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1238 Part VII Hematologic Malignancies

there was DLBCL–BL overlap, causing disagreement among patholo- than 16,000 adults diagnosed yearly in the United States. It is
gists. The outcome with CHOP-like chemotherapy in these instances characterized by significant heterogeneity with regards to histologic
was associated with poorer survival. Furthermore, classic MYC t(8;14) grade and overall survival, with more than 10% of patients sur-
rearrangements and intermediate molecular phenotypes were also viving at least 15 years after diagnosis. A spectrum of histologic
associated with worse overall survival. grading based on the density of centroblasts is also characteristic
The development of a molecular diagnosis for BL aids in distin- of this disorder, with higher FL grades resembling DLBCL. There
guishing BL from DLBCL and further illustrates the complexity of is no clear association between grade and clinical outcome in the
MYC rearrangements in NHL. Lymphoma entities containing MYC disease. Some patients with FL experience an aggressive clinical
rearrangement in addition to rearrangements in BCL2 or BCL6 course and transformation to aggressive lymphomas, but others
(double hit lymphomas) exhibit clinical behavior distant from BL may experience disease progression only after many years with the
and is often associated with progressive disease, a high International disease. This review focuses on the classic rearrangements of BCL2
Prognostic Index score, and poor response to intensive chemotherapy and the additional molecular changes associated with FL develop-
regimens. More work regarding this subtype of NHL is needed to ment and with histologic transformation of FL to more aggressive
understand its pathogenesis. subtypes.
Aside from gene expression patterns related to GC origin, further
genomic alterations may contribute to BL pathogenesis. As in DLBCL,
whole genome/exome/transcriptome approaches have deepened our BCL2 Rearrangements and Other Genomic Alterations
understanding of the importance of genetic lesions beyond MYC in Follicular Lymphoma
rearrangement in BL pathogenesis. While MYC mutation (occurring
in addition to MYC rearrangement) appears to be the most frequent Follicular lymphoma arises from GC B cells that have been immortal-
mutation in BL, mutations in the transcription factor TCF3 or its ized at this stage of B-cell differentiation (see E-Slide VM03961).
negative regulator ID3 occur in the majority of cases of BL and appear Cytogenetic studies performed in the early 1970s defined a recurrent
to lead to phosphoinositol-3-kinase activation and other complex translocation involving the long arms of chromosomes 14 and 18 in
transcriptional changes with BL cells. ID3 mutations may also serve more than 90% of FL cases. Further investigation revealed that this
as a regulator of MYC and directly influence cell cycle progression, places the gene encoding the important antiapoptotic gene BCL2
thus fostering BL development. TP53 is frequently also mutated or downstream of the Ig heavy chain transcriptional regulators. The
deleted in a subset of BL tumors. High throughput genomic tech- BCL2 protein inhibits the release of cytochrome c from mitochondria
niques have revealed many other novel BL cancer mutations in genes in the process of apoptosis. In normal GCs, BCL2 is essentially
such as SMARCA2 and CCND3 and recurrent copy number abnor- absent because selection of B-cell clones via apoptosis is an important
malities including gains of 1q and 18q and deletion of 19p13. Thus step in the production of high-affinity Ig idiotypes. The t(14;18)
these studies have revealed molecular complexity beyond the dysregu- (q32.3;q21.3) appears to be mediated by RAG1/RAG2 in pre-GC B
lation of MYC through cytogenetic rearrangement. cells because BCL2 is most often found juxtaposed to J chain exons.
EBV infection is also thought to play a role in the development Isolated t(14;18) is not sufficient to induce FL because transgenic
of BL because virtually 100% of cases of endemic BL and 30% to mice bearing this translocation develop lymphoid hyperplasia but
50% of all other BLs are associated with EBV positivity. The exact require other genetic lesions to develop FL. Additionally, B cells
role of EBV in BL is unclear. Endemic BL is frequently associated with t(14;18) can be isolated from apparently normal individuals
with endemic malaria, which further suggests a complex interaction who never develop lymphoma, and in situ follicular hyperplasia with
of the host immune response with microorganisms and other factors. BCL2 overexpression has been noted on examination of otherwise
Other host factors or genomic changes may further contribute to the normal lymph nodes. This suggests that other lesions must be acquired
development of BL. for development of FL; a preponderance of evidence suggests this
Further work is needed to define what other genomic changes and occurs in GCs. Histologically, FL is characterized by an abnormal
host–environmental interactions contribute to the pathogenesis of follicular architecture containing neoplastic cells. The follicles loosely
BL. Ongoing studies seeking to define the entire spectrum of molecu- resemble GCs but usually lack an appreciable mantle zone. The
lar, immunologic, genomic, and epigenetic changes associated with follicles generally occur in close proximity to follicular T-helper cells
BL pathogenesis may further elucidate this process. expressing CD3, CD4, CD57, PD1, and CXCL13. FL usually exhib-
its a CD10+BCL6+IRF8+ GC-like phenotype in association with
ongoing SHM, confirming GC or post-GC origin (Fig. 76.8). One
FOLLICULAR LYMPHOMA obvious hypothesis is that BCL2 overexpression dysregulates apopto-
sis such that GC transition and SHM result in further genomic and
Follicular lymphoma is a low-grade B-cell neoplasm that is also epigenomic changes that result in FL. This framework might need
characterized by recurrent chromosomal rearrangements involving to be reexamined in the small proportion of FL cases that do not
the IgH locus. It is the most common indolent NHL with more express BCL2.

BCL6 BCL2 control BCL2

A B C D
Fig. 76.8 FOLLICULAR LYMPHOMA (FL). Details from a case of FL, grade 1 of 3 associated with t(14;18)
(q32;q21). Malignant follicle (A) with immunohistochemical stains for the germinal center marker, BCL6 (B),
and BCL2 (C). Note the overexpression of BCL2 compared with a reactive follicle (D).