Diagnostic Algorithm of Common Mature B-Cell
Lymphomas by Immunohistochemistry
Huan-You Wang, MD, PhD; Youli Zu, MD, PhD
 Context.—Different types of mature B-cell lymphomas,
including plasma cell neoplasms, exhibit distinct immuno-
histochemical profiles, which enable them to be correctly
diagnosed. However, except for rare examples of lympho-
ma-specific immunohistochemistry, such as cyclin D1 in
mantle cell lymphoma and annexin A1 in hairy cell
leukemia, immunohistochemical profiles of mature B-cell
lymphomas overlap and lack specificity.
Objectives.—To systemically review immunohistochem-
ical features associated with commonly encountered
mature B-cell lymphomas based on the presence or
absence of CD5 and CD10; to review the immunopheno-
typic profile of plasma cells derived from plasma cell
myelomas and B-cell lymphomas; and to review a group of
rare, aggressive B-cell lymphomas with antigen expression
features of plasma cells.
Data Sources.—Published and PubMed-indexed English
literature was reviewed.
I mmunophenotyping with immunohistochemistry (IHC)
remains an essential diagnostic tool for mature lympho-
mas, in combination with cytogenetics, molecular genomics,
and clinical, radiologic, and other laboratory tests. As a
technique, IHC is relatively easy to perform and is readily
available in diagnostic laboratories compared with flow
cytometry (FC), genetics, and molecular studies. Although
FC is fast and requires less material, IHC is advantageous
because the immunohistochemical profiles and cytomor-
phologic features can be evaluated simultaneously.
Non-Hodgkin lymphomas can be classified into B-cell, T-
cell, and natural killer–cell lymphomas according to lineage
assignment, immaturity/maturity, genetics, immunopheno-
type, cell size, growth pattern, and clinical features. In this
Accepted for publication December 1, 2016.
Published as an Early Online Release June 13, 2017.
From the Department of Pathology, University of California San
Diego Health System, La Jolla, California (Dr Wang); and the
Department of Pathology and Genomic Medicine, Houston Meth-
odist Hospital, Houston, Texas (Dr Zu).
The authors have no relevant financial interest in the products or
companies described in this article.
Presented in part at the First Chinese American Pathologists
Association (CAPA) Diagnostic Pathology Course: Best Practices in
Immunohistochemistry in Surgical Pathology and Cytopathology;
August 22–24, 2015; Flushing, New York.
Reprints: Huan-You Wang, MD, PhD, Department of Pathology,
University of California San Diego Health System, 3855 Health
Sciences Dr, La Jolla, CA 92093-0987 (email: huw003@ucsd.edu).
1236 Arch Pathol Lab Med—Vol 141, September 2017
Conclusions.—Although the presence or absence of CD5
and CD10 expression should be included in the initial
immunohistochemistry screening panel for mature B-cell
lymphomas, appropriate and judicial use of other B-cell
antigens is necessary to ensure correct diagnoses. Further-
more, although the status of CD5 and CD10 expression is
associated with certain prototypes of B-cell lymphomas, their
expression is not specific. Plasma cells from plasma cell
neoplasias and B-cell lymphomas exhibit overlapping but
relatively distinct immunophenotypes; thus, a panel of
immunohistochemical markers (CD19, CD45, CD56, and
CD117) can be employed for their proper identification.
Lastly, CD138 staining results are almost always positive in a
group of aggressive B-cell lymphomas with plasmablastic
features, including plasmablastic plasma cell myeloma,
plasmablastic lymphoma, and ALK-1þ large B-cell lymphoma.
(Arch Pathol Lab Med. 2017;141:1236–1246; doi:
10.5858/arpa.2016-0521-RA)
review, we focus on the utility of IHC in diagnosing mature
B-cell lymphomas only.
CD5þ/CD10 B-CELL LYMPHOMA
The classic prototypes of CD5þ/CD10 B-cell lymphomas
are small lymphocytic lymphoma (SLL) and mantle cell
lymphoma (MCL). Small lymphocytic lymphoma and
chronic lymphocytic leukemia (CLL) are 2 different presen-
tations of the same disease. According to the International
Workshop on Chronic Lymphocytic Leukemia, the diag-
nostic criteria for SLL are lymphadenopathy, absence of
cytopenia because of bone marrow infiltration by CLL/SLL,
and fewer than 5 3 109/L peripheral blood B cells.1
Although CLL is the most common leukemia affecting
adults in Western countries,2 according to a recent study,
CLL/SLL is the second most frequent B-cell malignancy,
accounting for 18.6% of non-Hodgkin lymphomas in the
United States.3 According to published data, 80% to 92% of
CLLs stain positive for CD5,4,5 but the exact percentage of
SLL that is positive for CD5 is not known. Apart from CD5,
SLL is typically positive for other B-cell antigens, such as
CD19, CD20, CD22, CD23, CD79a, PAX5, and surface light-
chain immunoglobulins. In addition, SLL is negative for
CD10, CD81, and FMC-7, and negative to dimly positive for
CD79b. Notably, compared with other non-CLL/SLLs, SLL/
CLL is often dimly positive for B antigens, which are helpful
in distinguishing CLL/SLLs from other CD5þ non-CLL/
SLLs. In addition, the CD23þ/FMC-7 sets CLL/SLL apart
from MCL in most, but not all, cases.
B-Cell Lymphomas by Immunohistochemistry—Wang & Zu

Figure 1. Mantle cell lymphoma (MCL) in situ and SOX11 expression.
A, A case of MCL in situ in which cyclin D1þ cells are limited in the
mantle zone without thickening. B and C, A Case of MCL with nuclear
staining of SOX11 (panels B and C are courtesy of Yi-Hua Chen, MD,
Department of Pathology, Northwestern University, Chicago, Illinois
(original magnifications 340 [A] and 3200 [B and C]).
Similar to SLL/CLL, most (93%–95%) of MCLs are
positive for the antigen CD5.6,7 Besides CD5, MCL expresses
all other B-cell antigens, including CD19, CD20, CD22,
CD79a, CD79b, FMC-7, and PAX5. Mantle cell lymphoma is
usually, but not always, negative for BCL6, CD10 (see
below), and CD23. Almost all MCLs, including rare CD5
ones, are positive for cyclin D1, also known as BCL1,
Arch Pathol Lab Med—Vol 141, September 2017
CCND1, or PRAD1.8,9 Cyclin D1 is a member of the cyclin D
protein family.10 B cells from the mantle zone are negative
for cyclin D1. Thus, MCL in situ is usually an incidental
finding, and cyclin D1 IHC is required to recognize such rare
cases (Figure 1, A).11,12
Cyclin D1þ MCL is easily diagnosed, regardless of CD5
immunoreactivity. However, diagnosis of cyclin D1 MCL is
challenging. Several studies have shown that SOX11,13,14
cyclin D2, and/or cyclin D315,16 are positive in these cases.
Importantly, neither cyclin D2 nor cyclin D3 is specific for
MCL,17 but nuclear expression of SOX11 is a specific marker
associated with MCL, according to Chen et al18 (Figure 1, B
and C).
Lymphoplasmacytic lymphoma (LPL) is a rare type of
non-Hodgkin lymphoma usually involving bone marrow,
and less frequently, the lymph nodes and spleen. Although,
in LPL, CD5 expression is anecdotal by IHC,19 positive
expression of CD5 on the monotypic B cells ranges from 9%
to 43% based on FC studies.20,21
Marginal zone B-cell lymphoma (MZBCL) has 3 mor-
phologic types based on the sites involved, namely, nodal,
splenic, and extranodal MZBCL of mucosa-associated
lymphoid tissue (MALT lymphoma). In contrast to the
higher rates of nodal MZBCLs expressing CD5 (8.6%),22 less
than 1% of MALT lymphomas are positive for CD5.23
Splenic MZBCLs exhibit positive CD5 expression in about
20% of the cases.24,25 CD5þ splenic MZBCL is closely related
to its classic CD5 counterpart, except for higher lymphocyte
counts at diagnosis and more-diffuse bone marrow infiltra-
tion.26
From the 2 types of diffuse large B-cell lymphomas
(DLBCLs) expressing CD5, namely, de novo and trans-
formed/secondary DLBCLs, only CD5þ de novo DLBCL, not
otherwise specified (NOS), is reviewed in detail here.
Approximately 10% of DLBCLs NOS are CD5þ de novo
DLBCLs (Figure 2, A through D).27 These lymphomas have
higher rates of BCL2 expression (Figure 2, E) and recurrence
in the central nervous system and are more likely to exhibit
a nongerminal center B-cell phenotype28,29 (Figure 2, F
through H). Although there is no cytomorphologic differ-
ence between CD5þ and CD5 DLBCL NOS, cyclin D2 has
been reported to be highly specific for de novo CD5þ
DLBCL.30 For practical diagnostics, the pleomorphic variant
of MCL and the DLBCL variant of the Richter transforma-
tion from CLL/SLL should be ruled out in CD5þ B-cell
lymphomas with medium to large cell sizes. The CD5þ/
CD10 B-cell lymphomas are summarized in Table 1.
CD10þ/CD5 B-CELL LYMPHOMA
Follicular lymphoma (FL) and Burkitt lymphoma (BL) are
the 2 prototypical B-cell lymphomas expressing CD10. In
FL, the extent of CD10 expression varies by grade, even
within the same tumor. For example, CD10 is expressed in
80% of grade 1 versus 17% of grade 3 FLs.31 In addition,
CD10 expression is greater in neoplastic cells from
intrafollicular than from interfollicular regions.32 CD10 is
typically negative in FLs with marginal zone differentiation
(Figure 3, A through F).32 In addition to CD10, BCL2, an
antiapoptotic protein, is useful in differentiating FL from
reactive follicular hyperplasia, but expression of BCL2
depends on grade and location. For instance, although
85% to 90% of low-grade (grades 1 and 2) FLs express
BCL2, only 50% of grade 3 FLs are positive for BCL2.33
However, FLs testing negative for BCL2, based on standard
B-Cell Lymphomas by Immunohistochemistry—Wang & Zu 1237
Figure 2. CD5þ de novo diffuse large B-cell lymphoma, not otherwise specified with nongerminal center phenotype. A, Centroblast-like, atypical
lymphoid cells with frequent mitosis and scattered apoptotic bodies. B through E, Atypical lymphoid cells are positive for CD20 (B) and negative for
CD3 (C) but have an aberrant expression of CD5 (D) and BCL2 (E). F through H, The atypical cells are positive for BCL6 (F) and MUM1 (G) but
negative for CD10 (H) and BCL1 (data not shown) (hematoxylin-eosin, original magnification 3200 [A]; original magnification 3200 [B through H]).

1238 Arch Pathol Lab Med—Vol 141, September 2017 B-Cell Lymphomas by Immunohistochemistry—Wang & Zu
 Table 1. Expression Pattern and Frequency of CD5 and CD10 in Common, Mature B-Cell Lymphomas
Approximate %
Immunophenotype Type of Mature B-Cell Lymphoma
þ 
CD5 /CD10 MCL
SLL/CLL
LPL
MZBCL
Splenic MZBCL
Nodal MZBCL
MALT lymphoma
De novo DLBCL NOS
CD10þ/CD5 BL
FL (low grade)
DLBCL, NOS
HCL
FL (grade 3)
MCL
CD5/CD10 MZBCL
MALT lymphoma
Nodal MZBCL
Splenic MZBCL
LPL
HCL
DLBCL, NOS
FL (grade 3)
FL (low grade)
SLL/CLL
Abbreviations: BL, Burkitt lymphoma; CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; HCL,
hairy cell leukemia; LPL, lymphoplasmacytic lymphoma; MALT, mucosa-associated lymphoid tissue; MCL, mantle cell lymphoma; MZBCL,
marginal zone B-cell lymphoma; NOS, not otherwise specified; SLL, small lymphocytic lymphoma.
antibodies for residues 41 to 54, can test positive for BCL2
when different antibodies are used.34 Primary cutaneous
follicle center lymphoma is typically negative for BCL2.35
In our opinion, a minimal IHC panel for FL should include
BCL2, CD3, CD10, and CD20; however, ideally, BCL6, CD5,
and CD21 should be included as well. Recently, new
germinal center (GC)-associated markers, such as GCET1,
HGAL, and LMO2, have been introduced. Among these 3
markers, GCET1 shows the highest specificity for FL (60%
of cases). Both HGAL and LMO2 lack specificity for FL,
although they show stronger staining in FL compared with
other types of mature B-cell lymphomas.36
The classic immunohistochemical profile of BL is positive
for BCL6, CD10, and other B-cell antigens without
expression of BCL2,37–40 although BL with positive BCL2
staining can still be diagnosed if other characteristic features
of BL are present. Expression of CD38 and B-cell antigens,
including CD20, CD79a, and CD79b, is generally strong in
BL. In addition, Ki-67 and the Epstein-Barr virus (EBV) are
helpful in their diagnosis as well. Ki-67 usually has a 100%
proliferation index in BL. Epstein-Barr virus is typically
positive in endemic BL but is only 20% to 30% positive in
sporadic BL.41 In recent years, c-Myc IHC is more
commonly used in routine diagnosis. Burkitt lymphoma
has the highest level of immunoreactivity (60%) for c-Myc
among aggressive B-cell lymphomas.42
Hairy cell leukemia (HCL) and MCL can occasionally be
positive for CD10. CD10 expression can be detected by FC
in approximately 10% to 20% of HCL cases.43,44 A similar
percentage is expected for IHC (Figure 4, A and B), although
such studies have not, to our knowledge, been reported.
However, none of the 127 MCLs studied by Gualco et al7
were found to have CD10 expression in 30% or more of the
neoplastic cells. Akhter et al45 reported CD10 expression in
Arch Pathol Lab Med—Vol 141, September 2017
Staining Source, y
93–95 Dorfman and Shahsafaei,6 1997; Gualco et al,7 2010
80–92 Kurec et al,4 1992; Geiler et al,5 1991
9–43 Hunter et al,20 2005; Morice et al,21 2009
20 Gimeno et al,24 2005; Matutes et al,25 2008
8.6 Jaso et al,22 2013
1 Jaso et al,23 2012
10 Tagawa et al,27 2005
100 Dogan et al,37 2000
80 Eshoa et al,31 2001
10–40 Colomo et al,46 2003; Berglund et al,47 2005; Visco
et al,48 2012
10–20 Jasionowski et al,43 2003; Gupta et al,44 2015
17 Eshoa et al,31 2001
0–7 Akhter et al,45 2015
.99 Jaso et al,23 2012
92 Jasoco et al,22 2013
80 Gimeno et al,24 2005; Matutes et al,25 2008
57–91 Hunter et al,20 2005; Morice et al,21 2009
80–90 Jasionowski et al,43 2003; Gupta et al,44 2015
50–70 Tagawa et al,27 2005; Colomo et al,46 2003;
Berglund et al,47 2005; Visco et al,48 2012
83 Eshoa et al,31 2001
20 Eshoa et al,31 2001
8–20 Kurec et al,4 1992; Geiler et al,5 1991
approximately 7% of MCLs using the same cutoff (30%)
(Figure 5, A through C). According to the authors, the
molecular basis of positive CD10 expression in MCL is
related to a distinct GC signature rather than an immuno-
phenotypical aberrancy, but there were no significant
clinical or pathologic differences between CD10þ and
CD10 MCLs in their cohort.45
Despite recent advances, DLBCLs NOS remain a group of
aggressive, mature B-cell lymphomas with heterogeneous
clinical, morphologic, immunophenotypic, genetic, and
prognostic features. Although approximately 90% of
DLBCLs NOS are negative for CD5,27 10% to 40% of de
novo DLBCLs NOS are positive for CD10.46–48 Assessing
CD10 expression in DLBCLs NOS by IHC has dual benefits.
First, positive expression of CD10 in DLBCLs NOS should
alert the pathologist to exclude a secondary DLBCL
transformed from an underlying FL. Secondly, in the
absence of transformation, positive CD10 makes DLBCL a
de novo CD10þ DLBCL.
Positive CD10 expression in more than 30% of neoplastic
cells classifies a patient with DLBCL as having a GC
phenotype,32 which has a better overall survival rate than
that of patients with non-GC phenotype.49 CD10þ/CD5
mature B-cell lymphomas are summarized in Table 1.
CD5/CD10 MATURE B-CELL LYMPHOMAS
The prototypic CD5/CD10 mature B-cell lymphomas of
small cell size are MZBCL, LPL, and HCL. Most DLBCLs
NOS are also negative for both CD5 and CD10. In this
section, we focus on MALT lymphoma because it is the
most common form of MZBCL. Apart from all the B-cell–
associated antigens expressed by neoplastic cells from
MALT lymphoma, we have found that the addition of
CD43 and j and k light chains to the panel of IHC is often
B-Cell Lymphomas by Immunohistochemistry—Wang & Zu 1239
Figure 3. Follicular lymphoma with loss of CD10 expression in areas with marginal zone differentiation. A and B, Hematoxylin-eosin shows
numerous secondary, neoplastic follicles with marginal zone differentiation at the periphery of each follicle. C through E, Neoplastic cells within
follicles are diffusely positive for CD20 (C) and BCL2 (D), but only follicular lymphoma cells without marginal zone differentiation (at the center)
express CD10 (E). F, CD3 highlights T cells in the interfollicular regions (original magnifications 320 [A] and 3100 [B through E]).

useful in diagnosing B-cell malignancies including MALT
lymphoma. This addition is particularly important for cases
with scant amounts of diagnostic materials, such as those
from core needle biopsies or those associated with
1240 Arch Pathol Lab Med—Vol 141, September 2017
plasmacytic differentiation. Positive CD43 expression can
be detected in 20% to 40% of MALT lymphomas.50 Aberrant
coexpression of CD43 by neoplastic B cells in MALT
lymphoma can be site/location dependent. For example,
B-Cell Lymphomas by Immunohistochemistry—Wang & Zu
Figure 4. CD10þ hairy cell leukemia. A, The bone marrow shows
interstitial infiltrates by small to medium lymphoid cells, with irregular
nuclear contours and condensed nuclear chromatin. B, The lymphoid
cells are positive for CD10 (hematoxylin-eosin, original magnification
3200 [A]; original magnification 3100 [B]).

Arends et al51 found that CD43 was not helpful in

discriminating gastric MALT lymphoma from chronic
gastritis. Normal B cells from the terminal ileum, especially
Peyer patches, are positive for CD43.52 CD21 and another
dendritic cell antigen, CD35, but not CD23, can aid in the
diagnosis of MALT lymphoma in 2 ways. First, MALT
lymphoma cells usually express CD21.53 Second, the
characteristics of follicular dendritic meshwork, including
size, contour, uniformity, and density, serve as additional
indicators of MALT lymphoma.54 Sometimes MZBCL and
Figure 5. CD10þ mantle cell lymphoma (MCL). A, The MCL shows
SLL/CLL can exhibit plasmacytic differentiation. Plasma- mantle zone and diffuse growth pattern. B and C, The MCL cells are
cytic differentiation is detected in approximately 33% of positive for BCL1 (B) and weakly and partially positive for CD10 (C)
MALT lymphomas (Figure 6, A through F).55 This feature (CD10, original magnification 3100 [A and C]; original magnification
not only assists in making the correct diagnosis but also 3100 [B]).
helps in monitoring the disease status after treatment.
In contrast to MZBCL, LPL always contains a component
of monotypic plasma cells (PCs), as the name indicates. nophenotypic features; in those cases, a positive MYD88
Although MZBCL and LPL share many overlapping immu- L265P somatic mutation found in most LPLs can be
nophenotypic features, the immunoglobulin heavy chain employed.56 Notably, as demonstrated by FC, the monotypic
expressed by monotypic PCs from LPL is nearly always PCs derived from B-cell lymphoma have a similar immuno-
immunoglobulin (Ig) M, in contrast to the typical IgM phenotype to B cells and differ from those of PC myeloma.57
expressed in MZBCL. Lymphoplasmacytic lymphoma is Hairy cell leukemia is positive for all common B-cell
diagnosed by exclusion, and at times, MZBCL and LPL antigens (CD19, CD20, CD79a, FMC-7, and PAX5), with
cannot be distinguished based on morphologic and immu- characteristic expression of annexin A1 (Figure 7, A), CD11c,
Arch Pathol Lab Med—Vol 141, September 2017 B-Cell Lymphomas by Immunohistochemistry—Wang & Zu 1241
Figure 6. Extranodal marginal zone B-cell lymphoma (MZBCL) with concomitant, monotypic plasmacytic differentiation. A, This extranodal MZBCL
has a focal area of monocytoid differentiation (upper left) and plasmacytic differentiation (lower right corner). B through D, The plasma cells are
positive for CD138 (B) and dimly positive for CD19 (C) but negative for CD20 (D). E and F, These plasma cells are positive for j (E) but negative for k
(F) light chains (hematoxylin-eosin, original magnification 3100 [A]; original magnification 3200 [B through F]).

CD25, CD103, CD123, DBA-44 (CD72) (Figure 7, B), the
Hector Battifora mesothelial epitope-1 (HBME-1), pERK, T-
bet, and TRAP58–61 but is typically negative for CD5 and
CD10, although 10% to 20% of HCLs are positive for
1242 Arch Pathol Lab Med—Vol 141, September 2017
CD10.43,45 With the exception of annexin A1, which is a
specific marker for HCL,58 the previously so-called HCL
markers, including CD11c, CD103, DBA-44, and HBME-1,
are not specific for HCL. They can be found in splenic,
B-Cell Lymphomas by Immunohistochemistry—Wang & Zu

Figure 7. Expression of annexin A1, DBA-44, and BCL1 by hairy cell
leukemia (HCL). This HCL is the same case shown in Figure 4. A through C,
The atypical lymphoid cells are positive for annexin A1 (partial) (A), DBA-
44 (B), and BCL1 (partial) (C) (original magnification 3400 [A]; original
magnification 3200 [B]; original magnification 3200 [C]).
diffuse red pulp small B-cell lymphoma and the HCL
variant.60–62 Although annexin A1 is specific for HCL,58 its
expression in normal hematopoietic cells, especially in
neutrophils, makes it unsuitable for detection of minimal,
residual HCL, but T-bet was reported to be useful in those
cases.63 Weak cyclin D1 staining can be observed in most
HCLs (Figure 7, C), but there is no rearrangement of the
cyclin D1 gene at 11q13 locus.64
Arch Pathol Lab Med—Vol 141, September 2017
After excluding CD5þ27 and/or CD10þ46–48 DLBCL NOS,
approximately 50% to 70% of de novo DLBCLs NOS are
negative for both CD5 and CD10. Similar to other mature B-
cell lymphomas, DLBCL NOS is positive for B-cell–specific
and the associated antigens with varying frequencies.65 As
mentioned, apart from CD10, 2 additional antigens, BCL6
and MUM1, are included in the designation of GC versus
non-GC phenotypes of DLBCL in the Hans29 algorithm
with approximately 80% concordance with gene expression
profiling. By adding GCET1 and FOXP1, Choi et al66
increased the concordance of immunohistochemical classi-
fication of GC versus non-GC to 93%, as compared with
gene expression profiling.
Other rare CD5 and CD10 mature B-cell lymphomas are
CD5 MCLs and CD10 FLs. The CD5 MCLs are very rare
and account for only approximately 5% to 7% of MCLs.6,7
Cytologically, CD5 MCLs tend to display a marginal zone
or the so-called monocytoid differentiation.67,68 CD10 FL
was discussed previously. The CD5/CD10 mature B-cell
lymphomas are summarized in Table 1.
PC NEOPLASMS
Plasma cell neoplasms encompass plasmacytoma, plas-
ma cell myeloma (PCM), monoclonal gammopathy of
undetermined significance, and monoclonal immunoglob-
ulin deposition diseases; the first 2 are reviewed here.
Apart from CD38 and CD138, neoplastic PCs derived from
PCM exhibit a different immunophenotype from PCs
derived from B-cell lymphomas, according to Seegmiller
et al.57 Among all the antigens studied with FC, CD19
provided the best criterion for distinguishing between
these 2 types of neoplastic PCs. In particular, neoplastic
PCs from B-cell lymphomas are positive for CD19 and are
almost always negative in neoplastic PCs from PCM.69 In
fact, less than 1% of PCM cases were positive for CD19.69
According to the authors,57,69 expression of CD20, CD45,
and CD56 was detected in 9.3% to 27%, 8.8% to 41%, and
71.7% of neoplastic PCs from PCM, respectively, as
compared with 32%, 91%, and 33%, respectively, in PCs
from B-cell lymphomas.57 The frequency of CD117
expression in PCs from PCMs detected with FC correlated
perfectly with IHC according to Pruneri et al,70 who
reported 28.2% immunoreactivity of CD117 among PCMs.
CD117 is very rarely expressed in B-cell lymphomas.71
Cyclin D1, a hallmark for MCL, is expressed in 30% to 35%
of PCMs and in 0% to 17% of plasmacytomas.9,72,73 As
summarized in Table 2, the combination of BCL1, CD19,
CD45, CD56, and CD117 is sufficient to distinguish PCs
derived from PCMs and/or plasmacytomas from B-cell
lymphomas, even in cases in which there is exuberant
plasmacytic differentiation.74
A recent report suggested that IgA-expressing nodal and
extranodal plasmacytoma may represent a distinct form of
extramedullary plasmacytoma characterized by young age,
frequent nodal involvement, and low risk of progression to
PCM.75 Plasmablastic PCM shares similar immunohisto-
chemical profiles with PCM, which are described below.
AGGRESSIVE B-CELL LYMPHOMA WITH
IMMUNOPHENOTYPIC OR MORPHOLOGIC FEATURES
OF PLASMABLASTS
B-cell lymphomas in this category include plasmablastic
PCM; plasmablastic lymphoma (PBL); primary effusion
lymphoma (PEL), including the extracavitary variant; large
B-Cell Lymphomas by Immunohistochemistry—Wang & Zu 1243
 Table 2. Immunohistochemical Characteristics of ‘‘Plasma Cells’’ From B-Cell Lymphomas and Plasma Cell Myelomas
(PCMs)
BCL1 CD19
P/N staining P/N staining
(% staining) Source, y (% staining) Source, y
B-cell lymphomas N (except in MCL and HCL) P (~95) Molina et al,55 2011
PCMs P (30–35) Pruneri et al,70 2006; (,1) Seegmiller et al,57 2007
Bravo et al,71 2000

Abbreviations: ~, approximately; HCL, hairy cell leukemia; MCL, mantle cell lymphoma; N, negative; P, positive.

B-cell lymphoma arising in HHV8-associated multicentric
Castleman disease, and ALKþ large B-cell lymphoma.76 The
antigens CD38, CD138, and MUM1 are positive in all cases
of plasmablastic PCM, PBL, and PEL.77–79 However,
plasmablastic PCM and PBL cannot be separated from each
other based on an IHC panel that includes CD45, CD79a,
CD56, and PAX5, according to Vega et al77; however, EBV
was found to be 100% positive in 9 cases of PBL but
negative in 7 cases of plasmablastic PCM. In our opinion,
CD19 should be included in this panel, which may aid in
distinguishing these 2 lymphomas.
An extensive, large-scale immunohistochemical charac-
terization of PEL has not, to our knowledge, been
reported in the literature because PEL typically presents
as body cavity effusions, rather than tissue masses, except
for extracavitary PEL. The FC studies we conducted
showed that CD38, CD71, and CD30 were positive in
100% of PELs.78 Although PEL, including its solitary
variant and large B-cell lymphoma arising in HHV8-
associated multicentric Castleman disease, are both
positive for HHV8, the latter is typically negative for
CD138 and EBV,80 which distinguishes this type of
aggressive B-cell lymphoma from traditional PBL. ALKþ
large B-cell lymphoma is a rare, aggressive B-cell
lymphoma, which can be difficult to diagnose, and is
typically negative for most of the common B-cell antigens
but positive for PC markers such as CD138, VS38, EMA,
and MUM1.81,82 The immunophenotypic features of
plasmablastic PCM, PBL, PEL, and ALKþ large B-cell
lymphoma are summarized in Table 3.

Table 3. Immunophenotypic (Immunohistochemistry [IHC] and Flow Cytometry [FC]) Comparison Between
Plasmablastic Plasma Cell Myeloma (PCM), Plasmablastic Lymphoma (PBL), Primary Effusion Lymphoma (PEL),
and Anaplastic Lymphoma Kinase 1 (ALK1þ) Large B-Cell Lymphoma (LBCL)
Plasmablastic PCM (IHC), n/N (%)a PBL (IHC), n/N (%)b PEL (FC), n/N (%)c ALK1þ LBCL (IHC), n/N (%)d
CD38 7/7 (100) 9/9 (100) 12/12 (100) ND
CD138 7/7 (100) 19/19 (100) ND 56/57 (98)
MUM1 7/7 (100) 8/8 (100) ND 14/14 (100)
cK or cL restriction 6/7 (86) 7/21 (33) 3/6 (50) 43/72 (60)
BCL2 4/7 (57) 3/8 (38) ND ND
CD56 3/7 (43) 5/9 (56) ND ND
CD45 2/6 (33) 16/21 (76) 12/12 (100) 38/45 (84)
CD10 2/7 (29) 6/9 (67) ND ND
CD4 1/5 (20) 2/5 (40) 2/12 (17) 22/34 (65)
CD117 1/7 (14) 0 (0/4) ND ND
ALK1 ND ND ND 30/30 (100)
Bob1 ND ND ND 16/16 (100)
BCL6 0/7 (0) 1/16 (6.3) ND ND
CD19 ND ND 0/12 (0) ND
CD20 0/7 (0) 0/21 (0) 2/12 (17) 1/56 (1.8)
CD30 0/5 (0) 0/7 (0) 10/12 (83) 3/55 (5.5)
CD45RO ND ND 7/8 (88) ND
CD71 ND ND 12/12 (100) ND
CD79a 0/2 (0) 1/6 (17) ND 12/54 (22)
EMA ND ND ND 47/53 (89)
HLA-DR ND ND 6/8 (75) ND
OCT2 ND ND ND 13/16 (81)
PAX5 0/6 (0) 2/18 (11) ND 5/18 (2.8)
EBV (ISH) 0/7 (0) 17/17 (100) 5/9 (56) 0/18 (0)
HHV8 0/6 (0) 1/5 (20)e 10/10 (100) ND
Ki-67 (79) (87) ND NK
Abbreviations: cK, cytoplasmic kappa; cL, cytoplasmic lambda; EBV, Epstein-Barr virus; EMA, epithelial membrane antigen; HHV8, human
herpesvirus 8; ISH, in situ hybridization; ND, not done; NK, not known.
a
Source: Vega et al,77 2005.
b
Source: Vega et al,77 2005; and Dong et al,79 2005.
c
Source: Wang et al,78 2010.
d
Source: Reichard et al,81 2007; and Pan et al,82 2016.
e
Cited article (Vega et al,77 2005) was published in 2005 when HHV8 positivity was acceptable in PBL.
1244 Arch Pathol Lab Med—Vol 141, September 2017 B-Cell Lymphomas by Immunohistochemistry—Wang & Zu
 Table 2. Extended
CD45
P/N staining P/N staining
(% staining) Source, y (% staining)
55
P (~91) Molina et al, 2011 P (~33)
P (8.8–41) Molina et al,55 2011; P (71.7)
Seegmiller et al,57
2007
We thank Helen Chifotides, PhD, for her secretarial assistance.
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