such as a persistent cough or chest discomfort, might hint towards mediastinal involvement in lymphoma; however, sometimes, there might be no symptoms, only an abnormal chest x-ray. Accumulation of fluids in the abdomen due to lymphatic obstruction may be present.

Extranodal disease might occur in about 50% of patients, while 10-35% of patients will have primary extranodal lymphoma at the time of diagnosis. The most common site is the gastrointestinal tract, followed by the skin. Other sites involved might include the testis, bone, and kidney. Rare sites of occurrence include the ovary, bladder, heart, adrenal glands, salivary glands, prostate, and thyroid. Symptoms associated with extranodal disease are usually seen in aggressive NHL and are not common in slow-growing lymphomas.

Testicular NHL, most common in males over 60, generally manifests as a discreet mass and comprises 1% of all NHL and 2% of all extranodal lymphomas. Finally, it’s important to note that pressure on the spinal cord due to lymphoma can cause permanent loss of motor, sensory, and/or automatic functions. It’s thought that NHL first involves the paraspinal soft tissues and then makes its way to the cord via the vertebral foramen without first causing bone destruction.

Testing for Non-Hodgkin Lymphoma

Here’s a basic idea of how medical professionals investigate the possibility of Non-Hodgkin Lymphoma, a type of blood cancer. The main steps in this assessment include a number of tests:

Firstly, you’ll have a complete blood count test. This allows the doctor to see whether the levels of different types of cells in your blood are normal. Changes in this could indicate issues like bone marrow infiltration (cancer cells spreading to the bone marrow), hypersplenism (enlarged spleen), or blood loss, which can often occur if the cancer affects the gastrointestinal tract.

Next, there are serum chemistry tests. These tests can be used to rule out conditions that might be caused by certain types of lymphomas that grow rapidly, like Burkitt or lymphoblastic lymphoma. Another thing these tests might detect is high lactate dehydrogenase levels, which can be a sign of either a large number of cancer cells or cancer cells affecting the liver.

Imaging tests, usually CT or PET scans, help to provide a visual representation of what’s happening inside the body. These scans can show the neck, chest, abdomen, and pelvis – the main areas the disease could affect. Sometimes, more specific scans, like an MRI of the brain and spinal cord or testicular ultrasound, might be needed.

If your doctor finds a lymph node that is growing, lasting for more than 4-6 weeks, or increasing in size, they may decide to take a tissue sample from it. This is usually done through surgical removal, allowing the sample to be studied closely for signs of disease. However, if the lymph node is small, a fine needle aspiration might be done instead.

In cases with a high risk of cancer spread to the central nervous system, doctors may also carry out a lumbar puncture. This collects fluid from around the spinal cord to test for cancer cells.

An immunophenotypic analysis could be used to observe the specific characteristics displayed by the cancer cells present in the lymph node, peripheral blood, and bone marrow.

Lastly, a bone marrow aspiration and biopsy may be conducted to determine the extent of spread of lymphoma. But with the availability of PET scans these days, this isn’t as commonly needed.

Treatment Options for Non-Hodgkin Lymphoma

The way Non-Hodgkin lymphoma is treated depends on its type, stage, specific features, and the patient’s symptoms. The most common treatments are chemotherapy, radiotherapy, immunotherapy, stem cell transplant, and occasionally, surgery. Often, a drug called rituximab is combined with chemotherapy in a treatment method known as chemoimmunotherapy. Radiation is most commonly used in the early stages (I, II) of the lymphoma, while later stages can be treated with a mix of chemotherapy, immunotherapy, targeted therapy, and sometimes, radiation therapy.

Let’s look at the treatments according to the type of lymphoma:

B Cell Lymphoma

In Diffuse Large B cell lymphoma (DLBCL), a drug regimen called R-CHOP, which is often given for three to six cycles, is commonly used, sometimes combined with radiation treatment. Doctors also check the treatment response after two to four cycles using imaging scans. In some cases, other drugs are given to patients who have a high risk of the lymphoma involving the central nervous system. Immunotherapy, known as CAR-T therapy, is used particularly for lymphomas that don’t respond well to other treatments. CAR-T therapy uses the patient’s own genetically modified immune cells to target the cancer.

Follicular lymphoma usually responds well to treatment, though it’s difficult to cure and recurrence is common. Depending on the stage of the lymphoma, it can be treated with radiotherapy, chemotherapy, or a drug regimen that includes a monoclonal antibody. However, even after a good response to initial treatments, long-term maintenance therapy can be complicated.

In Mantle cell lymphoma (MCL), aggressive chemotherapy plus a drug named rituximab is commonly used. If patients respond well to initial chemotherapy, high-dose therapy followed by autologous stem cell transplantation is considered. This is typically followed by a maintenance plan involving rituximab for three years.

Burkitt lymphoma, which is a very fast-growing lymphoma, is normally treated with certain chemo regimens. Prophylaxis (treatment to prevent a disease) and monitoring are needed because of the likelihood of a common complication called tumor lysis syndrome.

Primary CNS lymphoma is often treated with a high-dose of a chemotherapy drug called methotrexate. If a patient responds well to this initial chemotherapy, high-dose therapy followed by autologous stem cell transplantation is usually considered.

T Cell Lymphoma

Anaplastic large cell lymphoma, which is a rapidly growing lymphoma that mainly affects the lymph nodes, can be treated using Brentuximab vedotin with CHP, CHOP, or CHOEP drug regimens.

Adult T-cell leukemia/lymphoma has four subtypes and is linked to infection with the HTLV-1 virus. Treatment depends on the subtype and may involve antiviral treatment, chemotherapy, or a stem cell transplantation, among others.

Enteropathy-associated T-cell lymphoma is highly associated with celiac disease. Combination chemotherapy is preferred. If lymphoma responds to chemotherapy, stem cell transplantation may be considered.

Other

People with HIV often have more aggressive forms of lymphoma, like diffuse large B-cell lymphoma, primary CNS lymphoma, or Burkitt lymphoma. Treatment typically involves the use of antiretroviral therapy for HIV in addition to immunotherapy and chemotherapy.

There are some specific types of lymphomas which can be treated differently. For example, Mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach can regress permanently with antibiotics and Histaminic (H2) blockers if the lymphoma is confined to the stomach, and peri-gastric lymph nodes, and there is a presence of a Helicobacter pylori infection. Mycosis fungoides, a type of T-cell lymphoma of the skin, is best treated with skin-directed treatments.

What else can Non-Hodgkin Lymphoma be?

There are several medical conditions that might seem like Non-Hodgkin lymphoma due to similar symptoms. These conditions include:

• Hodgkin lymphoma
• Epstein Barr virus infection
• Systemic lupus erythematosus
• Intussusception
• Appendicitis
• Toxoplasmosis
• Spread of the primary tumor to other parts of the body (metastasis), with common sources being nasopharyngeal carcinoma and soft tissue sarcoma
• Other types of cancer or diseases that produce excessive amounts of cells that make up the lymphatic system, like granulocytic sarcoma and multicentric Castleman disease
• Infections from mycobacteria and other bacteria can cause swelling of lymph nodes (benign lymph node infiltration) and increase in the size and number of lymph nodes (reactive follicular hyperplasia)

These diseases may lead to swelling of lymph nodes that are either localized (in one place) or generalized (spread throughout the body). Thus, they need to be differentiated from Non-Hodgkin lymphoma. If the diagnosis is unclear, it might be best to get a second opinion from an expert in the pathology of blood diseases (hematopathologists). Flow cytometry and cytogenetics are tests that can be done to help distinguish between these various conditions.

What to expect with Non-Hodgkin Lymphoma

The outlook of non-Hodgkin lymphoma, a type of cancer that starts in the cells of the immune system, largely depends on the characteristics of the cancer cells, how much the disease has spread, and on the patient’s overall health. A tool called the International Prognostic Index (IPI) is commonly used to help predict a patient’s chance of recovery after the standard treatment.

The IPI calculates a score based on five factors: age above 60 years, high levels of a protein called LDH in the blood (which can be an indication that cancer cells are dividing rapidly), a low performance status score (which means the patient is less able to carry out normal activities), advanced stage of disease (stage III or IV), and more than one part of the body outside of the lymph nodes being affected by the disease. Each factor counts as one point and the total score (ranging from 0 to 5) helps determine how high the risk is. Those who have two or fewer risk factors are considered low risk, those with two are intermediate risk, and those with three or more are considered high risk.

Patients born with, or who have developed, a state of weakened immunity are at higher risk of developing lymphoma and generally have a less successful response to treatment. The IPI tool has been adjusted for many types of non-Hodgkin lymphoma to more accurately predict prognosis, for example, the FLIPI for follicular lymphoma and the MIPI for mantle cell lymphoma.

It should be noted that patients with a subtype of non-Hodgkin lymphoma involving aggressive T- or NK cells (which are part of the immune system) usually have a poorer outlook. Patients with slow-growing lymphomas typically have a longer lifespan, usually 6 to 10 years. However, there’s a chance that these low-grade lymphomas could transform into fast-growing, or high-grade, lymphomas.

Possible Complications When Diagnosed with Non-Hodgkin Lymphoma

When diagnosing and evaluating Non-Hodgkin’s Lymphoma (NHL), it’s important to keep in mind that life-threatening emergencies can emerge. It’s crucial that these are recognized early and treatment starts promptly, as they could interfere with and delay the management of the NHL. Some of the possible emergencies include:

• Fever and reduced white blood cell count (Febrile neutropenia)
• Increased levels of uric acid and breakdown of cancer cells (Tumor lysis syndrome) – Symptoms may include fatigue, vomiting, less frequent urination, numbness, legs tingling, and joint pain. The laboratory tests might show increased levels of uric acid, potassium, creatinine, phosphate and lower levels of calcium. These can be prevented with proper hydration and use of allopurinol, a medicine.
• Compression of spinal cord or brain
• Compression at various locations depending on NHL type – this can lead to airway obstruction (in case of mediastinal lymphoma), intestinal obstruction, or kidney tube obstruction
• Obstruction of the superior or inferior vena cava (major blood veins in the body)
• A very high white blood cell count (Hyperleukocytosis)

The Adult T-cell leukemia-lymphoma variety of NHL can cause increased calcium levels in blood (hypercalcemia), and a condition called Lymphoplasmacytic lymphoma with Waldenstrom macroglobulinemia can cause the blood to become too thick (hyperviscosity syndrome). Other possible emergency situations include fluid collecting pressure around the heart (Pericardial tamponade), malfunctioning of liver (Hepatic dysfunction), blood clot in the vein (Venous thromboembolic disease), and certain autoimmune conditions where the body attacks its own blood cells, seen with small lymphocytic lymphoma.

Preventing Non-Hodgkin Lymphoma

Patients should be given plenty of detailed information regarding potential treatment routes, as well as the possible side effects of chemotherapy treatments. They should also be made aware of any situations related to their cancer that could require an urgent trip to the hospital’s emergency department. If the patient experiences feelings of anxiety and depression, it might be helpful to consider counselling services that can offer emotional support during this challenging time.

Healthy lifestyle changes, such as stopping smoking, maintaining a nutritious diet, regular exercise, and ensuring alcohol consumption is kept to a moderate level, can be beneficial for those recovering from cancer. Studies have shown that these habits can enhance overall quality of life, reduce the chance of cancer coming back, and may even improve overall survival rates. So, it is very much encouraged for patients to embrace these healthier lifestyle practices.

As part of their care, patients who have been cancer-free for a long period should be educated about secondary cancers and potential heart issues that they could potentially face. This knowledge equips them with the necessary know-how to safeguard their health in the long run.