AJCP / Original Article
IRTA1 and MNDA Expression in Marginal Zone Lymphoma
Utility in Differential Diagnosis and Implications for
Classification
Zhen Wang, MD, PhD, and James R. Cook, MD, PhD
From the Department of Laboratory Medicine, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH.
Key Words: IRTA1; MNDA; Marginal zone lymphoma
Am J Clin Pathol March 2019;151:337-343
DOI: 10.1093/AJCP/AQY144
ABSTRACT
Objectives: To evaluate the clinical utility of immune
receptor translocation-associated protein 1 (IRTA1)
and myeloid nuclear differentiation antigen (MNDA)
expression in the diagnosis and classification of marginal
zone lymphomas (MZLs).
Methods: IRTA1 was examined using a novel RNA in situ
hybridization assay and MNDA expression determined
by immunohistochemistry in 127 small B-cell neoplasms,
including 80 cases of MZL.
Results: IRTA1 expression was detected in 31 (42%)
of 74 MZLs vs one (2%) of 43 other small B-cell
neoplasms (P < .001). MNDA staining was positive in
51 (64%) of 79 MZLs vs 21 (45%) of 46 non-MZLs
(P = .06). MNDA expression was particularly uncommon
in follicular lymphoma (3/14, 21%; P = .003 vs MZL).
There was no association between MNDA and IRTA1
expression and the presence of monocytoid cytology.
IRTA1 expression was less frequent in cases with a diffuse
growth pattern.
Conclusions: IRTA1 and MNDA are useful markers in
the differential diagnosis of MZLs.
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The diagnosis of marginal zone lymphoma (MZL)
is frequently challenging and, in some cases, remains one
of exclusion.1-5 MZL is cytologically heterogeneous, with
cases showing varying proportions of monocytoid cells,
marginal zone-type cells, small lymphocytes, and plasma
cells.6,7 Architecturally, MZL may show a diffuse growth
pattern or contain varying numbers of follicular struc-
tures, which sometimes may be obscured by follicular
colonization by neoplastic cells.8-10 Compounding this
morphologic diversity, there are no MZL-specific pheno-
typic or genotypic markers currently available for routine
workup of small B-cell neoplasms.
Previous studies have described potential mark-
ers that might assist in the diagnosis of MZL, although
none are frequently used in routine practice. Immune re-
ceptor translocation-associated protein 1 (IRTA1), also
known as Fc receptor–like 4 (FCRL4), is a member of
a family of immunoglobulin-like proteins that mediate
B-cell immune responses.11-13 In normal lymphoid tissues,
IRTA1 is expressed in benign monocytoid B cells, some
marginal zone cells, and intraepithelial B cells.11,12,14,15
IRTA1 expression, as determined by immunohistochem-
istry (IHC), has been reported to be specific for MZL,16-18
but the antibodies used in prior studies are not currently
commercially available, and therefore IRTA1 immunohis-
tochemistry has not been widely adopted for routine clin-
ical use. Myeloid nuclear differentiation antigen (MNDA)
is expressed in myelomonocytic cells and is also found in
normal splenic marginal zone B cells.19,20 MNDA expres-
sion has been reported in many lymphoma subtypes, in-
cluding MZL, but MNDA is rarely expressed in follicular
Am J Clin Pathol 2019;151:337-343 337
DOI: 10.1093/ajcp/aqy144
Wang and Cook / IRTA1 and MNDA in MZL
lymphoma (FL).21,22 MNDA therefore may be useful in
the differential diagnosis of MZL vs FL. The relation-
ship, if any, between MNDA and IRTA1 expression and
correlations of MNDA and IRTA1 expression with mor-
phologic features have not been previously characterized.
In this study, we examine the expression of MNDA
and IRTA1 in 127 lymphomas, including 80 MZLs and 47
other small B-cell neoplasms. MNDA was examined by
IHC, while IRTA1, due to a lack of commercially avail-
able antibodies for IHC, was studied using a novel RNA
in situ hybridization assay.23 In lymph node samples in-
volved by MZL, results of MNDA and IRTA1 studies
were correlated with the architectural growth pattern and
with the cytologic features.
Materials and Methods
Case Selection and Morphologic Evaluation
This study was approved by the Cleveland Clinic
Institutional Review Board. In total, 127 small B-cell neo-
plasms from 127 patients were identified from the Cleveland
Clinic archives, including 15 bone marrows, 21 spleens,
and 91 lymph node or tissue biopsy specimens. The cases
examined included 80 MZLs (23 nodal MZL [NMZLs],
31 mucosa-associated lymphoid tissues [MALTs], and
26 splenic MZLs [SMZLs]) and 47 other small B-cell neo-
plasms: nine MYD88 L265P–mutated lymphoplasmacytic
lymphomas (LPLs; five nodal, four bone marrow), 14 FLs,
15 chronic lymphocytic leukemias (CLLs; 11 bone marrow,
four nodal), and nine mantle cell lymphomas (MCLs). Ten
reactive lymph nodes, selected to contain areas of monocy-
toid B cells, two benign tonsils, and 10 benign spleens, were
also examined. In 36 lymph nodes involved by MZL, phe-
notypic results were correlated with the cytologic features
and architectural growth pattern. The percentage of tumor
cells showing moderate to abundant cytoplasm, consistent
with a monocytoid appearance, was recorded. The archi-
tectural growth pattern was classified as nodular, mixed, or
diffuse based on the presence of nodular structures iden-
tified on routine H&E stains (>75%, 25%-75%, or <25%
nodular, respectively).
IRTA1 Messenger RNA In Situ Hybridization
IRTA1 messenger RNA in situ hybridization
(ISH) was performed on 4-μm paraffin sections on the
BenchMark XT platform with open probe software
(Roche Ventana Medical Systems) using probes for IRTA1
(cat 433309; Advanced Cell Diagnostics) and UBC (cat
312029; Advanced Cell Diagnostics) as a positive control
338 Am J Clin Pathol 2019;151:337-343
DOI: 10.1093/ajcp/aqy144
for RNA integrity. The bacterial gene DapB (cat 312039;
Advanced Cell Diagnostics) served as a negative con-
trol in each run. Cases with RNA in situ hybridization
(RISH) signal for IRTA1 associated with more than 20%
of neoplastic cells were classified as positive.
IHC
IHX was performed using antibodies for MNDA
(anti-MNDA, clone ab188566, 1:40; Abcam) and CD21
(anti-CD21, mouse monoclone 1F8; Abcam) on a
Ventana BenchMark XT with an OptiView Amplification
Kit and an OptiView DAB IHC Detection Kit (Roche
Ventana Medical Systems). Nuclear staining for MNDA
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associated with more than 20% of neoplastic cells was
classified as positive.
Statistics
Categorical variables were compared using the Fisher
exact test or χ2 test, as appropriate, with Prism 7.0 soft-
ware (GraphPad Software).
Results
In reactive lymph node specimens ❚Image 1❚, IRTA1
ISH showed consistent staining in monocytoid B cells with
approximately 30% to 50% of monocytoid cells staining
positively. Only rare scattered positive cells were noted in
the mantle/perifollicular zones. In tonsil controls, IRTA1
staining was also identified in intraepithelial lymphocytes.
Benign spleens showed 0% to 20% of marginal zone cells
to show weak to moderately intense IRTA1 staining, with
fewer positive cells in the mantle zones and only rare posi-
tive cells within germinal centers. IHC for MNDA showed
consistent staining in the mantle/perifollicular zone of re-
active follicles of reactive lymph nodes, with 10% to 50% of
cells showing nuclear staining, as well as scattered interfol-
licular lymphocytes. MNDA expression was also present
in granulocytes and macrophages, with only occasional
staining noted in monocytoid B-cell areas, likely repre-
senting admixed neutrophils. In normal spleens, MNDA
staining was present in marginal zone cells (weaker than
granulocytes/macrophages), while the inner mantle zone
and germinal center lymphocytes were negative.
IRTA1 and MNDA expression was examined in 127
small B-cell neoplasms, including 80 MZLs (23 NMZLs,
31 MALTs, and 26 SMZL), 15 CLLs, 14 FLs, nine MCLs,
and nine LPLs. Demographic information for the MZL
cases examined is shown in ❚Table 1❚. In 10 samples,
MNDA expression was successfully determined by IHC,
but inadequate RNA preservation precluded evaluation
of IRTA1 by ISH. Conversely, two cases were successfully
© American Society for Clinical Pathology
 AJCP / Original Article

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❚Image 1❚ Expression of myeloid nuclear differentiation antigen (MNDA) and immune receptor translocation-associated pro-
tein 1 (IRTA1) in benign lymph nodes. Monocytoid B cells (top row) are negative for MNDA but show strong staining for
IRTA1. The mantle/perifollicular region surrounding reactive germinal centers contains scattered MNDA-positive cells with only
rare scattered IRTA1-positive cells. (All images ×400.)

❚Table 1❚
Demographics of MZL Cases
Diagnosis Age, Median (Range), y Sex, F/M, No. (%)
NMZL, n = 23
Conventional (adult) type, n = 22 66 (52-89) 10 (45)/12 (55)
Pediatric type, n = 1 15 1F
MALT, n = 31 68 (42-85) 16 (52)/15 (48)
SMZL, n = 26 64 (43-84) 18 (69)/8 (31)

MALT, mucosa-associated lymphoid tissue; NMZL, nodal marginal zone lymphoma; SMZL, splenic marginal zone lymphoma.

examined by IRTA1 ISH, but insufficient tissue remained
for evaluation of MNDA staining.
Results of IRTA1 and MNDA studies are detailed
in ❚Table 2❚ and illustrated in ❚Image 2❚ and ❚Image 3❚.
Overall, IRTA1 expression was identified in 31 (42%) of
74 MZLs vs one (2%) of 43 non-MZL cases (P < .001,
Fisher exact test). Within MZL, IRTA1 expression was
similar in NMZL (10/23, 43%) and MALT (16/31, 52%)
and slightly lower in SMZL (5/20, 25%) (P = .17, χ2 test).
The single non-MZL case positive for IRTA1 ISH was a
grade 1 to 2 FL with staining in approximately 20% of
cells, located predominantly within the neoplastic folli-
cles. This case of FL contained CD10-positive monotypic
B cells by flow cytometry, coexpressed CD10 and BCL2
by IHC, and was morphologically typical for a low-grade
FL. MNDA expression was observed in 51 (64%) of 79
MZLs vs 21 (45%) of 46 non-MZL cases (P = .06, Fisher
exact test). Notably, however, MNDA expression was sig-
nificantly less common in FL (3/14, 21%) compared with
MZL (P = .003, Fisher exact test).Within MZL, MNDA
expression was similar in NMZL (12/22, 54%), MALT
(21/31, 68%), and SMZL (18/26, 69%) (P = .51, χ2 test).
Expression of either IRTA1 or MNDA was found in 64
(84%) of 76 MZLs, while coexpression of both markers
was less frequently seen (22/73, 30%).
In 36 lymph node samples involved by MZL (four
SMZLs, 10 MALTs, and 22 NMZLs), the expression of
MNDA and IRTA1 was assessed in relationship to the
morphologic features. IRTA1 expression showed no cor-
relation with predominantly monocytoid cytology (6/15
[40%] cases with >50% monocytoid cells vs 12/21 [57%]
with <50% monocytoid cells; P = .50, Fisher exact test).
IRTA1 expression was observed less commonly in cases
with a diffuse pattern (4/16, 25%) vs cases with a nondif-
fuse growth pattern (14/20, 70%) (P = .018, Fisher exact
test). CD21 stains, available in 15 of the 16 cases with a
diffuse growth pattern on routine H&E stains, showed
background residual dendritic cell meshworks in three
(75%) of four cases positive for IRTA1 and six (54%) of
11 cases negative for IRTA1 (P = .60, Fisher exact test).

© American Society for Clinical Pathology Am J Clin Pathol 2019;151:337-343 339

DOI: 10.1093/ajcp/aqy144
Wang and Cook / IRTA1 and MNDA in MZL

❚Table 2❚
IRTA1 and MNDA Expression in MZL and Other Small B-Cell Neoplasmsa
No./Total No. (%)
Characteristic IRTA1 MNDA Either Both
All MZLs (n = 80) 31/74 (42) 51/79 (64) 64/76 (84) 22/73 (30)
NMZL (n = 23) 10/23 (43) 12/22 (54) 18/22 (82) 7/22 (32)
MALT (n = 31) 16/31 (52) 21/31 (68) 26/31 (84) 12/31 (39)
SMZL (n = 26) 5/20 (25) 18/26 (69) 20/23 (87) 3/20 (15)
LPL (n = 9) P vs all MZLs 0/7 (0) .040 3/8 (37) .25 3/7(43) .02 0/8 (0) .10
FL (n = 14) P vs all MZLs 1/14 (7) .015 3/14 (21) .003 3/14 (21) <.001 1/14 (7) .10
CLL (n = 15) P vs all MZLs 0/13 (0) .003 8/15 (53) .56 8/13 (61) .12 0/14 (0) .017
MCL (n = 9) P vs all MZLs 0/9 (0) .023 7/9 (78) .72 7/9 (78) .64 0/9 (0) .10

CLL, chronic lymphocytic leukemia; FL, follicular lymphoma; IRTA1, immune receptor translocation-associated protein 1; LPL, lymphoplasmacytic lymphoma;
MALT, mucosa-associated lymphoid tissue; MCL, mantle cell lymphoma; MNDA, myeloid nuclear differentiation antigen; MZL, marginal zone lymphoma; NMZL,
nodal marginal zone lymphoma; SMZL, splenic marginal zone lymphoma.

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a
P value determined using Fisher exact test.

❚Image 2❚ Examples of myeloid nuclear differentiation antigen (MNDA) and immune receptor translocation-associated pro-
tein 1 (IRTA1) staining in selected marginal zone lymphoma (MZL) cases. A case of nodal MZL (NMZL) is negative for MNDA
but shows staining for IRTA1. A case of splenic MZL (SMZL) involving a hilar lymph node shows staining for both MNDA and
IRTA1. A case of gastric mucosa-associated lymphoid tissue (MALT) lymphoma shows staining for both MNDA and IRTA1. (All
images ×400.)

MNDA expression was also similar in cases with (9/15, Discussion

60%) and without (10/21, 48%) more than 50% monocy-
toid cells (P = .5, Fisher exact test). No significant differ-
ence was observed in MNDA expression between cases
with a diffuse (11/16, 69%) or nondiffuse (8/20, 40%)
growth pattern (P = .11, Fisher exact test).
In routine clinical practice, phenotypic and/or molec-
ular markers are available to facilitate the recognition of
most small B-cell neoplasms.5,24,25 FLs express germinal
center antigens (CD10, BCL6, HGAL, MEF2B, GCET1,

340 Am J Clin Pathol 2019;151:337-343 © American Society for Clinical Pathology

DOI: 10.1093/ajcp/aqy144
 AJCP / Original Article

LMO2) and are associated with BCL2 or BCL6 transloca-
tions. MCL expresses CD5 and cyclin D1 and/or SOX11,
while CLL/small lymphocytic lymphoma expresses CD5
and LEF1. LPL lacks specific phenotypic markers but is
highly associated with the MYD88 L265P point mutation
detectable by molecular studies.26-29 MZLs, in contrast,
often remain a diagnosis of exclusion. Translocations
involving the MALT1 gene are highly specific for extran-
odal MALT lymphomas, but these rearrangements are
found in only a subset of cases, are predominantly re-
stricted to cases arising at specific anatomic sites, and do
not occur in cases of nodal MZL or SMZL.5,30 For these
reasons, there remains a pressing need for biomarkers that
marginal zones are reportedly negative.11,12,14,15,17 Previous
studies have reported IRTA1 expression in 67% to 73% of
NMZLs and 93% of extranodal MALT lymphomas,17,18
but antibodies used in these prior studies are not commer-
cially available, limiting the utility of this potential marker.
In this study, we designed a novel RNA ISH method23 to
evaluate IRTA1 expression. Using RISH, IRTA1 stain-
ing was found in 43% of NMZLs, 52% of extranodal
MALT lymphomas, and 25% of SMZLs. The cause of
the lower incidence of IRTA1 staining noted by RISH in
this study compared with prior IHC reports is uncertain,
but this might reflect differential stability of IRTA1 RNA
vs protein or perhaps staining by IHC that is not com-

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can serve as positive markers of MZL. In this study, we
have examined a large series of MZLs for expression of
two potential markers of MZL, IRTA1 and MNDA.
The IRTA1 protein, also known as FCRL4, is a
member of the immunoglobulin superfamily first iden-
tified in a t(1;14)(q21;q32) translocation with IGH in a
multiple myeloma cell line.12 IRTA1 has been shown to
be expressed in normal, nodal monocytoid B cells and in
the intraepithelial lymphocytes and some marginal zone
cells of normal MALT tissue, while nodal perifollicular/
pletely specific for IRTA1. Nevertheless, IRTA1 staining
was highly specific for MZL, with staining observed in
31 (42%) of 74 MZLs vs one (2%) of 43 non-MZL cases.
Importantly, IRTA1 was negative in each of seven cases
of LPL tested, showing potential value in the differential
diagnosis of these small B-cell neoplasms, which exhibit
similar CD5-negative, CD10-negative phenotypes.
MNDA is an interferon-responsive protein expressed
in benign and neoplastic myelomonocytic cells, as well as
subsets of B cells.20,31-33 An expression microarray study

❚Image 3❚ Examples of myeloid nuclear differentiation antigen (MNDA) and immune receptor translocation-associated protein
1 (IRTA1) staining in selected non–marginal zone lymphoma cases. Cases of follicular lymphoma (FL) and lymphoplasmacytic
lymphoma (LPL) are negative for both MNDA and IRTA1. A case of mantle cell lymphoma (MCL) is positive for MNDA and
negative for IRTA1. (Top left panel ×100, all other images ×400.)

© American Society for Clinical Pathology Am J Clin Pathol 2019;151:337-343 341

DOI: 10.1093/ajcp/aqy144
Wang and Cook / IRTA1 and MNDA in MZL
comparing FL and MZL identified MNDA as strongly
differentiating between these two entities.22 In this study,
we confirmed that MNDA expression is seen in normal
splenic marginal zone B cells and is absent in normal
monocytoid B cells. Within small B-cell neoplasms,
MNDA positivity was frequent in MZL and uncommon
in FL (51/79 [64%] vs 3/14 [21%], respectively; P = .003).
MNDA expression was frequent in other small B-cell
neoplasms, such that the utility of MNDA IHC staining
appears limited to the specific differential diagnosis of FL
vs MZL. This result is consistent with prior reports show-
ing MNDA expression in most cases of small B-cell lym-
phomas other than FL.21,22 MNDA expression was seen
in three (37%) of eight LPLs (P = .25 vs MZL), indicating
that MNDA staining offers little utility in the differential
diagnosis between LPL and MZL.
MZLs expressing either MNDA or IRTA1 were more
common (54%) than cases coexpressing both markers
(30%), and neither marker showed a significant associa-
tion with monocytoid morphology. This latter observation
has implications for the classification of MZL. Normal
monocytoid B cells and normal marginal zone B cells are
known to differ in their phenotype: monocytoid B cells
are commonly negative for BCL2 and immunoglobulin M
(IgM), while splenic and nodal marginal zone B cells ex-
press BCL2 and IgM.14,34,35 Moreover, as reported by oth-
ers11,14,15,17,21 and reported in this study, monocytoid B cells
express IRTA1 and are negative for MNDA while splenic
marginal zone B cells are positive for MNDA and at least
predominantly negative for IRTA1. These differing phe-
notypic profiles reflect the longstanding uncertainty re-
garding the relationship between normal marginal zone
B cells and monocytoid B cells,15,36 and they raise the
question of whether lymphomas that morphologically re-
semble monocytoid B cells are appropriately classified as
MZL or whether these lymphomas should be considered
a distinct entity. The observation that IRTA1 and MNDA
are frequently seen in cases with and without monocytoid
morphology supports the concept underlying the current
World Health Organization classification scheme that
considers lymphomas resembling monocytoid B cells or
marginal zone B cells as part of the spectrum of MZL.
IRTA1 expression, but not MNDA expression, was
less common in cases with a diffuse growth pattern on
H&E staining. Residual CD21-positive follicular den-
dritic cell meshworks, often irregular, distorted, or
overrun, were detected in nine (60%) of 15 cases with
an apparently diffuse growth pattern on H&E, including
cases with and without positive IRTA1 staining. This
observation suggests IRTA1 expression is likely not re-
lated directly to the presence of follicular dendritic cell
meshworks. Additional studies will be required to further
342 Am J Clin Pathol 2019;151:337-343
DOI: 10.1093/ajcp/aqy144
elucidate the factors promoting IRTA1 expression in
MZL with or without a diffuse growth pattern.
Overall, these results demonstrate frequent expres-
sion of IRTA1 and MNDA in a variety of MZLs. MNDA
expression is particularly useful in cases with a differential
diagnosis with FL. IRTA1 offers particular advantages in
differential diagnosis as it appears to be highly specific
for MZL, being rarely expressed in other lymphomas
examined. The RISH assay employed in this study can
be adopted for routine clinical use on commercially avail-
able IHC platforms and provides a practical alternative to
IHC given that suitable IRTA1 antibodies remain com-
mercially unavailable. These additional markers there-
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fore represent suitable additions to an IHC panel for the
workup of small B-cell neoplasms.
Corresponding author: James R. Cook, MD, PhD; cookj2@ccf.
org.
Acknowledgments: We thank Advanced Cell Diagnostics for
providing the ISH probes used in this study.
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DOI: 10.1093/ajcp/aqy144