Follicular Lymphoma (FL)
Follicular lymphoma (FL) is one of the most common indolent non-Hodgkin lymphomas in Western Europe and the USA. The median age of onset at first diagnosis is between 60 and 65 years, with women being affected slightly more often than men. Follicular lymphoma arises from follicular center B cells (centroblasts), or from malignant transformation of mature B cells and aberrant proliferation of germinal center-like B cells in lymphoid organs. It has as a genetic characteristic the t(14;18)(q32;q21) translocation between the locus IGH and the gene BCL2 (Swerdlow et al. 2017), resulting in constitutive expression of the anti-apoptotic gene BCL2 at all stages of B cell development. Follicular lymphomas are often initially asymptomatic, which is why they are often diagnosed at an advanced stage. Follicular lymphomas are mainly nodal diseases, but can also affect the spleen or the Waldeyer's pharyngeal ring (Nadel 2014).
According to the WHO classification 2017, follicular lymphoma is a mature B-cell neoplasm. Currently, four variant forms of follicular lymphoma are distinguished in addition to the classic follicular lymphoma (see Table 1).
Table 1: Follicular lymphoma WHO classification 2017
Diffuse follicular lymphoma variant
In situ follicular neoplasia
Partial or total colonization of germinal centres by clonal B cells carrying the BCL2 translocation characteristic of FL; low risk of progression
Primary intestinal follicular lymphoma
IGH/BCL2/t(14;18) positive, in the mucosa/submucosa, low risk of progression
Testicular follicular lymphoma
No BCL2 translocation
Diffuse variant of follicular lymphoma
No IGH-BCL2/t(14;18) translocation, similarities to expression profil of FL
WHO classifies follicular lymphomas histologically based on their centroblast content into grades 1, 2, 3A, and 3B, with grades 1-3A belonging to indolent lymphomas and grade 3B being classified as aggressive lymphomas. Only about 15-20% of patients have grade 1-2 follicular lymphoma at the time of diagnosis. Grade 3B follicular lymphomas are biologically more similar to diffuse large B-cell lymphomas (DLBCL) than other follicular lymphomas. They rarely carry BCL2 translocations and have a high centroblast content (Nadel 2014, Swerdlow et al. 2017). The spread of lymphoma is assessed using the Ann Arbor classification (see Table 2).
Table 2: Staging of follicular lymphoma according to the Ann Arbor classification
|Single lymph node region (I) or one extralymphatic site (IE)|
Tow or more lymph node regions, on the same side of the diaphragm (II) or local extralymphatic extension plus one or more lymph node regions on the same side of the diaphragm (IIE)
Lymph node regions on both sides of the diaphragm (III), which may be accompanied by local extralymphatic extension (IIIE)
diffuse involvement of one or more extralymphatic organs or sites
In addition - A: – without systemic symptoms” and B: – with systemic symptoms:
Another subtype of follicular lymphoma is cutaneous follicular lymphoma, which is the most common extranodal follicular lymphoma. It usually presents on the head or trunk, where it can be treated as a local disease. Extranodal Follicular Lymphoma can furthermore affect organs such as the thyroid or ovaries in addition to the skin, duodenum and testes. If these lymphomas arise primarily in the aforementioned extranodal organs and do not have BCL2 rearrangement but have a high histologic grade, they form a distinct subgroup of extranodal follicular lymphomas. In contrast, most low-stage extranodal non-intestinal follicular lymphomas likely reflect disseminated nodal disease (Chott 2014, Swerdlow et al. 2017).
The IGH-BCL2 rearrangement could also be detected by nested-PCR or RT-PCR in peripheral blood or reactive lymph nodes in more than 50% of healthy individuals, with an increased prevalence up to the age of 50 years (Schüler et al. 2009, Nadel 2014). Therefore, this genetic alteration does not appear to be solely responsible for the development of follicular lymphoma (Summers et al. 2001, Roulland et al. 2003, Schmitt et al. 2006, Nadel 2014). The frequency also appears to be age-dependent; at all ages, it was a median of 5.8 x 10-6 cells in a study of 715 healthy subjects and increased to 13.2 x 10-6 in the 60-69 age range (Schüler et al. 2009). A longitudinal study suggests that the increased frequency in this is most likely due to the expansion of one or more persistent t(14;18)-positive clones rather than the occurrence of additional t(14;18) translocations (Roulland et al. JEM 2006, Nadel 2014).
The risk of developing follicular lymphoma is increased 23-fold if one in 10,000 cells is t(14;18)-positive. The number of cells with this abnormality may increase due to contact with pesticides and viral diseases, such as with the hepatitis C virus. The occurrence of this genetic alteration in healthy individuals may complicate the interpretation of measurable residual disease in patients with follicular lymphoma. It is believed that t(14;18)-positive cells may be present in healthy-appearing individuals for up to 15 years without developing follicular lymphoma and that precursors of follicular lymphoma develop over a long period of time. However, the distinction between healthy and subclinical individuals is in a gray area and the impact of t(14;18) in healthy individuals cannot be clearly assessed (Nadel 2014).
Follicular Lymphoma International Prognostic Index (FLIPI) is used for risk classification in follicular lymphoma.
The Follicular Lymphoma International Prognostic Index (FLIPI) is used for risk assessment of follicular lymphoma (Solal-Celigny et al. 2004). This clinical risk score considers the following parameters:
Follicular lymphoma risk factors:
>4 involved nodal areas
Age >60 years
Ann Arbor stage III or IV
Hemoglobin <12 g/dL
Table 5: Follicular lymphoma - FLIPI risk score
No. of risk factors
Outcome, 10-y-OS (%)
When the FLIPI is expanded to include the mutation status of the 7 genes EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11, as well as the Eastern Co-operative Oncology Group (ECOG) performance status, the result is the m7-FLIPI score, which is a clinical genetic model for risk calculation (Pastore et al. 2015).
The presence of a TP53 mutation is associated with shortened progression-free survival and overall survival in follicular lymphoma, similar to other hematologic diseases (O'Shea et al. 2008, Qu et al. 2019). Based on multivariable analyses, TP53 mutation is nevertheless not accounted for in the m7-FLIPI score, whose development is based on the complex interplay between genetic and clinical factors, not every single genetic risk factor playing a role (Pastore et al. 2015). CDKN2A deletions are also associated with shortened progression-free survival (Qu et al. 2019). Because mutations can be present in progenitor cells that are not fully malignant long before disease onset, resident progenitor cells that migrate to lymphoid organs could be a cause of recurrence. However, to date, these progenitors have not been fully characterized (Nadel 2014).
Follicular Lymphoma: Prognosis Calculation
Influence of tumor microenvironment on prognosis
The development and progression of follicular lymphomas is influenced by complex interactions between neoplastic B cells and surrounding cells (tumor microenvironment). Analysis of gene expression profiles of infiltrating T cells has shown that they too - in addition to B cells - have an impact on the prognosis of follicular lymphomas. Here, increased expression of proliferation genes and decreased expression of T cell genes are indicative of a worse prognosis (Rimsza & Jaramillo 2014).
Cytotoxic T cells and T helper cells influence anti-tumor immunity and thus disease progression. Regulatory T cells expressing CD25 and regulated by FOXP3 (forkhead box protein P3) have been implicated in suppressing the immune response and could be found increased in follicular lymphoma. Here, not only the number of cells seems to play a role, but also their specific localization. In patients with longer overall survival, FOXP3+ cells were found preferentially around follicles and not in the follicles (Rimsza & Jaramillo 2014).
Macrophages in the tumor microenvironment have also been studied for their impact on follicular lymphomas, but the results are less clear compared to T cells. Thus, both positive and negative prognostic relevance in follicular lymphomas has been described for macrophages. Overall, however, the tumor microenvironment appears to have a presumably dynamic impact on the development of follicular lymphomas, depending on the distribution and interplay of T helper cells, regulatory T cells, and macrophages. However, translation of these findings into routine diagnostics remains a challenge (Smith 2013, Rimsza & Jaramillo 2014).
Important notes on the examination material
The diagnosis of follicular lymphoma should be based on surgical lymph node extirpation, if possible, and also from peripheral blood and bone marrow in advance or in parallel. For initial screening in inaccessible, e.g. retroperitoneal lymph nodes, a lymph node biopsy can be performed alternatively. Fine-needle aspiration (cytology) alone is not sufficient because of possible focal heterogeneity of lymphoma tissue and the possible need for further immunologic and molecular genetic testing.
If lymphoma cells are detected in peripheral blood, the diagnosis can initially be made with a high degree of confidence without bone marrow biopsy or lymph node sampling. If enlarged lymph nodes are clinically prominent, a lymph node should be removed and histologically and immunohistologically processed. Based on these findings, an extended sampling of material, e.g. bone marrow, may be useful in individual cases and if clinically relevant.
PET/CT (positron emission tomography / computed tomography) can be used to determine the total tumor mass, the Ann Arbor stage and the response to therapy (based on tumor regression or metabolic activity). PET/CT can also provide evidence of transformation via metabolic activity. Thus, PET/CT can contribute to treatment planning and prognostic assessment, but it cannot replace bone marrow biopsy in initial diagnosis (Guidelines Program Oncology - S3 Guideline 2020).
Many follicular lymphoma patients do not show any symptoms or complications even in advanced stages and if no cytopenias are present, a wait-and-see strategy with close monitoring can be applied here ("watch and wait"). Early therapeutic treatment shows no survival benefit.
Rituximab and obinutuzumab are anti-CD20 antibodies and represent today an essential pillar in the therapy of follicular lymphoma. They are used in both induction therapy and maintenance therapy. While obinutuzumab is only used in combination with chemotherapeutic agents in induction therapy, treatment with rituximab can take the form of monotherapy or chemoimmunotherapy. Since the pivotal study showed an improvement in progression-free survival compared to rituximab + chemotherapy, particularly for patients with intermediate or high FLIP index, obinutuzumab-based chemoimmunotherapy is indicated for patients in stages III or IV, while rituximab alone or in combination with chemotherapy is a treatment option at any disease stage. When used as maintenance therapy, anti-CD20 antibodies show a favorable impact on progression-free survival, but whether there is an advantage in terms of overall survival has not yet been conclusively determined; however, the incidence of infections is increased with maintenance therapy (Onkopedia guideline FL 2019, Freedman & Jacobsen 2020, Guidelines Program in Oncology - S3 guideline 2020).
Radiation therapy, which can be combined with chemo(immuno)therapy as needed, may also be considered. Combining radiotherapy with rituximab resulted in improved progression-free survival in one study, but showed no impact on overall survival. In patients with stage I-II and grade 1-2 follicular lymphoma, radiotherapy alone within the first year of diagnosis may prolong disease-specific survival as well as overall survival, or lead to cure (Pugh et al. 2010, Freedman & Jacobsen 2020).
Autologous and allogeneic stem cell transplants represent a curative treatment option, but are necessary only in rare cases. Allogeneic stem cell transplantation may be a curative option after relapse for young patients with resistant follicular lymphoma. In the group of patients with early relapse, autologous stem cell transplantation resulted in improved overall survival.
In relapse, lenalidomide in combination with rituximab is another therapeutic option and offers a chemotherapy-free alternative. In addition, treatment with the PI3 kinase inhibitor idelalisib as well as anti-CD20-based therapies can be given with or without chemotherapy.
CAR T-cell therapies are still being evaluated in trials and may influence treatment strategies in second-line therapies in the future (Freedman & Jacobsen 2020).
Choice of therapy for follicular lymphoma
According to the S3 guideline of the Arbeitsgemeinschaft der wissenschaftlichen Medizinischen Fachgesellschaften e. V. (AWMF), German Cancer Society e. V. (DKG) and German Cancer Aid (DKH), treatment decisions are based on various parameters. These include the Ann Arbor stage, the patient's condition, age, comorbidity, and the goal of therapy. Treatment options include "watch & wait" as described above, radiation therapy, anti-CD20 antibodies, immunochemotherapy, and stem cell transplantation. The various options can also be combined differently, and maintenance therapies with anti-CD20 antibodies can be used when complete or partial remission is achieved. Detailed treatment regimens are mapped in the S3 guideline as well as the Onkopedia guideline for follicular lymphoma (Onkopedia guideline FL 2019, Guideline Program Oncology - S3 guideline 2020). In addition, an overview of the different options in first-line therapy is given in Figure 1. (Note: Click on the figure to enlarge it).