Follicular lymphoma (FL), a rare blood cancer of the lymphatic system, is one type of non-Hodgkin lymphoma. Follicular lymphoma is considered an indolent — or low-grade — cancer, which means it tends to be nonaggressive and grows slowly. FL is not yet considered curable with standard therapy, but because it is slow growing and usually appears in older people, it is often managed as a relapsing chronic illness.
FL is a cancer of the B cells, a type of white blood cell that produces antibodies and protects against bacteria and viruses as part of the immune system. In B-cell lymphomas such as FL, the bone marrow overproduces B cells that are abnormal and have lost their ability to fight infection.
To learn more about follicular lymphoma, MyLymphomaTeam spoke with Dr. Timothy Fenske. Dr. Fenske is a hematologist and medical oncologist who specializes in lymphoma at Froedtert & Medical College of Wisconsin in Milwaukee.
“One of the biggest challenges for people with follicular lymphoma is understanding this idea that it's a slow-growing process, and we have some flexibility in terms of how we might approach it,” said Dr. Fenske. “In many cases, we are able to effectively manage follicular lymphoma, such that the patient still achieves a normal life span.”
Follicular lymphoma is a rare disease. Approximately 15,000 to 20,000 new cases are diagnosed each year in the United States. Women and men are both affected by FL, with a slightly higher rate of occurrence among women. The mean age of diagnosis is 65. FL accounts for 20 percent to 30 percent of all cases of non-Hodgkin lymphoma. FL occurs throughout the world and affects people of all races, although people of Asian and African descent have a slightly lower rate of the disease.
There are three main variants of follicular lymphoma that are distinct from most cases of FL. These subtypes are rare.
Since follicular lymphoma is a slow-growing indolent cancer, some people with early stage FL may have the disease without any noticeable symptoms. Dr. Fenske explained that the disease may be discovered during routine blood work or tests for other conditions, prior to experiencing symptoms of FL itself. “In many cases the patient may be in their 60s, 70s, or 80s, and we incidentally diagnosed them with follicular lymphoma. They may not really have symptoms, and it's not really affecting them,” he said.
The most common symptom of FL is painless swelling in lymph nodes in the neck, armpits, or groin, due to tumorous clumping from the overproduction of B cells. Less common symptoms include:
Between 40 percent and 70 percent of all people with FL have follicular lymphoma cells in bone marrow. In approximately 50 percent of FL cases, the spleen is affected and causes splenomegaly (enlargement of the spleen). Abnormal blood counts can be an indication of FL in bone marrow or the spleen. Symptoms include:
One of the challenges in diagnosing FL is that swollen lymph nodes can be a symptom of many other diseases. “When people get lymphoma, the symptoms can often mimic other conditions, like inflammatory conditions or autoimmune diseases. It can be tricky sometimes to get that diagnosis sorted out,” said Dr. Fenske.
In fact, dozens of other conditions have symptoms similar to lymphoma. These include common illnesses, like colds, flus, and sinus infections, along with more serious diseases like AIDS, breast cancer, and the fungal infection histoplasmosis.
FL is diagnosed through a lymph node biopsy — a microscopic examination of blood cells. The biopsy may be performed as a needle core biopsy, in which a long hollow needle is used to extract tissue from a lymph node. Alternatively, an entire lymph node may need to be removed for a biopsy, a procedure that can be performed under local anesthesia.
As Dr. Fenske explained, a diagnosis may require considerable analysis. “Once a person does have a biopsy, being able to say with certainty that, ‘Yes, in fact this is lymphoma and this is the exact type.’ can also be tricky,” he said. “Sometimes you need a pathologist who really has a lot of experience diagnosing lymphomas to really pin that down. It’s never a bad idea to get a second opinion on the pathology reading.”
Additional blood tests may be performed to evaluate kidney and liver function. Blood tests can also determine dormant viral infections that may be activated during treatment.
The Ann Arbor staging system can be used to diagnose the progress of the disease:
Most people with FL are not diagnosed until the disease has progressed to advanced stage 3 or stage 4. Less than 20 percent of people with early stage 1 or stage 2 FL are diagnosed, due to a lack of discernible symptoms.
The Follicular Lymphoma International Prognostic Index assesses risk factors that can indicate the prognosis for a case of FL. Scores can help doctors decide how aggressively to treat a case of FL. Five risk factors are scored for one point each, including whether a person:
A score of 0 or 1 indicates a low-risk group. A score of 2 indicates intermediate risk, and a score of 3 or more indicates high risk for more aggressive disease.
In addition to stage, a case of FL will be assessed for the rate at which malignant cells are growing and assigned the grade number 1, 2, 3A, or 3B. This scale is called the histologic grade. Grade 3B is often fast-growing. A pathologist determines the grade when looking at the biopsy.
Since FL is usually slow-growing, many people with FL do well with no treatment for many years. As Dr. Fenske explained, “More indolent or low-grade lymphomas like follicular lymphoma are slow-growing, and actually don't even always require treatment.”
At the same time, a number of effective treatment options are available for people with more advanced symptoms of FL.
Active surveillance — also called watchful waiting or “watch and wait” — is a method of monitoring asymptomatic or low symptomatic FL cases with regular checkups and evaluations. These may include blood tests and computed tomography (CT) scans. Watchful waiting can be used with new cases of FL, as well as cases in remission after treatment. Studies show that people with FL who use active surveillance have the same survival rate as those who undergo treatment before experiencing advanced symptoms.
“People have a really hard time sometimes wrapping their head around that idea,” Dr. Fenske said. “‘OK, you're telling me I have cancer. And then in the next sentence, you're telling me we're not going to do anything about it.’ This can be difficult for patients to accept, especially when they are initially diagnosed and scared. But [FL] can be so slow-moving that, in some cases, five or more years later the person still hasn't required treatment.”
When someone with FL is first diagnosed and has few or no symptoms, Dr. Fenske is keen to determine how the condition is progressing. “Usually I will see them back in about three months. And somewhere between three and six months after the initial diagnosis, I will typically get another CT scan to get a feel for how these lymph nodes are changing,” he explained.
“If they've increased significantly in a matter of a few months, that's somebody that we're probably going to need to treat,” he said. “Other times, they really have not changed at all six months later, 12 months later, two years later. Sometimes they even regress somewhat on their own.”
With longer term watchful waiting cases, Dr. Fenske tends to limit CT scans. ”If someone is in their 40s or 50s, we could be doing a CT scan every six months for 10 or more years, and that ends up being a lot of radiation exposure,” he said. “And we don't have any studies in follicular lymphoma that say routinely scanning people leads to people living longer.”
In localized, early stage FL cases that require treatment, low-dose radiation therapy is considered highly effective and may provide long-term remission. Some studies also indicate that very low-dose radiation therapy can be effective for more advanced stages of FL, while at the same time shortening the course of treatment and reducing side effects.
Radiation therapy for non-Hodgkin lymphomas, such as FL, involves a tightly focused beam of radiation aimed at the affected area from outside the body. Treatments are typically scheduled five days a week over the course of several weeks. Side effects may include:
Chemotherapy and monoclonal antibodies are drug therapies used to treat FL. Regimens often consist of a combination of drugs, such as:
People with non-Hodgkin lymphomas, such as FL, are at risk for distinctive side effects from chemotherapy and monoclonal antibody therapies. These include:
Other side effects that are common with chemotherapy include:
For FL cases that do not respond well to other treatments, stem cell transplantation, known as either autologous transplantation or allogeneic transplantation, may be effective and even curative. An autologous transplant uses a person’s own stem cells, while an allogeneic transplant uses stem cells from a donor. Stem cell transplants were previously referred to as “bone marrow transplants.” Because of the risks associated with stem cell transplantation, the treatment may not be recommended for some people with FL.
CAR-T cell therapy is a promising new treatment for FL and other blood cancers. The treatment uses T cells — a type of white blood cell that is part of the immune system — from the person’s own blood. These cells are then genetically modified in a laboratory to produce chimeric antigen receptors (CAR) that can attack cancer cells.
CAR-T cell therapy has been shown to produce a complete remission rate of 90 percent in some forms of leukemia. It is currently approved by the U.S. Food and Drug Administration (FDA) for transformed follicular lymphoma and other aggressive forms of non-Hodgkin lymphoma, but it is not yet approved for indolent lymphomas such as FL.
“In the last few years we've really gotten a lot into this new, exciting immunotherapy called CAR-T cell therapy,” said Dr. Fenske, who is currently involved in clinical trials using this treatment. “Most resources that you read about follicular lymphoma will say that it is not considered curable. But I would qualify that by saying that it’s not routinely curable with conventional therapy,” he said. “Data for CAR-T cell therapy in follicular lymphoma is just emerging now, so we don't really know what the long-term outcomes are going to look like with that.”
Advances in diagnostic methods and treatment protocols have increased the overall survival rate for people with FL. A recent study of 1,088 people with FL showed an overall survival rate of 92 percent at five years, 80 percent at 10 years, and 65 percent at 15 years. This is a big improvement from the 1960s through the 1980s, when the survival rate was about 50 percent at 10 years. The American Cancer Society estimates an overall survival rate of 88 percent at five years for people with FL.
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