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Follicular lymphoma grade 3B
Best Practice & Research Clinical Haematology, 2, 24, pages 111 - 119
Follicular lymphoma (FL) grade 3B (FL3B) is defined as FL with more than 15% centroblasts per high resolution field present as solid sheets. Coexistence with diffuse large B-cell lymphoma (DLBCL) is frequent. In contrast to other FL, FL3B frequently lack CD10 expression (approximately 50% of cases), show lower probability of BCL2 expression (69% positive) and increased TP53 expression (31% positive). The t(14;18) hallmark translocation of FL is present in only around 13% of FL3B. In contrast, translocations affecting the BCL6 locus in 3q27 are frequent (44%). Overall, FL3B in many features resembles DLBCL. The presence of a diffuse component in FL3B has been related to an unfavorable outcome except for pediatric FL3B that presents in 60% of the cases this DLBCL component. In this chapter we sought to review the present knowledge on morphological, cytogenetic and molecular features in FL3B.
Keywords: follicular lymphoma, FL3B, diffuse large B-cell lymphoma, pediatric lymphoma, BCL6, t(14;18).
Definition and morphology of follicular lymphoma 3B
By the updated WHO classification  , follicular lymphoma (FL) grade 3B (FL3B) has been defined as FL with more than 15% centroblast per high resolution field present as solid sheets. The proportion of centroblast (>15% centroblast × high resolution field) distinguishes FL3 from FL1/2 with the latter having a less extensive centroblast component with a predominance of centrocytes. FL3B is distinguished from FL3A by the presence of characteristic areas of sheet-like growth of centroblasts (Fig 1 and Fig 2). Demarcation of follicles is often poorly defined and areas resembling diffuse large B-cell lymphoma, exist frequently  . In many aspects FL3B is reminiscent of de novo (DLBCL).
In the past, in different classifications systems FL has been subjected to “grading”. This created large debates about the optimal method and the clinical significance of such grading systems ( Table 1 ). Historically, in the Working Formulation and in the Kiel classification FL3B would most likely corresponded to “follicular lymphoma, predominately large cell” and “centroblastic, follicular lymphoma”, respectively  . The Revised European American Lymphoma (REAL) classification from 1994  described FL as “follicle center lymphoma, follicular”, and introduced the graduation of “germinal center 1–3” according to proportion of large cells  . Follicle center lymphomas with “predominantly large cells” were assigned to “follicle center lymphoma, follicular grade 3” independent of the pattern of large cells distinguishing FL3A and FL3B. Thus, this would include FL3A and FL3B.
|Working formulation||Follicular lymphoma, predominately large cell a|
|Kiel classification||Centroblastic lymphoma, follicular a|
|REAL||Follicle center lymphoma, follicular grade 3 a|
|WHO classification 2001||Follicular lymphoma, grade 3B|
|WHO classification 2008||Follicular lymphoma, grade 3B|
a Includes also other lymphoma subtypes.
The WHO classification 2001, updated in 2008,  and  follows the graduation of the REAL classification from 1 to 3 but distinguished FL3A and FL3B as described above. Interestingly, the WHO classification from 2001  stated that any area of DLBCL in an FL indicates transformation and has to be reported as a separate diagnosis estimating the proportion of each. The updated WHO classification from 2008  is more precise and clarifies that only diffuse areas comprised entirely or predominantly of large blastic transformed cells in an FL in any grade is equivalent to DLBCL and a separate diagnosis has to be performed  . Again it recommends quoting the relative proportion of the FL and DLBCL. Thus, the “FL3B transforming into DLBCL” according to the 2001 classification nowadays would likely be called DLBCL/FL. Given that simultaneous areas of FL3B and diffuse areas or DLBCL are quite frequent this could potentially lead to the assignment of a considerable number of cases to different diagnosis and even clinical trials (FL vs. DLBCL). In general, FL3B with a purely follicular architecture is quite extremely rare. Finally, the WHO 2008 classification states that “rare lymphomas with the morphology and immunophenotype of FL and entirely diffuse growth pattern do exist”.
With regard to the present chapter a major challenge for reviewing FL3B comes from the fact, that the classification systems have been changed during the past and that even nowadays many studies do not really distinguish between FL3A and FL3B. In principle, studies before the introduction of the WHO classification cannot reflect the current definition of FL3B. But even nowadays, definition of FL3B is sometimes ambiguous and according to the WHO 2008 several FL3B with DLBCL component might now have the leading diagnosis of DLBCL. Finally, many FL3B are likely hidden in studies on t(14;18) negative FL, CD10-negative FL, 3q27 altered FL or FL transformed to DLBCL but cannot be purely extracted from them. Because of all these limitations, data characterizing “true” FL3B are poor and the number of well characterized cases low. Thus, a major conclusion of this review is that studies relying on the principles of the current WHO classification are urgently needed to get a better understanding of the molecular pathophysiology and clinical behavior of FL3B.
FL accounts for 32% of all B-cell lymphomas in the western countries  . Approximately 80–90% of FL are FL1/2. From the remaining 10–20% it is estimated that approximately one quarter are FL3B , , and . The male/female ratio of FL3B has not been described to be different to the rest of FL (1:1.7)  .
Although FL mainly affects adults, FL3B have been described in all age groups  and . Variable frequencies of FL3 in pediatric lymphomas have been observed along the years, using diverse graduation systems (33–100%) , , , , , , , and . Actual studies indicate that the vast majority of pediatric FL to be FL3 with/without DLBCL component. A recent population-based study on pediatric FL classified 60% of cases as FL3A and 40% as FL3B  . DLBCL component within the same biopsy has been noted in 36% of these pediatric cases  . The patients with pediatric FL are predominantly male (68%) , , and . The peculiarities of pediatric specimens are revised in detail in Pediatric FL3B of this book chapter.
Immunohistochemical features of FL3B
FL3B expresses BCL2 in 69% of cases and, thus, slightly less frequent than FL1-3A. In comparison to FL1-FL3A, where CD10 expression is present it almost all cases, CD10 absent in around 50% of FL3B ( Fig. 1 )  and . Increased expression of TP53 is common (31% of FL3B vs. 9% of FL3A)  . Moreover 38% of CD10−/t(14;18)-FL (mainly FL3B) express MUM1/IRF4 ( Fig. 1 )  . Of these MUM1/IRF4 positive cases, 55% present with diffuse proliferation. BCL2 protein expression is less frequent in these cases (59%) as compared to CD10+/MUM1 − FL (94%)  and . This MUM/IRF4 expression could in part be related with cytogenetically cryptic IRF4 translocations described recently in a series of mainly pediatric lymphomas enriched in FL3A/3B with DLBCL component  . Thus, many FL3B show a protein expression profile different from typical FL. The CD10− and MUM1/IRF4+ phenotype observed in a considerable number of cases resembles that of the non-germinal center (non-GCB) type DLBCL. Along with the predominance of centroblasts as defining morphologic feature of FL3B and the frequent coexistence of DLBCL this might suggest that FL3B could in some instances represent a follicular growth variant of non-GCB DLBCL. This view is fostered by the observation, that a subset of FL3B displays a gene expression profile characteristic of activated B-cell like (ABC)-DLBCL (Molecular Mechanisms in Malignant Lymphomas, unpublished data).
Genetic feature of FL3B
Cytogenetic aberrations in FL3B
Only few studies have dedicatedly investigated FL3B on the cytogenetic level using chromosomal banding analysis. Indeed, the Mitelman database, which summarizes all cytogenetic data published in the literature, contains only 38 cases diagnosed as FL3B ( Fig. 3 )  and . Overall, the number of karyotypic alterations in FL3B is higher (mean 8.9 alterations) than in FL3A (mean 6.5) and FL1-2  . Probably the most comprehensive cytogenetic study has been published by Bosga-Bouwer and collaborators  . They described the presence of both t(14;18)-positive and t(14;18)-negative FL3B. Moreover, by characterizing the pattern of other chromosomal changes they show that both t(14;18)-positive and t(14;18)-negative FL3B share some cytogenetic alterations like deletions in 6q or presence of an isochromosome 6, as well as alterations or gains of chromosome 3 (26%)  . Though changes of chromosome 6 and gains of chromosome 3 are rather unspecific findings in B-cell lymphoma, they are particularly prominent in DLBCL of the activated B-cell (ABC) type as well as MALT lymphoma  and . Gains of chromosome 7 were mainly observed in FL3B with t(14;18) rearrangements being present in 62% of t(14;18)-positive in contrast to 32% of t(14;18)-negative FL3B cases. This finding is in concordance with gains of chromosome 7 being recurrent findings in t(14;18)-positive lymphomas  . Karube and collaborators described a cytogenetic group of FL characterized by BCL6 amplifications/gains enriched in grade FL3B (47%)  . Additionally, this group of cases showed frequent presence of 18q21/BCL2 amplification. Overall, these cytogenetic studies reinforce the view that only a minority of FL3B reflects features typical for classical FL, i.e. presence of t(14;18) with the typical spectrum of recurrent secondary changes. The t(14;18)-negative cases present again characteristics of non-GCB type DLBCL including gains of chromosomes 3 and 18 and deletions in 6q  .
Hallmark chromosomal translocations and breakpoints in FL3B
As compared to other grades of FL, the translocation t(14;18)(q32;q21) juxtaposing the IGH and BCL2 genes is rare in FL3B. As outlined above, it has been detected in only around 13% of FL3B as compared to 73% in FL3A and more than 85% of FL1/2. In contrast, 3q27/BCL6 translocations seem to be more frequent in FL3B (44%) than in other FL including FL3A (18%)  . Again the pattern of these chromosomal translocations resembles that of DLBCL, particularly the non-GCB DLBCL which are characterized by the low frequency or complete absence of the t(14;18) and a comparably high frequency of BCL6 translocations.
Bousga-Bower and colleagues have proposed that FL3B includes 3 cytogenetically defined subgroups based on the t(14;18)/BCL2 and t(3q27)/BCL6 translocations status  :
- group I: t(14;18)+ and 3q27− (40%)
- group II: t(14;18)−, 3q27− (40%) and other cytogenetic aberrations and
- group III: t(14;18)− with 3q27 aberrations (20%).
Molecular features of BCL2 translocations in FL3B
Although infrequent, BCL2 translocations are also present in FL3B. In FL in general, approximately 60% of BCL2 translocations occur in the major breakpoint region (MBR) in the 3′ non-coding part of the third exon, and in 5–25% of the cases in the minor cluster region (mcr). With regard to FL3B, molecular studies analyzing FL of different grades for BCL2 breakpoints have yet not found correlations between a specific breakpoint and grading  and . JH segment usage is specific of GC-derived FL cells independently of BCL2 breakpoints.  Again, no differences have been described in the different grades.
Molecular features of BCL6 translocations in FL3B
t(14;18)-negative FL  and more specifically FL3B  are characterized by 3q27/BCL6 breaks affecting an alternative breakpoint region (ABR) in BCL6 locus (66% of FL3B vs. 2% in DLBCL)  . ABR is located between 245 and 285 kb 5′ of BCL6 whereas the major breakpoint region (MBR) defined in DLBCL comprises a 4 kb region located in the first non-coding exon and 5′ region of the first intron. Juxtaposition to a foreign enhancer could be the prevalent mechanism in these cases with ABR breakpoints and therefore t(3;14)(q27;q32) or variants should be expected in such cases. Nevertheless, no differences have been observed with respect to the use of partner chromosomes between the cases with an MBR or ABR breakpoint  and .
MYC translocations in FL3B
In the FL3B the presence of MYC translocations in chromosomal region 8q24 has been reported in 3 of 27 cases studied (14%)  . Thus, MYC translocations are unlikely to be initial events in FL3B as they are in Burkitt lymphomas. Considering the low number of informative cases the frequency of MYC translocations seems to be similar like that in DLBCL or other B-cell lymphomas. Whether they confer clinical aggressiveness like in DLBCL needs to be addressed in future studies.
IGH translocations in FL3B breakpoints
Overall, there has yet no recurrent hallmark translocation of FL3B though in pediatric FL3B IG-IRF4 translocations are recurrent  . Analysis of the rare cytogenetic data on FL3B besides t(14;18) and t(3;14) identified only one case with a 14q32 translocation containing the IGH locus, namely a t(1;14) (q21;q32)  . The region 1q21 contains several potential oncogenes activated by IG translocations including BCL9, FCGR2B or IRTA1/2. Differences between FL and DLBCL have been observed with regard to the IGH breakpoints in t(3;14): switch γ translocations seem to be more prominent in FL (70%) whereas switch μ are mainly present in DLBCL (89%)  . Nevertheless, in this study no differences between FL according to grades have been assessed and only one FL3B has been analyzed.
Somatic IGHV and BCL6 mutations
Extensive and ongoing somatic hypermutation has been described in the variable regions IGH locus in FL  and . There is some evidence that CD10−/MUM1 + FL (90% grade 3A/B) shows higher rates of somatic hypermutation and ongoing mutation than the rest of FL  . The 5′ non-coding region of the BCL6 gene is also subjected to somatic hypermutation though to a lower extent. Mutations of BCL6 have been extensively described in FL in this region  . Although some studies provide information of the grade of the FL studied, no characteristic differences in the BCL6 mutation pattern or frequency can be established between the grades  .
Prognosis and optimal treatment
Since many features of FL3B resemble DLBCL it has been suggested that FL3B behaves more like a DLBCL and should be treated accordingly  and . Indeed, also clinical presentation of FL3B in several aspects like e.g. frequency and type of bone marrow infiltration resembles more DLBCL than FL.
Many studies have concluded that the grading in FL predicts the clinical outcome but indeed most studies have not shown a survival difference between FL3A and FL3B. In this line Hans and colleagues performed a clinical study in 190 cases including 107 FL3A, 51 FL3B and 30 follicular large cleaved cell type, in which the percentage of diffuse component was also recorded  . The conclusions of this study were that no significant differences in the prognosis of these groups do exist. Nevertheless, the presence of the diffuse component accounting for more than 50% of the surface area had a significant association to a worse prognosis. If these cases would indeed correspond to composite DLBCL and FL according the present WHO classification  is not known.
Chau and collaborators performed a clinical trial with anthracycline-containing regimens examining the difference in behavior between FL3A and FL3B. 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)  .
Another study from Hsi et al. reaches similar results. In this study of 45 FL3 (35 FL3A and 10 FL3B) no significant differences in terms of overall survival between FL3A and FL3B were observed  .
To sum up, there is currently no firm evidence that subclassification of grade 3 FL into type 3A and type 3B has clinical or prognostic significance. Nevertheless, it needs to be considered that large systematic studies are missing. Moreover, follow-up times might yet be too short to draw conclusions as the distinction of FL3A and FL3B has been introduced by the WHO classification less than ten years ago. Moreover, very likely FL3B is still a wastebasket of heterogeneous lymphoma subtypes including e.g. “high-grade t(14;18)-positive FL” and “low-grade t(14;18)-negative DLBCL”.
Pediatric FL are considered to be a separate variant of FL. More than 50% of these pediatric FL are FL3 , , , , , , , and  with 40% being FL3B  . Pediatric FL has many features indistinguishable from those seen in adults. Nevertheless, these lymphomas are more frequently localized, lack BCL2 expression and exhibit grade 3 histology  .
Pediatric FL often involves cervical lymph nodes and the Waldeyer ring. Most patients present with clinically restricted stages of disease  . The t(14;18)(q32;q21) translocation is rare to absent in pediatric patients with FL , , and . In this sense, a recent study in which 25 cases of pediatric FL (age <18 years) were studied by morphology, immunohistochemistry and FISH the genetic hallmark of adult FL, t(14;18)(q32;q21), was not detectable in any of the pediatric FL, although the BCL2 protein was expressed in 55% of the cases. No correlation between BCL2 protein expression and outcome was observed  . Moreover, preliminary results of a molecular study in the identification of IRF4 translocations in aggressive lymphomas has shown that these translocations are recurrent in pediatric FL grade 3A/B carrying frequently DLBCL component  . The prognosis of the pediatric cases seems to be good with the majority of reported cases disease free survival at time of last follow-up  and .
FL3B is defined as FL with more than 15% centroblasts per high resolution field present as solid sheets. Coexistence with DLBCL is frequent. FL3B frequently lack t(14;18) and CD10 expression, two defining features of classical FL. In contrast, MUM1/IRF4 expression as well as BCL6 translocation are frequent. The histomorphologic appearance, the immunophenotypic profile and the pattern of chromosomal aberrations resembles in many aspects that of DLBCL, particularly of the non-GCB type. Thus, it is meanwhile widely accepted that FL3B is distinct from the other types of FL. It is intriguing to speculate, that FL3B is a follicular growing variant of DLBCL. Nevertheless, this view needs future confirmation on an extensive set of FL3B because the current knowledge is strongly limited by the low number of well characterized cases studied. Indeed, most studies lump together FL3 as well as t(14;18)- or CD10-negative FL which makes distinction of FL3B difficult. This also affects conclusions on the clinical outcome of FL3B.
Conflict of interest
Employment on leadership position: none. Consultant or advisory role: Reiner Siebert, Abbott/Vysis, Kreatech and MetaSystems FISH probe providers. Stock ownership: none. Honoraria: Reiner Siebert, Abbott/Vysis. Research funding: Reiner Siebert, Abbott/Vysis: reduced fees for FISH probes, Illumina and Affymetrix: testing of array platforms. Expert testimony: none. Other remuneration: none.
The authors gratefully acknowledge Dr. Monika Szczepanowski and Dr. Ria Winkelmann for pictures of Fig. 1 as well as Dr. Michael Baudis (Progenetix database) for providing Fig. 3 . The authors’ own projects on the topic are supported by grants from the Deutsche Krebshilfe (Network project “Molecular Mechanisms in Malignant Lymphomas, 70-3173-Tr3), the BMBF (HämatoSys, 01GM0886), the Kinderkrebsinitative Buchholz/Holm-Seppensen and the Alexander von Humboldt Foundation.
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