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Follicular Lymphoma Grade 3: Review and Updates
Clinical Lymphoma Myeloma and Leukemia
Follicular lymphoma (FL), Grade 3, is recognized as a distinct entity in the World Health Organization classification of lymphoma. It is further classified into Grade 3a and Grade 3b depending on the Bernard cell counting system and percentage of centroblasts. Grade 3 has molecular and genetic characteristics that distinguish it from other grades of FL. There is confusion and misunderstanding about the natural history and clinical course of Grade 3a and 3b because some studies indicate them as having indolent behavior and others describe more aggressive biology. The purpose of this article is to understand the concept of Grade 3 FL, especially the fundamental differences between Grade 3a and Grade 3b FL. Grade 3 FL is still an evolving subclass in FL and the practicing physician should understand the aggressive nature of Grade 3b, which typically requires timely attention, compared with Grade 3a. Grade 3a FL has more indolent characteristics but can possibly progress to Grade 3b and/or transform to diffuse large B-cell lymphoma at a future time. Nevertheless, large prospective studies are missing for an optimal evidence-based management approach for patients with Grade 3 FL at this time.
Keywords: B-cell lymphoma, Follicular lymphoma grade 3a, Follicular lymphoma grade 3b, Grade 3 follicular lymphoma, Indolent lymphoma.
Follicular lymphoma (FL) is the second most common subtype of non-Hodgkin lymphoma (NHL). It is defined as a lymphoma of follicle center B cells, and virtually always demonstrates a growth pattern that is partially follicular and accounts for 22% of newly diagnosed NHL. 1 The classification of FL has evolved through major changes over the past century. These were formally recognized as centroblastic/centrocytic follicular or follicular centroblastic according to the Kiel classification2, 3, and 4 and follicular small cleaved, mixed, or large cell according to the International Working Formulation (IWF) classification. The Revised European American lymphoma (REAL) classification 5 and the most recent World Health Organization (WHO) classification 6 proposes the term, follicle center cell lymphoma, follicular Grade 1, 2, 3a, and 3b. Grade 3 (largely follicular large cell according to the IWF) is discriminated from Grades 1 and 2 (predominantly follicular small cleaved cell and mixed small and large cell according to the IWF).
The Bernard cell counting method is used by the WHO classification schema to “grade” FL. Grade 1 is defined when 0 to 5 centroblasts per high-power field (HPF) are counted; Grade 2 when 6 to 15 centroblasts per HPF are counted; and > 15 centroblasts per HPF is accounted as Grade 3, which is again subdivided into Grade 3a when centrocytes are present and Grade 3b when solid sheets of centroblasts are present. 7
The purpose of this article is to understand the concept of Grade 3 FL, especially the fundamental differences between Grade 3a and Grade 3b FL.
Pathology and Biology
Follicular lymphoma is a heterogeneous clinicopathologic entity that includes tumors derived from germinal center B cells, centrocytes (small cleaved follicular center cells), and centroblasts (large noncleaved follicular center cells). 8 The germinal center ancestry of these cells is principally supported by the identification of somatic mutations in the variable region of the immunoglobulin (Ig) genes (IgVH), which serve as a marker of germinal center transit. 9 The cells of FL express surface Igs, IgM > IgD > IgG > IgA, B-cell–associated antigens (CD19, CD20, CD22, CD79a, and CD79b), and CD10 positivity or negativity. 2
Follicular lymphoma generally expresses CD10, B-cell lymphoma 2 (bcl-2) and bcl-6. CD10 is expressed more commonly among FL Grade 1 and 2 (> 90%) compared with FL Grade 3.10, 11, 12, and 13 Moreover, CD10 positivity was observed in 91% of cases of FL Grade 1 and 2, 48% in Grade 3a, and 57% in Grade 3b. Multiple myeloma oncogene-1 (MUM1) antigen is expressed on late stage germinal center B cells and postgerminal center B cells. It is expressed in 50% to 75% of diffuse large B-cell lymphoma (DLBCL). The incidence of MUM1 in FL has been reported to be more common in Grade 3 (especially Grade 3b) than Grade 1 and 2.14 and 15 The t(14;18) is present in 70% to 95% of FL involving the rearrangement of the bcl-2 gene.16, 17, and 18 Increased expression of bcl-2 is more frequently seen in FL Grades 1 and 2 than in Grade 3. 19 Bcl-2 protein was expressed in only 48% of lymphomas classified as Grade 3a and 57% of Grade 3b. Furthermore bcl-6 rearrangements are frequently encountered in DLBCL/FL Grade 3b, but again, they are rare in FL Grades 1 and 2.13 and 20
Ki-67 staining was reported to be greater in Grade 3 compared with Grades 1 and 2.21 and 22 Other groups also demonstrated greater Ki-67 staining in large-cell FL and Grade 3 FL compared with other FLs.23 and 24 An interesting phenomenon is the decreased incidence of MYC rearrangement and distribution of double hit or triple hit in all categories of FL (13%-22%).25, 26, 27, 28, 29, and 30
There are conflicting results regarding the biological differences between FL Grade 3a and 3b. Studies20 and 24 have reported that the biopsies of FL Grade 3b sometimes had a DLBCL component and were significantly less likely to express CD10 and more likely to express cytoplasmic Igs and to differentiate into a plasmocytoid variant. FL Grade 3b is also less likely to harbor the t(14;18) but more likely to display aberrations in chromosome band 3q27 when a coexisting diffuse large B-cell component existed. FL Grade 3b will also more likely express tumor suppressor gene p53 when a diffuse large B-cell component is present. 31 In Table 1 the basic differences between FL Grades 3a, 3b, and DLBCL are summarized. 32
|Characteristics||FL (1-3a)||FL (3b)||DLBCL|
|Morphology||Follicular pattern||Common diffuse component||Diffuse architecture with large cells|
|Age||Mainly in adults||Also present in children||Also present in children|
|Prognosis||Favorable prognosis (except 3a)||Generally bad prognosis||Generally bad prognosis|
Simplified scheme indicating frequent/predominant patterns. ‘+’ Indicates positivity, ‘−’ indicates negativity, and ‘±’ indicates positivity or negativity.
Abbreviations: ABR = alternative breakpoint region; chr = chromosome; FL = follicular lymphoma; IGH = immunoglobulin heavy chain; IHC = immunohistochemistry; MBR = major breakpoint region; MUM1 = multiple myeloma oncogene-1; neg = negative; transl = translocation.
Follicular lymphoma occurs most commonly in middle-aged and elderly patients,33 and 34 although it has been reported that FL Grades 3a and 3b are more common in the older population, with a low male:female ratio (0.9 vs. 1.8). 35
Clinical presentation and behavior of FL differs according to the histological grade. It presents as advanced disease in 80% to 85% of FL Grade 1; 70% to 75% in Grade 2; and 65% to 70% of Grade 3. Systemic symptoms are observed 30% of Grade 3 FL compared with 20% in Grade 1 and 2 FL. 2
The Follicular Lymphoma International Prognostic Index (FLIPI) is a prognostic scoring system based on age, Ann Arbor stage, number of nodal sites involved, hemoglobin levels, and serum lactate dehydrogenase levels. 36 The FLIPI was developed based on a large set of retrospective data from patients with FL, and established 3 distinct prognostic groups with 5-year survival outcomes ranging from 52.5% to 91% (before the use of rituximab therapy). 36 In the National Lympho Care study, which analyzed the treatment options and outcomes of 2728 patients with newly diagnosed FL, use of the FLIPI allowed categorization of patients into 3 distinct prognostic groups. 37 In a more recent study conducted by the International Follicular Lymphoma Prognostic Factor Project, a prognostic model (FLIPI-2) was developed based on prospective collection of data from patients with newly diagnosed FL treated with rituximab-era–containing chemotherapy regimens. 38 The final model included age, hemoglobin levels, longest diameter of largest involved lymph node, β-2 microglobulin levels, and bone marrow involvement. FLIPI-2 is highly predictive of treatment outcomes and allows separation of patients into 3 distinct risk groups with 3-year progression-free survival (PFS) rates ranging from 51.5% to 91% and overall survival (OS) rates ranging from 82% to 99%; the FLIPI-2 also allowed definition of distinct risk groups among the subgroup of patients treated with rituximab-containing regimens, with a PFS rate ranging from 57% to 89%. 38 Thus, FLIPI-2 might be useful for assessing prognosis in patients receiving active therapy with rituximab-based treatments. The FLIPI and FLIPI-2 allow prediction for prognosis, but these index scores have not yet been established as a means of selecting treatment options.
Follicular lymphoma tumors are graded from 1 to 3, and this grade has some prognostic utility. Differences in molecular genetics and clinical behavior suggest that FL Grade 3a is an indolent disease and 3b is an aggressive disease.8 and 39 Although the follicular architecture is intact, the clinical presentation, behavior, and outcome with treatment in many patients with Grade 3b FL more closely approximates that of DLBCL.40, 41, and 42 In contrast to DLBCL, the relapse rate of FL Grade 3b in some series is higher, but survival is longer. 43 Investigation of the cellular microenvironment of FL has provided interesting insights into prognosis.44, 45, 46, 47, and 48 It has been suggested that FL is an immunologically functional disease in which an interaction between the tumor cells and the microenvironment determine overall clinical behavior.
Risk of Transformation
A pivotal event in the natural history of FL is histological transformation to more aggressive malignancies, most commonly DLBCL.49, 50, 51, and 52 The reported frequency of higher grade FL transformation varies significantly, ranging from 10% to 60% of patients. A number of immunophenotypic and genetic features suggest that Grade 3b FL may be more akin to de novo DLBCL, however, most clinical studies have not shown a survival difference between Grade 3a versus 3b FL if cases with a diffuse component are excluded.41 and 42
Transformation is defined as pathologically demonstrated and clonally confirmed progression of FL Grades 1, 2, and 3a to DLBCL or less commonly the intermediate gray-zone category of unclassifiable B-cell lymphoma, lymphoblastic lymphoma, or acute lymphoblastic leukemia (ALL). Progression from FL Grades 1 and 2 to FL Grade 3a is not considered histologic transformation, but a common progression event during the course of disease. 53
Risk Factors for FL
Although there is no definite association between a risk factor and the incidence of FL, various studies have been done. Significant associations between diet and the incidence of NHL have been observed and published. 54 Casey et al created a standard questionnaire-based interview and collected clinical and biological data from 298 lymphoma (34 FL) patients. 55 Wine consumption marginally increased the risk of FL. According to Morton et al, smoking is associated with increased risk estimates for FL (n = 1452). 56 In 2007, Larsson and Wolk performed a meta-analysis of studies that examined the association between NHL and obesity. 57 Their study found an overall significant positive association (odds ratio [OR], 1.20; 95% confidence interval [CI], 1.07-1.34), and this significance was maintained in their analysis of obesity and the diffuse large B-cell subtype, but disappeared in their analysis of FL. Their meta-analysis identified 6 studies, 5 of which were case-control studies, that specifically addressed the relationship between obesity and FL, and they estimated an overall OR of 1.10 (95% CI, 0.82-1.47). FL has been found to be more common in North America, the United Kingdom, and South Africa than in other regions of the world. The incidence of FL is not only decreased in populations in China and Japan, but it is actually increased in individuals born in the United States of Chinese or Japanese descent, suggesting that FL risk has an important environmental component. 58
Although FL Grades 1 and 2 are generally considered to have an indolent behavior, the clinical course of FL Grade 3 is a subject of intense debate. 59 One of the major reasons for the controversy regarding the behavior of patients with FL Grade 3 has been the lack of a uniform classification system. Most of the clinical trials either exclude Grade 3 or include only a very small subset of patients with Grade 3a and Grade 3b disease.
Selection of a watch-and-wait management for patients with Grade 3 disease might be problematic because there are no set rules. Traditionally, a palliative approach to management was taken in patients with stage III to IV disease, progressing systematically through watchful waiting, radiotherapy, oral alkylating agents, and, eventually, combination chemotherapy, as deemed necessary. This approach was based on early research findings that have influenced treatment practices for the past 2 to 3 decades, as reviewed in recent literature. 60
The role of anthracyclines in Grade 3 FL has been studied in the past.43, 59, and 61 The Nebraska Lymphoma study group 59 and a study by Overman et al 61 clearly stated the benefit of anthracycline especially in Grade 3b FL, and Chau et al 43 did not find any benefit of anthracyclines in the first-line setting for Grade 3 FL. The role of adding rituximab to chemotherapy was studied in the GELA-GOELAMS FL2000 study, 62 which included subset of Grade 3a FL patients, that demonstrated that the combination of rituximab with chemotherapy and interferon improves the outcome of FL patients with a high tumor burden.
Because many features of FL Grade 3b resemble DLBCL, it has been suggested that FL Grade 3b behaves more like a DLBCL and should be treated accordingly.23 and 40 Indeed, the clinical presentation of FL, Grade 3b in several aspects resembles more DLBCL than FL (eg, frequency and type of bone marrow infiltration).
Many studies have concluded that the grading in FL predicts the clinical outcome but indeed most studies have not shown a survival difference between FL Grade 3a and Grade 3b. In this respect, Hans and colleagues performed a clinical study in 190 cases including 107 patients with FL Grade 3a, 51 with FL Grade 3b, and 30 with follicular large cleaved cell type, in which the percentage of diffuse component was also recorded. 41 The conclusions of this study were that no significant differences in the prognosis between these groups exist. Nevertheless, the presence of the diffuse component accounting for more than 50% of the surface area had a significant association with a worse prognosis. If these cases would indeed correspond to composite DLBCL and FL (according to the present WHO classification) is not known.
Chau and collaborators performed a clinical trial with anthracycline-containing regimens examining the difference in behavior between FL Grade 3a and 3b. Although the small number of cases needs to be considered, they concluded that no significant survival differences between these grades exist (median survival 11.5 vs. 22.2 months, respectively). 43
Another study from Hsi et al reached similar results. In this study of 45 FL Grade 3 patients (35 FL Grade 3a and 10 FL Grade 3b) no significant differences in terms of OS between FL Grade 3a and 3b were observed. 35
Two randomized trials comparing high-dose chemotherapy (HDT) with autologous stem cell transplant versus conventional chemotherapy to consolidate first remission were published before the rituximab era, which included FL Grade 3b patients.63 and 64 There was an advantage in that the HDT/American Society of Clinical Oncology (ASCO) arm in terms of PFS or event-free survival in 2 studies, but this was not translated into any difference in OS. Another study in the rituximab era confirmed the advantage in PFS without OS improvement 65 (which again included FL Grade 3b patients).
Grade 3 FL is still an evolving subclass in FL and the practicing physician should understand the highly aggressive nature of Grade 3b disease, which typically requires timely attention compared with Grade 3a FL. FL Grade 3a has more indolent characteristics but the disease can eventually progress to Grade 3b and/or transform to DLBCL. Nevertheless, large prospective studies evaluating the optimal evidence-based management approach for patients with Grade 3 FL are lacking at this time and are needed.
The authors have stated that they have no conflicts of interest.
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Department of Medicine, Lymphoma/Myeloma Section, Roswell Park Cancer Institute, Buffalo, NY
∗ Address for correspondence: Myron S. Czuczman, MD, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263 Fax: 716-845-3894
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