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Diagnostic Algorithm of Common Mature B-Cell Lymphomas by Immunohistochemistry.

Immunophenotyping with immunohistochemistry (IHC) remains an essential diagnostic tool for mature lymphomas, 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 cytomorphologic features can be evaluated simultaneously.

Non-Hodgkin lymphomas can be classified into B-cell, Tcell, and natural killer-cell lymphomas according to lineage assignment, immaturity/maturity, genetics, immunophenotype, cell size, growth pattern, and clinical features. In this review, we focus on the utility of IHC in diagnosing mature B-cell lymphomas only.

[CD5.sup.+]/[CD10.sup.-] B-CELL LYMPHOMA

The classic prototypes of [CD5.sup.+]/[CD10.sup.-] B-cell lymphomas are small lymphocytic lymphoma (SLL) and mantle cell lymphoma (MCL). Small lymphocytic lymphoma and chronic lymphocytic leukemia (CLL) are 2 different presentations of the same disease. According to the International Workshop on Chronic Lymphocytic Leukemia, the diagnostic criteria for SLL are lymphadenopathy, absence of cytopenia because of bone marrow infiltration by CLL/SLL, and fewer than 5 X [10.sup.9]/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 [CD5.sup.+] non-CLL/ SLLs. In addition, the [CD23.sup.+]/[FMC-7.sup.-] sets CLL/SLL apart from MCL in most, but not all, cases.

Note: Illustration(s) are not available due to copyright restrictions.

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.sup.-] ones, are positive for cyclin D1, also known as BCL1, 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 D1IHC is required to recognize such rare cases (Figure 1, A). (11, 12)

Cyclin [D1.sup.+] MCL is easily diagnosed, regardless of CD5 immunoreactivity. However, diagnosis of cyclin [D1.sup.-] MCL is challenging. Several studies have shown that SOX11, (13, 14) cyclin D2, and/or cyclin D3 (15, 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 al (18) (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 morphologic 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) [CD5.sup.+] splenic MZBCL is closely related to its classic [CD5.sup.-] counterpart, except for higher lymphocyte counts at diagnosis and more-diffuse bone marrow infiltration. (26)

From the 2 types of diffuse large B-cell lymphomas (DLBCLs) expressing CD5, namely, de novo and transformed/secondary DLBCLs, only [CD5.sup.+] de novo DLBCL, not otherwise specified (NOS), is reviewed in detail here. Approximately 10% of DLBCLs NOS are [CD5.sup.+] 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 phenotype (28, 29) (Figure 2, F through H). Although there is no cytomorphologic difference between [CD5.sup.+] and [CD5.sup.-] DLBCL NOS, cyclin D2 has been reported to be highly specific for de novo [CD5.sup.+] DLBCL. (30) For practical diagnostics, the pleomorphic variant of MCL and the DLBCL variant of the Richter transformation from CLL/SLL should be ruled out in [CD5.sup.+] B-cell lymphomas with medium to large cell sizes. The [CD5.sup.+]/ [CD10.sup.-] B-cell lymphomas are summarized in Table 1.

[CD10.sup.+]/[CD5.sup.-] 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 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)

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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 al (7) were found to have CD10 expression in 30% or more of the neoplastic cells. Akhter et al (45) reported CD10 expression in 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 immunophenotypical aberrancy, but there were no significant clinical or pathologic differences between [CD10.sup.+] 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 [CD10.sup.+] 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) [CD10.sup.+]/[CD5.sup.-] mature B-cell lymphomas are summarized in Table 1.

[CD5.sup.-]/[CD10.sup.-] MATURE B-CELL LYMPHOMAS

The prototypic [CD5.sup.-]/[CD10.sup.-] 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 [kappa] and [lambda] light chains to the panel of IHC is often 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 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, Arends et al (51) 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 SLL/CLL can exhibit plasmacytic differentiation. Plasmacytic differentiation is detected in approximately 33% of MALT lymphomas (Figure 6, A through F). (55) This feature not only assists in making the correct diagnosis but also helps in monitoring the disease status after treatment.

Note: Illustration(s) are not available due to copyright restrictions.

In contrast to MZBCL, LPL always contains a component of monotypic plasma cells (PCs), as the name indicates. Although MZBCL and LPL share many overlapping immunophenotypic features, the immunoglobulin heavy chain expressed by monotypic PCs from LPL is nearly always immunoglobulin (Ig) M, in contrast to the typical IgM expressed in MZBCL. Lymphoplasmacytic lymphoma is diagnosed by exclusion, and at times, MZBCL and LPL cannot be distinguished based on morphologic and immu nophenotypic features; in those cases, a positive MYD88 L265P somatic mutation found in most LPLs can be employed. (56) Notably, as demonstrated by FC, the monotypic PCs derived from B-cell lymphoma have a similar immunophenotype to B cells and differ from those of PC myeloma. (57) Hairy cell leukemia is positive for all common B-cell antigens (CD19, CD20, CD79a, FMC-7, and PAX5), with characteristic expression of annexin A1 (Figure 7, A), CD11c, CD25, CD103, CD123, DBA-44 (CD72) (Figure 7, B), the Hector Battifora mesothelial epitope-1 (HBME-1), pERK, Tbet, and TRAP58-61 but is typically negative for CD5 and CD10, although 10% to 20% of HCLs are positive for 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, 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)

After excluding [CD5.sup.+] (27) and/or [CD10.sup.+] (46-48) DLBCL NOS, approximately 50% to 70% of de novo DLBCLs NOS are negative for both CD5 and CD10. Similar to other mature Bcell 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 Hans (29) algorithm with approximately 80% concordance with gene expression profiling. By adding GCET1 and FOXP1, Choi et al (66) increased the concordance of immunohistochemical classification of GC versus non-GC to 93%, as compared with gene expression profiling.

Other rare [CD5.sup.-] and [CD10.sup.-] mature B-cell lymphomas are [CD5.sup.-] MCLs and [CD10.sup.-] FLs. The [CD5.sup.-] MCLs are very rare and account for only approximately 5% to 7% of MCLs. (6, 7) Cytologically, [CD5.sup.-] MCLs tend to display a marginal zone or the so-called monocytoid differentiation. (67, 68) [CD10.sup.-] FL was discussed previously. The [CD5.sup.-]/[CD10.sup.-] mature B-cell lymphomas are summarized in Table 1.

PC NEOPLASMS

Plasma cell neoplasms encompass plasmacytoma, plasma cell myeloma (PCM), monoclonal gammopathy of undetermined significance, and monoclonal immunoglobulin 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 immunohistochemical 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 lymphoma arising in HHV8-associated multicentric Castleman disease, and [ALK.sup.+] 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 al (77); 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 characterization 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. [ALK.sup.+] 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 [ALK.sup.+] large B-cell lymphoma are summarized in Table 3.

We thank Helen Chifotides, PhD, for her secretarial assistance.

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Huan-You Wang, MD, PhD; Youli Zu, MD, PhD

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 Methodist 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).

Caption: Figure 1. Mantle cell lymphoma (MCL) in situ and SOX11 expression. A, A case of MCL in situ in which cyclin [D1.sup.+] 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 X40 [A] and X200 [B and C]).

Caption: Figure 2. [CD5.sup.+] 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 X200 [A]; original magnification X200 [B through H]).

Caption: 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 Tcells in the interfollicular regions (original magnifications X20 [A] and X100 [B through E]).

Caption: Figure 4. [CD10.sup.+] 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 X200 [A]; original magnification X100 [B]).

Caption: Figure 5. [CD10.sup.+] mantle cell lymphoma (MCL). A, The MCL shows mantle zone and diffuse growth pattern. B and C, The MCL cells are positive for BCL1 (B) and weakly and partially positive for CD10 (C) (CD10, original magnification X100 [A and C]; original magnification X100 [B]).

Caption: 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 k (E) but negative for k (F) light chains (hematoxylin-eosin, original magnification X100 [A]; original magnification X200 [B through F]).

Caption: 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), DBA44 (B), and BCL1 (partial) (C) (original magnification X400 [A]; original magnification X200 [B]; original magnification X200 [C]).
Table 1. Expression Pattern and Frequency of CD5 and CD10 in
Common, Mature B-Cell Lymphomas

                                        Approximate %
Immunophenotype     Type of Mature        Staining
                    B-Cell Lymphoma

[CD5.sup.+]/      MCL                       93-95
[CD10.sup.-]

                    SLL/CLL                 80-92

                    LPL                     9-43
                    MZBCL

                      Splenic MZBCL          20

                      Nodal MZBCL            8.6
                      MALT lymphoma           1
                    De novo DLBCL NOS        10
[CD10.sup.+]/       BL                       100
[CD5.sup.-]         FL (low grade)           80
                    DLBCL, NOS              10-40

                    HCL                     10-20

                    FL (grade 3)             17
                    MCL                      0-7
[CD5.sup.-]/        MZBCL
[CD10.sup.-]          MALT lymphoma          >99
                      Nodal MZBCL            92
                      Splenic MZBCL          80

                    LPL                     57-91

                    HCL                     80-90

                    DLBCL, NOS              50-70

                    FL (grade 3)             83
                    FL (low grade)           20
                    SLL/CLL                 8-20

Immunophenotype     Type of Mature             Source, y
                    B-Cell Lymphoma

[CD5.sup.+]/      MCL                   Dorfman and
[CD10.sup.-]                              Shahsafaei, (6)
                                          1997;   Gualco et
                                          al, (7) 2010

                    SLL/CLL             Kurec et al, (4)
                                          1992; Geiler et al,
                                          (5) 1991

                    LPL                 Hunter et al, (20)
                    MZBCL                 2005; Morice et al,
                                          (21) 2009

                      Splenic MZBCL     Gimeno et al, (24)
                                          2005; Matutes et al,
                                          (25) 2008

                      Nodal MZBCL       Jaso et al, (22) 2013
                      MALT lymphoma     Jaso et al, (23) 2012
                    De novo DLBCL NOS   Tagawa et al, (27) 2005
[CD10.sup.+]/       BL                  Dogan et al, (37) 2000
[CD5.sup.-]         FL (low grade)      Eshoa et al, (31) 2001
                    DLBCL, NOS          Colomo et al, (46)
                                          2003; Berglund et
                                          al,   (47) 2005;
                                          Visco et al, (48)
                                          2012

                    HCL                 Jasionowski et al,
                                          (43) 2003; Gupta
                                          et al, (44) 2015

                    FL (grade 3)        Eshoa et al, (31)
                    MCL                   2001 Akhter
[CD5.sup.-]/        MZBCL                 (45) 2015
[CD10.sup.-]          MALT lymphoma     Jaso et al, (23) 2012
                      Nodal MZBCL       Jasoco et al, (22) 2013
                      Splenic MZBCL     Gimeno et al, (24)
                                          2005; Matutes et al,
                                          (25) 2008

                    LPL                 Hunter et al, (20)
                                          2005; Morice et al,
                                          (21) 2009

                    HCL                 Jasionowski et al,
                                          (43) 2003; Gupta
                                          et al, (44) 2015

                    DLBCL, NOS          Tagawa et al, (27)
                                          2005; Colomo et al,
                                          (46) 2003; Berglund
                                          et al, (47) 2005;
                                          Visco et al, (48)
                                          2012

                    FL (grade 3)        Eshoa et al, (31) 2001
                    FL (low grade)      Eshoa et al, (31) 2001
                    SLL/CLL             Kurec et al, (4)
                                          1992; Geiler et al,
                                          (5)   1991

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.

Table 2. Immunohistochemical Characteristics of "Plasma Cells"
From B-Cell Lymphomas and Plasma Cell Myelomas (PCMs)

                                    BCL1
                      P/N staining         Source, y
                      (% staining)

B-cell lymphomas    N (except in MCL
                      and HCL)
PCMs                P (30-35)           Pruneri et al,
                                          (70) 2006;
                                            Bravo et al,
                                             (71) 2000

                                CD19
                    P/N staining        Source, y
                    (% staining)

B-cell lymphomas      P (~95)       Molina et al,
                                      (55) 2011
PCMs                    (<1)        Seegmiller et al,

                                      (57) 2007

                                CD45

                    P/N staining    Source, y
                    (% staining)
B-cell lymphomas
                    P (~91)         Molina et al, (55) 2011
PCMs                P (8.8-41)      Molina et al, (55) 2011;
                                      Seegmiller et al, (57)
                                      2007

                                CD56

                    P/N staining    Source, y
                    (% staining)
B-cell lymphomas
                      P (~33)       Molina et al, (55) 2011
PCMs                  P (71.7)      Treon et al, (56) 2012;
                                      Seegmiller et al, (57)
                                      2007

                                CD117

                    P/N staining        Source, y
                    (% staining)
B-cell lymphomas
                    Very rarely    Lin et al, (69) 2004
PCMs                  P (~28)      Mansoor et al, (68)
                                     2007

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

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 ([ALK1.sup.+]) Large B-Cell
Lymphoma (LBCL)

                       Plasmablastic   PBL (IHC),     PEL (FC),
                        PCM (IHC),     n/N (%) (b)   n/N (%) (c)
                        n/N (%) (a)

CD38                     7/7 (100)      9/9 (100)    12/12 (100)
CD138                    7/7 (100)     19/19 (100)       ND
MUM1                     7/7 (100)      8/8 (100)        ND
cK or cL restriction     6/7 (86)       7/21 (33)     3/6 (50)
BCL2                     4/7 (57)       3/8 (38)         ND
CD56                     3/7 (43)       5/9 (56)         ND
CD45                     2/6 (33)      16/21 (76)    12/12 (100)
CD10                     2/7 (29)       6/9 (67)         ND
CD4                      1/5 (20)       2/5 (40)      2/12 (17)
CD117                    1/7 (14)        0 (0/4)         ND
ALK1                        ND             ND            ND
Bob1                        ND             ND            ND
BCL6                      0/7 (0)      1/16 (6.3)        ND
CD19                        ND             ND         0/12 (0)
CD20                      0/7 (0)       0/21 (0)      2/12 (17)
CD30                      0/5 (0)        0/7 (0)     10/12 (83)
CD45RO                      ND             ND         7/8 (88)
CD71                        ND             ND        12/12 (100)
CD79a                     0/2 (0)       1/6 (17)         ND
EMA                         ND             ND            ND
HLA-DR                      ND             ND         6/8 (75)
OCT2                        ND             ND            ND
PAX5                      0/6 (0)       2/18(11)         ND
EBV (ISH)                 0/7 (0)      17/17 (100)    5/9 (56)
HHV8                      0/6 (0)       1/5 (20)e    10/10 (100)
Ki-67                      (79)           (87)           ND

                       [ALK1.sup.+] LBCL
                          (IHC), n/N
                            (%) (d)

CD38                          ND
CD138                     56/57 (98)
MUM1                      14/14 (100)
cK or cL restriction      43/72 (60)
BCL2                          ND
CD56                          ND
CD45                      38/45 (84)
CD10                          ND
CD4                       22/34 (65)
CD117                         ND
ALK1                      30/30 (100)
Bob1                      16/16 (100)
BCL6                          ND
CD19                          ND
CD20                      1/56 (1.8)
CD30                      3/55 (5.5)
CD45RO                        ND
CD71                          ND
CD79a                     12/54 (22)
EMA                       47/53 (89)
HLA-DR                        ND
OCT2                      13/16 (81)
PAX5                      5/18 (2.8)
EBV (ISH)                  0/18 (0)
HHV8                          ND
Ki-67                         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.
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