By Tom Iarocci, MD 

 Medically reviewed by Erika Prouty, PharmD

There are many different types of B-cell lymphomas. Two of the most common B-cell lymphomas are diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. Both may cause enlargement of one or more lymph nodes, in addition to other signs and symptoms.

People learn which of the many types of B-cell lymphoma they have during their diagnosis and evaluation. This article will discuss the main types of B-cell lymphoma, how they are diagnosed, and targeted treatments.

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Main Types

The two major categories of lymphoma are Hodgkin and non-Hodgkin lymphoma. B-cells and their lineage are important in both categories of lymphoma. In fact, most non-Hodgkin lymphomas (about 85%) are B-cell lymphomas. Although Hodgkin lymphomas typically involve B cells, too, they are often considered separately, in part for historical reasons.

The main types of B-cell non-Hodgkin lymphoma (NHL) are listed here, along with estimates for the number of new cases annually expected in the United States:

• Diffuse large B-cell lymphoma (DLBCL): More than 18,000 new cases 

• Follicular lymphoma (FL): 15,000 new cases 

• Marginal zone lymphomas (MZL): 6,000 new cases 

• Mantle cell lymphoma (MCL): 4,000-5,000 new cases

• Small lymphocytic lymphoma (SLL)/Chronic lymphocytic leukemia (CLL): About 2,100 cases annually present with the non-leukemic picture (SLL)

Today, SLL and CLL are often considered two forms of the same malignancy. SLL connotes disease with predominance in the lymph nodes (lymphoma) while CLL refers to the predominance of the malignant white blood cells in the circulation (leukemia). SLL is much less common than CLL.

Rare Types

• Burkitt lymphoma

• Waldenstrom macroglobulinemia (Lymphoplasmacytic lymphoma)

• Primary central nervous system lymphoma

• Primary intraocular lymphoma 

• Cutaneous lymphoma, B-cell type

• A handful of rare B-cell lymphomas that were previously included as subtypes of DLBCL but are now listed separately in the World Health Organization classification system

• Hairy cell leukemia is considered a rare, B-cell lymphoma, despite the name

What Does the Type Tell You?

Despite their shared cell lineage, B-cell lymphomas can differ strikingly in their aggressiveness, clinical course, response to treatment, and prognosis. Some B-cell lymphomas can be cured, while others as yet have no cure.

Sometimes the subsets or subcategories of B-cell lymphoma can be more telling than the main classification. For example, “the indolent subset of MCL” may not produce symptoms for years and may not require immediate treatment; whereas aggressive forms of MCL require intensive treatment so that a person can survive beyond a few years, to hopefully live long enough to see the next treatment breakthrough.

Another example of the same B-cell lymphoma type behaving differently by individual occurs with DLBCL. Some people with DLBCL have an excellent response to intensive therapy, such that they are cured. Unfortunately, this is not the case for everyone.

For the person with lymphoma, the type of B-cell lymphoma is important, but the staging and prognostic scoring (looking at the cellular and clinical risk factors) are also key in helping you and your healthcare provider to plan for the future and evaluate your best options for treatment.

NHL is typically divided by types into indolent or aggressive malignancies; this applies specifically to many B-cell lymphomas, as well. Indolent lymphomas typically grow more slowly, while aggressive lymphomas tend to grow more quickly.

Indolent B-Cell Lymphomas

To generalize, indolent B-cell lymphomas tend to have a relatively good prognosis, with long survival times, but they are not curable in advanced stages. With indolent lymphomas, there is also a possibility that what begins as an indolent disease will later transform to become a more aggressive disease. This might happen relatively soon after diagnosis, decades after diagnosis, or, in the case of many people with indolent B-cell lymphomas, not at all.

Two examples of indolent B-cell lymphomas are follicular lymphoma and small lymphocytic lymphoma.

Follicular Lymphoma

Follicular lymphoma, an indolent lymphoma, often grows slowly and responds well to treatment, but it is very hard to cure and it usually comes back after treatment.

Many people with follicular lymphoma can live long lives. Certain cases of follicular lymphoma that are not causing problems other than mildly swollen lymph nodes may not even need treatment. Some people with follicular lymphoma will never need treatment at all and for those who do, it might be years before treatment is needed.

Unfortunately, in a subset of people with follicular lymphoma, the disease has a worse prognosis. About 20% of patients with stage II, III, and IV follicular lymphoma will relapse within two years of front-line therapy, and the prognosis is not as good in these cases.

Small Lymphocytic Lymphoma (The Lymphoma Version of CLL)

Small lymphocytic lymphoma is another indolent B-cell lymphoma. It is very similar to chronic lymphocytic leukemia (CLL), except that the disease tends to be located in the lymph nodes.

Often, more than one group of lymph nodes is affected in SLL. The cancer cells may also be present in other areas such as the blood or bone marrow, but to a lesser extent than in CLL.

As is characteristic of indolent lymphoma, many patients with SLL live with their malignancy for years, ultimately passing away for reasons that are completely unrelated to the malignancy.

Aggressive B-Cell Lymphomas

Although the term “aggressive” sounds like it would always be bad, some aggressive B-cell lymphomas respond very well to treatment and can even be cured with intensive chemoimmunotherapy—that is, treatment with chemotherapy plus antibody therapy. Other aggressive lymphomas are more difficult to control; the goal becomes to achieve remission for a span of years, perhaps 5-10 years, maintain quality of life, and hope that treatment breakthroughs occur by the time relapse occurs.

Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL), the most common high-grade (aggressive) form of NHL, tends to grow quickly. Although it can occur in childhood, rates of DLBCL increase with age, and most patients are over the age of 60 at diagnosis.

It usually starts deep inside the body in lymph nodes, although DLBCL can develop in areas outside the lymph nodes, such as the gastrointestinal tract, testes, thyroid, skin, breast, bone, or brain. At the time it’s diagnosed, DLBCL may be present in just one spot or multiple spots throughout the body.

Despite being an aggressive lymphoma, DLBCL is considered potentially curable. The treatment of choice is usually chemoimmunotherapy. Often, chemotherapy is given in a regimen of four drugs known as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), plus the monoclonal antibody rituximab.

Known as R-CHOP, this regimen is typically given in cycles three weeks apart, with varying schedules. The particular treatment, its intensity, and its duration depends on the stage of the disease, the risk of the malignancy, and individual patient characteristics.

DLBCL can be cured in about half of all patients, but the stage of the disease and the prognostic score (IPI score, which estimates disease risk) can have a large effect on this. Patients with lower stages and lower IPI scores tend to have better survival rates. Overall, about three out of four people will have no signs of disease after the initial treatment, and many are cured.

Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is another lymphoma that is typically aggressive. It affects more men than women and tends to be diagnosed in individuals older than 60 years.

There is a subset of MCL that behaves more like an indolent lymphoma, where a watch and wait strategy may be appropriate at first. Quite the opposite is true of the blastoid variant of MCL, a very aggressive form of the disease.

People with the blastoid variant of MCL who are younger and otherwise healthy are usually treated aggressively, typically with rituximab plus fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (also known as the R-Hyper-CVAD regimen) followed by autologous stem cell transplant, or ASCT.

CNS prophylaxis, or administering anti-cancer agents that can penetrate the central nervous system, might be considered in someone with a blastoid variant of MCL, as well. ASCT or even allogeneic stem cell transplant may be considered following the initial round of therapy to induce remission.

How Type Is Determined

A variety of tools help determine the lymphoma type. These include the microscopic appearance of the malignant cells, which are often taken from a lymph node biopsy, as well as tools that detect the presence or absence of surface markers on the involved lymphocytes. Genetic testing of the cancerous cells is also often used to fine-tune the evaluation, especially when certain the presence of mutations may be important to diagnosis and treatment.

A technique known as immunohistochemistry helps differentiate between the types of B-cell lymphoma by detecting protein markers, or CD markers, on the surface of the malignant cells. Not all malignancies of a particular lymphoma type will always make the same markers, but analysis of these markers can help narrow the field, diagnostically.

CD5 and CD10 serve to help sort out B-cell lymphoma types:

• Classic examples of CD5+/CD10- B-cell lymphomas (they have the CD5 marker but lack the CD10 marker) are small lymphocytic lymphoma and mantle cell lymphoma.

• Classic examples of CD5+/CD10+ B-cell lymphomas expressing are follicular lymphoma and Burkitt lymphoma. Hairy cell leukemia and mantle cell lymphoma can occasionally be positive for CD10. Some forms of DLBCL can also be CD10-positive. Positive CD10 expression in more than 30 percent of cancer cells classifies a patient with DLBCL as having a particular subtype (GC, or germinal center type), which has a better overall survival rate than that the non-GC phenotype.

• Classic examples of CD5-/CD10-, mature B-cell lymphomas of small cell size include marginal zone lymphomas (with MALT lymphoma the most common form), Waldenstrom macroglobulinemia, and hairy cell leukemia. Most DLBCLs in the "not otherwise specified" category are also negative for both CD5 and CD10.

Targeting Different Types of B-Cell Lymphoma

Despite many important differences in the B-cell lymphomas, there are also several important similarities. These cancers tend to mimic the stages of normal B-cells as they develop and mature. The extent to which they mimic these stages is a big part of the lymphoma naming and classification system.

Additionally, treatments for people with B-cell lymphoma make use of some of the shared targets that originate with the healthy B lymphocyte and its “family tree.” These targets include surface markers (e.g., the CD20 antigen) and also cell signaling mechanisms (e.g., B-cell receptor signaling and BCL-2 signaling).

The CD20 Marker and Rituximab

Healthy B-lymphocytes have an antigen, or marker, on the surface called CD20, and so do many of the B-cell lymphomas. Antibodies that are specific to this surface antigen can be administered to patients with B-cell lymphomas either as part of their treatment, along with chemotherapy, or, in some cases, as the only treatment (anti-CD20 monotherapy). The antibodies bind to the CD20 of the malignant (and normal) B cells and lead to the depletion of B cells, thus helping to destroy the tumor.

Rituximab and obinutuzumab are both anti-CD20 monoclonal antibodies (laboratory-engineered, identical clones of antibodies that are manufactured to target the CD20 antigen). Rituximab was the first CD20 antibody to become widely used. Since its approval for relapsed/refractory NHL in 1997, rituximab has been adopted in the treatment of many B-cell malignancies, as well as autoimmune conditions, including rheumatoid arthritis.

Rituximab has a role in the treatment of indolent B-cell lymphomas such as follicular lymphoma and marginal zone lymphoma; and also, in aggressive B-cell lymphomas like DLBCL and MCL. Risks with anti-CD20 monoclonal antibodies include those associated with kidney problems due to tumor destruction, known as tumor lysis syndrome.

In December 2022, the FDA approved Lunsumio (mosunetuzumab) for the treatment of adults with relapsed or refractory FL who have received at least two prior systemic therapies. Lunsumio targets the CD20 cells of FL and the CD3 cells of cytotoxic T cells, offering a viable solution for individuals with multiple relapses.1

B-Cell Receptor (BCR) Signaling and Ibrutinib

What B cells do in their normal, day-to-day, lives is intimately connected with the function of their B-cell receptor (BCR). This receptor is sort of like an immune system “taster” of antigens.

The receptor has both the tasting component and a signaling component. When the right antigen binds to the tasting component of the receptor, it sets off a series of chain reactions, ultimately leading to B-cell signaling. If the antigen is from an infectious foreign invader, that B-cell signaling is a good thing, causing the B-cell to ramp up activities that may be helpful in fighting infection.

However, B-cell lymphomas often hijack this normal BCR signaling pathway to take advantage of this pre-existing mechanism for B-cell reproduction and survival. Thus, newer treatment strategies have emerged in recent years to target and block this signaling.

The Bruton tyrosine kinase (BTK) inhibitors ibrutinib and acalabrutinib work by blocking the Bruton tyrosine kinase enzyme. BTK is an enzyme that transmits signals from a variety of cell-surface molecules, including the B-cell receptor, but also receptors that act like homing devices, telling the B-cell where to travel.

Ibrutinib has revolutionized the treatment of B-cell malignancies such as CLL/SLL and Waldenstrom Macroglobulinemia. Ibrutinib is also used in certain settings for patients with previously treated B-cell lymphoma (ie, MCL and MZL).

Acalabrutinib also blocks BTK and has been approved for previously treated MCL, as well as CLL/SLL. While BTK inhibition has been a major advance and is generally well-tolerated, there is a risk profile that is taken into consideration, and other options might be considered for people who have concurrent heart problems, arrhythmias, or who are at risk of major bleeding events.

BCL-2 Signaling and Venetoclax

In addition to BCR signaling, B-cell lymphomas have long been known to hijack BCL-2 signaling. B-cell leukemia/lymphoma-2 (BCL-2) protein family members are key regulators of the programmed cell death (apoptosis) pathway. Overexpression of BCL-2 has been demonstrated in CLL, where BCL-2 signaling helps tumor cell survival and has been associated with resistance to chemotherapy.

In follicular lymphoma, an estimated 90 percent of patients have a genetic change in tumor cells that is thought to cause overexpression of BCL-2 protein. More than 40 percent of diffuse large B-cell lymphoma patients were categorized as having relatively high BCL-2 expression.

Venetoclax is a treatment that blocks BCL-2 and has been approved for CLL, with many trials investigating additional potential uses in the treatment of other B-cell malignancies. Venetoclax helps restore the process of programmed cell death by binding directly to the BCL-2 protein. Laboratory data has shown that venetoclax has cell-killing activity against cells used to study follicular lymphoma, MCL, and DLBCL, however, its use in these malignancies is considered investigational at this time.

Like other targeted therapies, venetoclax may not be the right option for all patients with the applicable malignancies. For those with kidney problems, for instance, healthcare providers might need to balance the risk of a worsening of those problems with venetoclax, owing to a condition known as tumor lysis syndrome.

 Source

Food and Drug Administration. FDA grants accelerated approval to mosunetuzumab-axgb for relapsed or refractory follicular lymphoma.

Additional Reading

de Vos S, Swinnen LJ, Wang D, et al. Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase Ib dose-finding study. Ann Oncol. 2018;29(9):1932–1938. doi:10.1093/annonc/mdy256

Wang HY, Zu Y. Diagnostic Algorithm of common mature B-cell lymphomas by immunohistochemistry. Arch Pathol Lab Med.2017;141(9):1236-1246. doi:10.5858/arpa.2016-0521-RA

By Tom Iarocci, MD
Tom Iarocci, MD, is a medical writer with clinical and research experience in hematology and oncology.