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1626 Part XI: Malignant Lymphoid Diseases Chapter 98: Diffuse Large B-Cell Lymphoma and Related Diseases 1627

TABLE 98–1. Diffuse Large B-Cell Lymphoma: Variants gene-expression profile. The presence of a p53 mutation in combination
with BCL2 denotes that the tumor is derived from a histologic transfor-
and Subtypes 2
mation of a prior follicular lymphoma. 13
I. Diffuse large B-cell lymphoma, NOS Normally, mutations in the variable region of the Ig genes confer
A. Common morphologic variants antibody diversity in germinal center B cells. However, aberrant somatic
1. Centroblastic hypermutation occurs in more than 50 percent of cases of DLBCL. Such
2. Immunoblastic alterations target multiple loci, including the protooncogenes PIM1,
MYC, RhoH/TTF (ARHH), and PAX5. The c-MYC gene rearrange-
11
3. Anaplastic ment occurs in 10 percent of patients with DLBCL.
B. Rare morphologic variants Gene-expression profiling studies have distinguished three molec-
C. Molecular subgroups ular subtypes of DLBCL known as (1) germinal center B-cell–like
1. Germinal center B-cell–like (GCB), (2) activated B-cell–like (ABC), and (3) primary mediastinal
2. Activated B-cell–like B-cell lymphoma (PMBCL). 14–17 GCB DLBCLs are believed to arise
D. Immunohistochemical subgroups from normal germinal center B cells, whereas ABC DLBCLs appear
to arise from postgerminal center B cells that are arrested during plas-
1. CD5-positive DLBCL macytic differentiation, and PMBCLs arise from thymic B cells. These
2. Germinal center B-cell–like DLBCL subtypes arise by distinct pathogenetic mechanisms, as judged
3. Nongerminal center B-cell–like by high-resolution, genome-wide copy-number analysis coupled with
18
II. Diffuse large B-cell lymphoma subtypes gene-expression profiling. Furthermore, genomic studies employing
A. T-cell/histiocyte-rich large B-cell lymphoma massively parallel sequencing (genome/exome/RNAseq) have demon-
strated common recurrent mutations in histone modification and
B. DLBCL associated with chronic inflammation* chromatin remodeling genes in the GCB-DLBCL subtype of DLBCL,
C. EBV-positive DLBCL of the elderly* whereas mutations affecting the B-cell signaling pathway and nuclear
III. Related mature B-cell neoplasms factor (NF)-κB family are typical of the ABC subtype of lymphoma, as
A. Primary mediastinal (thymic) large B-cell lymphoma 15 summarized in Table 98–2. 19–23 In addition, GCB DLBCLs often exhibit
B. Intravascular large B-cell lymphoma amplification of the oncogenic microRNA (miRNA)-17–92 cluster and
C. Primary cutaneous DLBCL, leg type* deletion of the tumor-suppressor PTEN, whereas these events are rare
in the ABC-type of DLBCL.
D. Lymphomatoid granulomatosis
E. ALK-positive DLBCL
F. Plasmablastic lymphoma (Chap. 81) CLINICAL FEATURES
G. Large B-cell lymphoma arising in HHV-8–associated
multicentric Castleman disease (Chap. 81)* SIGNS AND SYMPTOMS
H. Primary effusion lymphoma (Chap. 81) Patients with DLBCL typically present with rapidly enlarging, symp-
IV. Borderline cases tomatic, lymphatic masses, typically in the neck or abdomen. B symp-
A. B-cell lymphoma, unclassifiable, with features interme- toms (drenching night sweats, fever, weight loss) are observed in
diate between diffuse large B-cell lymphoma and Burkitt approximately 30 percent of patients. Extranodal disease occurs in
lymphoma* approximately 40 percent of patients, most commonly involving the
B. B-cell lymphoma, unclassifiable, with features intermediate gastrointestinal tract or marrow. 24,25 Other sites that may be affected
between diffuse large B-cell lymphoma and classical include the testis, bone, thyroid, salivary glands, skin, liver, breast, nasal
Hodgkin lymphoma cavity, paranasal sinuses, and CNS. DLBCL may cause local compres-
ALK, anaplastic lymphoma kinase; DLBCL, diffuse large B-cell lym- sion of vessels (e.g., superior vena cava syndrome) or airways (e.g., tra-
phoma; EBV, Epstein-Barr virus; HHV, human herpes virus; NOS, not cheobronchial compression) requiring urgent treatment.
otherwise specified. Unusual symptoms and presentations occur with some subtypes
*These represent provisional entities or provisional subtypes of other of DLBCL, such as intravascular large B-cell lymphoma, which may
neoplasms. present with unexplained fever, or primary effusion lymphoma, which
may present in immunocompromised hosts with human herpesvirus-8
infection. Approximately 60 percent of patients present with dissemi-
domain. This process occurs through reciprocal translocations between nated DLBCL (stage III or IV). Marrow involvement occurs in approx-
3q27 and chromosomal partner sites, including 14q32 (IgH), 2p11 imately 15 percent of patients. Discordant disease in which the lymph
(Igκ), and 22q11 (Igλ). 10,11 The BCL6 protein mediates the specific bind- nodes are involved with DLBCL but the marrow contains an indolent
ing of several transcription factors to DNA. It also may be involved in lymphoma may occur. This combination is not associated with a poorer
induction of germinal-center-associated functions, as it is expressed in prognosis but increases the risk of late relapse. CNS dissemination
germinal center B cells but not in plasma cells. Therefore, downregula- occurs more frequently in patients with multiple extranodal sites of
tion of BCL6 may be necessary for terminal differentiation of B cells to disease, particular testicular, paranasal sinus or marrow involvement
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memory B cells and plasma cells. 12 and in patients with marked elevations of serum lactic dehydrogenase
Approximately 30 percent of DLBCLs possess a t(14;18) translo- (LDH). Patients at high risk for CNS involvement should undergo an
cation involving the Ig heavy-chain gene and BCL2. Such BCL2 gene examination of spinal fluid by flow cytometry for clonal B cells, which
rearrangements occur in DLBCL in either of two circumstances: (1) is the most sensitive method for detection of CNS disease. Patients with
in DLBCLs arising by histologic transformation of a previous fol- involvement of Waldeyer ring have an increased risk of gastrointestinal
licular lymphoma or (2) in de novo DLBCLs with a germinal center lymphoma.

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