www.nature.

com/modpathol

ARTICLE
Histopathologic, immunophenotypic, and mutational
landscape of follicular lymphomas with plasmacytic
differentiation
1,2,3 ✉ 2,3,4
Sarah E. Gibson , Yen-Chun Liu , Svetlana A. Yatsenko2,3, Nicholas J. Barasch3,5 and Steven H. Swerdlow 2,3

© The Author(s), under exclusive licence to United States & Canadian Academy of Pathology 2021

Follicular lymphomas with plasmacytic differentiation (FL-PCD) include two major subtypes: one with predominantly interfollicular
PCD that usually harbors a BCL2 rearrangement (BCL2-R), and a second that has predominantly intrafollicular PCD and the frequent
absence of a BCL2-R. It is proposed that these latter cases share some features with marginal zone lymphomas (MZL). To further
explore this hypothesis in an expanded cohort of FL-PCD, a clinicopathologic investigation of 25 such cases was undertaken
including an analysis of their mutational landscape. The 10 interfollicular FL-PCDs exhibited typical intrafollicular centrocytes/
centroblasts (90%), CD10 expression (90%), full PCD including expression of CD138 by the plasma cells (PC) (100%), and PCs with
class-switched immunoglobulin heavy chains (70%). These cases were BCL2-R positive (100%), BCL6-R positive in 30%, lacked extra
BCL2 copies, and only 22% had extra copies of BCL6. Similar to classic FLs, 80% of interfollicular FL-PCDs harbored mutations in
epigenetic regulators KMT2D (70%), CREBBP (40%), and/or EZH2 (30%). In contrast, only 45% of 11 intrafollicular FL-PCDs
demonstrated typical intrafollicular centrocytes/centroblasts, 55% were CD10(-), 80% contained IgM+ PCs, and only 27% harbored
BCL2-Rs. BCL6-Rs were identified in 27% of intrafollicular FL-PCD, while 60% showed extra copies of BCL2 and 50% extra copies of
BCL6, consistent with complete or partial trisomies of chromosomes 18 and 3, respectively. Only 54% of intrafollicular FL-PCDs
showed mutations in epigenetic regulators. Both subtypes showed mutational differences compared to classic FL, but only the
interfollicular subtype showed differences from what is reported for nodal MZL. Four additional cases showed mixed intra- and
interfollicular PCD. These results suggest that FL-PCD has some distinctive features and supports the existence of two major
subtypes. The interfollicular PCD subtype shares many features with classic FL. The intrafollicular FL-PCDs are more heterogeneous,
have differences from classic FL, and have a greater morphologic, immunophenotypic, and genetic overlap with MZL.

Modern Pathology (2022) 35:60–68; https://doi.org/10.1038/s41379-021-00938-z

INTRODUCTION expression8. FLs with MZD also show an increased frequency of

Follicular lymphomas (FLs) are prototypical follicular/germinal
center (GC)-derived B-cell lymphomas that express GC-associated
markers, show evidence of ongoing somatic hypermutation, and,
in most cases, have a gene expression profile related to that of a
light zone B cell1–3. The genetic hallmark of 80–90% of FLs is the
t(14;18)(q32.33;q21.3) translocation, which juxtaposes BCL2 with
the IGH enhancer, leading to constitutive expression of BCL2 and
resistance to apoptosis1,2. Although the BCL2 translocation is
found in most FLs, it is thought that additional genetic alterations
are required for malignant transformation2. Many, but not all, FLs
that lack BCL2 rearrangements have BCL6 rearrangements and
some FLs have both1,4,5.
Similar to non-neoplastic GC cells, it is recognized that a subset
of FLs shows further post-GC differentiation to memory/marginal
zone type B cells or plasma cells1,6. Marginal zone type
differentiation (MZD) is well described, occurring in approximately
9% of FLs7. The MZD component of these FLs harbors the BCL2
translocation, but demonstrates downregulation of GC marker
numerical chromosomal alterations, in particular trisomy 3, which
is associated with marginal zone lymphomas (MZL)9,10.
Plasmacytic differentiation (PCD) is less common, estimated to
occur in 3.5% of FLs, with a clonal relationship between the
neoplastic B cells and plasma cells confirmed in a subset of
reported cases6,11,12. In a previous study, it was shown that FLs
with PCD (FL-PCD) are composed of two major subtypes6. One
subtype shows features of classic FL with maturation to plasma
cells in a predominantly interfollicular distribution, similar to
normal post-follicular development. These cases are generally
associated with a BCL2 rearrangement. The other subtype has a
predominantly intrafollicular plasma cell distribution and usually
lacks a BCL2 translocation. Although it has been suggested that
FLs with intrafollicular PCD share features with MZLs with
extensive follicular colonization, fluorescence in situ hybridization
studies performed on these cases have shown no evidence of
MZL-associated chromosomal abnormalities, such as a MALT1
translocation, trisomy 3, or trisomy 181,6.

1
Mayo Clinic Arizona, Phoenix, AZ, USA. 2University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. 3University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA.
4
Present address: St. Jude Children’s Research Hospital, Memphis, TN, USA. 5Present address: Columbia University Medical Center, New York, NY, USA. ✉email: Gibson.
Sarah@mayo.edu

Received: 11 August 2021 Revised: 15 September 2021 Accepted: 16 September 2021

Published online: 2 October 2021

Since the publication of the prior series of FL-PCD, the
mutational profiles of FL and MZLs have been more widely
investigated5,13–26. Sequencing studies of FL have revealed a
variety of genetic alterations in genes involved in epigenetic
regulation (e.g., KMT2D, CREBBP, EZH2, EP300, MEF2B, STAT6),
interaction with the microenvironment (e.g., TNFRSF14), and
other signaling pathways2,5,13–22. A recent study of t(14;18)-
negative FLs has shown that these lymphomas harbor similar
copy number alterations and mutations as conventional
t(14;18)-positive FLs, but with an increased frequency of STAT6
mutations5. Alterations in epigenetic regulators are also
found in nodal MZL (NMZL), albeit at lower frequencies than
are seen in FL, as well as mutations targeting NF-κB (e.g.,
TNFAIP3, BCL10, CARD11) and NOTCH (e.g., NOTCH2, SPEN)
signaling pathways23–26.
Given the recognized mutational differences between FL and
NMZL, we aimed to determine if mutational profiling could
identify specific genetic characteristics of FL-PCD and to clarify if
these lymphomas, in particular the subtype with predominantly
intrafollicular PCD, display a mutational profile that overlaps that
of NMZL. We therefore performed high throughput sequencing of
25 FL-PCD, and investigated their clinical, morphologic, immuno-
phenotypic, and genetic features.
1234567890();,:
S.E. Gibson et al.
61
MATERIALS AND METHODS
Case selection
The pathology archives of the University of Pittsburgh Medical Center
(UPMC) were searched from January 2002 to September 2018 for cases of
FL-PCD that had formalin-fixed paraffin-embedded (FFPE) tissue available.
In total, 25 cases were identified with sufficient material available for
additional studies. Six of these cases were included in the previous
studies6,27. All available clinical and laboratory data, diagnostic slides, and
FFPE tissue blocks or unstained slides were obtained with the approval of
the University of Pittsburgh Institutional Review Board.
Histologic and immunophenotypic review
All available hematoxylin and eosin-stained tissue sections and immuno-
histochemical stains performed at the time of diagnosis were reviewed.
Additional immunohistochemical stains for IgA (polyclonal, Ventana,
Tucson, AZ), IgD (polyclonal, GeneTex, Irvine, CA), IgM (polyclonal,
Ventana), IgG (polyclonal, Ventana), kappa (clone L1C1, Dako, Santa Clara,
CA), lambda (clone HP6054, Thermo Fisher Scientific, Waltham, MA), CD138
(clone MI15, Dako), CD38 (clone SP149, Cell Marque, Rocklin, CA), CD20
(clone L26, Ventana), CD3 (clone 2GV6, Ventana), CD10 (clone 56C6, Cell
Marque), BCL6 (clone LN22, Biocare Medical, Pacheco, CA), BCL2 (clone
124, Ventana), BCL2 (clone E17, Abcam, Cambridge, MA), IRF4/MUM1
(clone MUM1p, Dako), MEF2B (polyclonal, Sigma-Aldrich, St. Louis, MO),
HGAL (clone MRQ-49, Cell Marque), CD21 (clone 1F8, Dako), and Ki-67

Table 1. Clinical Features of 25 Follicular Lymphomas with Plasmacytic Differentiation.

Intrafollicular PCDc Interfollicular PCDc Mixed intra/ interfollicular PCDc
No. 11 10 4
Median age (yrs) 63 60 64
Gender 7 M/4 F 5 M/5 F 3 M/1 F
Biopsy site
Lymph node 10 (91%) 7 (70%) 4 (100%)
Extranodal 1 (9%) 3 (30%) 0 (0%)
Ann Arbor stagea
I–II 2 (18%) 1 (11%) 0 (0%)
III–IV 9 (82%) 8 (89%) 4 (100%)
FLIPI risk groupa
Low 4 (40%) 2 (29%) 0 (0%)
Intermediate 3 (30%) 2 (29%) 0 (0%)
High 3 (30%) 3 (43%) 2 (100%)
Treatmentb
Multiagent immunochemotherapy 8 (80%) 8 (80%) 4 (100%)
Rituximab only 2 (20%) 1 (10%) 0 (0%)
None 0 (0%) 1 (10%) 0 (0%)
Response to treatmentb
CR 6 (60%) 2 (22%) 3 (75%)
PR 1 (10%) 2 (22%) 1 (25%)
Progression 3 (30%) 2 (22%) 0 (0%)
CR with relapse 0 (0%) 3 (33%) 0 (0%)
Status at last follow upb
ANED 6 (60%) 2 (20%) 3 (75%)
AWD 2 (20%) 3 (30%) 1 (25%)
DWD 2 (20%) 5 (50%) 0 (0%)
Median follow up time (yrs)b 4.9 6.7 6.4
PCD plasmacytic differentiation, No., number, yrs years, FLIPI follicular lymphoma international prognostic index, CR complete response, PR partial response,
ANED alive with no evidence of disease, AWD alive with disease, DWD died with disease, M male, F female
a
Ann Arbor stage was not available for 1 patient and a FLIPI score was not available for 6 patients.
b
Treatment and follow-up information was not available for 1 patient.
c
There were no statistically significant differences in clinical features between the 3 groups.

Modern Pathology (2022) 35:60 – 68

 S.E. Gibson et al.
62
(MIB-1, Dako) were performed, if not already available, using a Benchmark
Ultra automated immunostainer (Ventana).
The histologic assessment included confirmation of the diagnosis and
evaluation of the following features: histologic grade following WHO
criteria1; cytologic features of the cells within the neoplastic follicles;
presence or absence of Dutcher bodies; and distribution and degree of
PCD as assessed from CD138, CD38, IRF4/MUM1, immunoglobulin light
chain, and immunoglobulin heavy chain immunohistochemical stains.
Cases were divided into those with either predominant intrafollicular (11
cases) or interfollicular (10 cases) monotypic plasmacytic cells, as well as a
smaller subset (4 cases) that had relatively equal proportions of
intrafollicular and interfollicular PCD. For further analysis, monotypic cells
with plasmacytoid cytologic features that expressed CD138, CD38, and
IRF4/MUM1 were considered to have full PCD, while those lacking
significant CD138 and CD38 expression were considered to demonstrate
plasmacytoid differentiation.
Fluorescence in situ hybridization
Fluorescence in situ hybridization (FISH) studies to assess for BCL2 (Vysis
LSI BCL2 dual-color break apart, Abbott Molecular, Abbott Park, IL) and
BCL6 (Vysis LSI BCL6 dual-color break apart, Abbott Molecular) gene
rearrangements were performed on 17 cases that did not have this testing
performed at diagnosis. FISH to evaluate for an IRF4 (G110997R-5’/
G110997G-3’ break apart, Agilent Technologies, Santa Clara, CA) rearrange-
ment was additionally performed on 3 cases that had strong, diffuse IRF4/
MUM1 staining by immunohistochemistry. FISH was performed on 4-6-µm
FFPE whole tissue sections, and signal patterns from a minimum of 60 cells
were scored, using positive cut-offs for each probe determined by previous
clinical laboratory validation studies.
High throughput sequencing
All 25 cases had sufficient FFPE tissue to perform high throughput
sequencing mutation analysis. Genomic DNA was extracted from the FFPE
tissue and sequencing was performed using a targeted hybrid-capture
next-generation sequencing panel comprising 4099 target coding regions
within 220 genes recurrently mutated in lymphoma (Cancer Genetics
Incorporated [CGI], Rutherford, NJ; Supplemental Table 1). Non-
synonymous variants and insertions/deletions were recorded using the
CGI pipeline followed by manual review (S.E.G, Y-C.L). Variants were
classified as pathogenic/likely pathogenic or as variants of unknown
significance (VUS) based on the in silico prediction and literature review
according to Association for Molecular Pathology guidelines28–32. VUS that
may represent germline variants with an allele fraction between 40-60%
were excluded from further analysis. The remaining VUS were reported,
but not discussed further. The results of high throughput sequencing were
compared to mutation data obtained from previously published studies of
FL and NMZL, as detailed previously13–26,33.
Fig. 1 Follicular lymphoma with intrafollicular plasmacytic differentiation (Case 2). The neoplastic follicles (A) contain mostly small
lymphoid cells with more rounded nuclear contours, plasmacytoid cells, and rare Dutcher bodies (B–C). The neoplastic B cells co-express CD20
(D), CD10 (E), and BCL2 (F). The intrafollicular monotypic plasmacytoid cells are kappa negative (G) and lambda positive (H), with a few
interfollicular polytypic plasma cells and what appear to be polytypic mantle zones. (A–C, H&E, and D–H, immunohistochemical stain with
hematoxylin counterstain; A, ×40; B, ×500; C, ×1000; D–H, ×100).
Statistics
Statistical analyses, including Student’s t-test and two-tailed Fisher’s exact
test, were calculated using the GraphPad Prism software package, version
7 (GraphPad Software Inc., La Jolla, CA).
RESULTS
Clinical Features
The patients included 15 males and 10 females with a median age
of 62 years (range 38–84 years) (Table 1 and Supplemental
Table 2). The lymphomas were diagnosed from lymph node
biopsies in 21 of 25 cases (8 axillary, 7 cervical, 2 inguinal, 2
retroperitoneal, and 2 mediastinal), while the remaining 4 cases
were diagnosed in the parotid (2 cases) or small intestine (2 cases).
Twenty-one of 24 patients presented with stage III-IV disease. Of
the 19 patients with sufficient clinical and laboratory information
available to determine the follicular lymphoma international
prognostic index (FLIPI), 6 patients were in the low-risk category,
5 patients were intermediate risk, and 8 patients were high risk.
Additional treatment and follow-up information were available for
24 of the 25 patients. Twenty patients received multiagent
immunochemotherapy, 3 patients received rituximab alone, and
one patient did not receive chemotherapy during a follow-up
period of 1.1 years. Of the 23 patients who were treated, 11
achieved a complete response, 4 had a partial response, 3
achieved a complete response with subsequent relapse, and 5 had
progressive disease. At a median follow-up time of 5.7 years
(range 1.0–18.4 years), 11 were alive with no evidence of disease, 6
were alive with persistent disease, and 7 had died with the
disease. Five of the latter 7 patients also had diffuse large B-cell
lymphoma present. There were no statistically significant differ-
ences in clinical features between cases classified as having
intrafollicular PCD, interfollicular PCD, or mixed intrafollicular/
interfollicular PCD.
Histologic and Immunophenotypic Features
Eleven cases had predominantly intrafollicular PCD, 10 cases had
predominantly interfollicular PCD, and 4 cases demonstrated
relatively equal proportions of both intrafollicular and interfolli-
cular PCD (Figs. 1 and 2, Table 2, and Supplemental Table 3).
Fifteen of 25 (60%) cases were histologic grade 1–2 of 3, 6 cases
were grade 3 A, and 4 cases were grade 3B. Two cases that were
predominantly grade 1–2 also contained focal areas that were
considered grade 3 A. A component of diffuse large B-cell
Modern Pathology (2022) 35:60 – 68
 S.E. Gibson et al.
63

Fig. 2 Follicular lymphoma with interfollicular plasmacytic differentiation (Case 18). The neoplastic follicles (A) contain mostly centrocytes
and occasional plasma cells (B), while the interfollicular areas contain many plasma cells (C). The neoplastic B cells co-express CD20 (D), CD10
(E), and BCL2 (F). The kappa monotypic plasma cells are predominantly interfollicular (G), while a lambda stain shows only rare positive plasma
cells (H). (A–C, H&E, and D–H, immunohistochemical stain with hematoxylin counterstain; A, ×100; B, ×500; C, ×1000; D–H, ×100).

Table 2. Histopathologic and Immunophenotypic Features of 25 Follicular Lymphomas with Plasmacytic Differentiation.
Intrafollicular PCD Interfollicular PCD Mixed intra/interfollicular PCD
No. 11 10 4
Histologic grade
1-2 5 (45%) 7 (70%) 3 (75%)
3A 5 (45%) 1 (10%) 0 (0%)
3B 1 (9%) 2 (20%) 1 (25%)
DLBCL present 3 (27%) 4 (40%) 0 (0%)
Predominant cytology of follicle center cells
Plasmacytoid 4 (36%)a 0 (0%) 3 (75%)a
Centrocytes 1 (9%) 6 (60%) 1 (25%)
Centroblasts 4 (36%) 3 (30%) 0 (0%)
Small, round cells 2 (18%) 1 (10%) 0 (0%)
CD10 + 5 (45%)b 9 (90%) 1 (25%)b
BCL6 + 11 (100%) 10 (100%) 4 (100%)
MEF2B + 9 (100%) 3 (60%) 4 (100%)
HGAL + 7 (78%) 5 (100%) 3 (75%)
IRF4/MUM1 + c 4 (36%) 0 (0%) 2 (50%)
BCL2 + 10 (91%) 9 (90%) 4 (100%)
IgM + 8 (80%)d 3 (30%) 4 (100%)d
Kappa + 8 (73%) 3 (30%) 2 (50%)
Immunophenotype of monotypic plasmacytoid cells
Plasmacytic (CD138 + /CD38 + /IRF4/MUM1 + ) 3 (27%) 10 (100%)e 2 (50%)
Plasmacytoid (IRF4/MUM1 + only) 8 (73%) 0 (0%) 2 (50%)
Ki-67 ≥ 30% 6 (55%) 3 (30%) 3 (75%)
No. number; PCD plasmacytic differentiation, DLBCL diffuse large B-cell lymphoma
a
Plasmacytoid cytology was more frequent in cases that had a predominant component of intrafollicular PCD (p = 0.09), including cases with mixed
intrafollicular/interfollicular PCD (p = 0.02).
b
CD10 was more often negative in cases that had a predominant component of intrafollicular PCD (p = 0.06), including cases with mixed intrafollicular/
interfollicular PCD (p = 0.02).
c
Refers to positivity on non-plasmacytic/plasmacytoid cells.
d
IgM was more commonly expressed by intrafollicular PCD cases (p = 0.07), including cases with mixed intrafollicular/interfollicular PCD (p = 0.01).
e
The monotypic plasmacytoid cells showed full PCD, with expression of CD138, CD38, and IRF4/MUM1, more often in FL with predominantly interfollicular
PCD (p = 0.001).

Modern Pathology (2022) 35:60 – 68

 S.E. Gibson et al.
64
lymphoma was identified in 7 cases (3 cases with intrafollicular
PCD and 4 cases with interfollicular PCD).
The follicles in 15 of 25 (60%) cases contained predominantly
centrocytes or centroblasts typical of FL. However, in 7 (28%) cases
(4 cases with intrafollicular PCD and 3 cases with mixed
intrafollicular/interfollicular PCD) the follicle center cells had
plasmacytoid cytologic features with more rounded nuclei, which
were sometimes eccentrically located, and a moderate amount of
amphophilic cytoplasm. Although plasmacytoid cells within
follicles were more common in the cases that had a predominant
component of intrafollicular PCD, including those cases with
mixed intrafollicular/interfollicular PCD (p = 0.02), occasional
plasmacytoid cells could also be identified within the follicles of
2 of 9 interfollicular PCD cases that contained predominantly
centrocytes or centroblasts. In 3 cases (2 with intrafollicular PCD
and 1 with interfollicular PCD), the neoplastic cells within the
follicles were small with round nuclei, but were not overtly
plasmacytoid in appearance.
The neoplastic B cells in all 25 cases had a GC immunopheno-
type, confirmed with a combination of CD10, BCL6, MEF2B, and
HGAL stains. BCL6 was expressed by all 25 cases, MEF2B by 16 of
18 (89%) cases, HGAL by 15 of 18 (83%) cases, and CD10 by 15 of
25 (60%) cases. CD10 was more commonly negative in cases that
had predominantly intrafollicular PCD, including cases with mixed
intrafollicular/interfollicular PCD (p = 0.02). BCL2 was positive in 23
of 25 (92%) cases. IRF4/MUM1 showed strong staining on most of
the neoplastic B cells in 3 of 25 cases (12%; 2 cases with
intrafollicular PCD and 1 case with mixed intrafollicular/inter-
follicular PCD) and showed moderate staining on <50% of
neoplastic B cells in 3 additional cases (2 intrafollicular PCD cases
and 1 mixed intrafollicular/interfollicular PCD case). The Ki-67
proliferation index was ≥30% in 12 of 25 cases, including 6 cases
that were considered to be histologic grade 1–2 of 3. The Ki-67
proliferation index was not significantly different between
intrafollicular and interfollicular PCD cases.
Fig. 3 Genomic findings in follicular lymphomas with plasmacytic differentiation. Only somatic variants considered to be pathogenic/likely
pathogenic are included. Abbreviations: PCD plasmacytic differentiation, BCL2 R BCL2 rearrangement; BCL6 R BCL6 rearrangement, FISH
fluorescence in situ hybridization, NGS next-generation sequencing.
The plasmacytic/plasmacytoid cells were kappa monotypic in 13
of 25 (52%) cases and lambda monotypic in the remaining 12
cases. Fifteen of 24 (63%) cases evaluated contained IgM-positive
plasmacytic/plasmacytoid cells, with the remaining cases showing
plasmacytic/plasmacytoid cells with IgG (8 cases) or IgD (1 case)
expression. Two of the IgM-positive cases also contained
plasmacytic/plasmacytoid cells expressing IgD, and 1 IgM-
positive case contained plasmacytic/plasmacytoid cells with both
IgD and IgG expression. Cases with a predominant component of
intrafollicular PCD, including cases with mixed intrafollicular/
interfollicular PCD, more commonly expressed IgM compared to
cases with mostly interfollicular PCD (p = 0.01). The monotypic
plasmacytic/plasmacytoid cells identified in 8 of 11 (73%) cases
with predominantly intrafollicular PCD were IRF4/MUM1-positive,
but lacked significant CD138 and CD38 expression, and were
considered to have plasmacytoid differentiation rather than full
PCD. In contrast, the monotypic plasmacytic/plasmacytoid cells in
the cases with a predominantly interfollicular distribution
expressed CD138 and CD38 compatible with full PCD. The
difference in the degree of PCD between intrafollicular and
interfollicular cases was statistically significant (p = 0.001). Two
cases with predominantly intrafollicular plasmacytoid differentia-
tion also contained a minor component of interfollicular
plasmacytic cells with full PCD and expression of CD138 and CD38.
Genomic Features
FISH studies detected BCL2 gene rearrangements in all 10 cases
with interfollicular PCD, but in only 3 of 11 (27%) cases with
intrafollicular PCD (p = 0.001) and 1 of 4 (25%) cases with mixed
intrafollicular/interfollicular PCD (Fig. 3 and Supplemental Table 3).
BCL6 gene rearrangements were detected in 3 intrafollicular PCD
cases that lacked BCL2 rearrangements, in 3 interfollicular PCD
cases, and in 1 case with mixed intrafollicular/interfollicular PCD
that also harbored a BCL2 rearrangement. Unrearranged extra
BCL2 copies were identified in 6 of 10 (60%) cases with
intrafollicular PCD, 2 of 4 (50%) cases with mixed intrafollicular/
Modern Pathology (2022) 35:60 – 68
 S.E. Gibson et al.
65

Fig. 4 Comparison of mutations identified in follicular lymphomas with plasmacytic differentiation (FL-PCD) to published follicular
lymphomas (FL)13–22 and nodal marginal zone lymphomas (NMZL)23–26. Genes shown had pathogenic/likely pathogenic mutations in ≥10%
of FL-PCD, published FL, or published NMZL. Overall, FL-PCD showed fewer BCL2 mutations than published FL (p = 0.0001). Comparisons
between cases with intrafollicular and interfollicular PCD showed a significant difference in the frequency of CREBBP mutations (p = 0.04) and
a trend for differences in the frequency of KMT2D and TNFAIP3 mutations (p = 0.09). While intrafollicular PCD cases showed a lower frequency
of CREBBP and KMT2D mutations compared to published FL (p ≤ 0.003), cases with interfollicular PCD showed a higher frequency of these
mutations compared to published NMZL (p ≤ 0.04). Abbreviations: FL follicular lymphoma, Inter-PCD interfollicular plasmacytic differentiation,
Intra-PCD intrafollicular plasmacytic differentiation, NMZL nodal marginal zone lymphoma.

interfollicular PCD, and in 0 of 8 cases with interfollicular PCD (p =
0.01, comparing cases with intrafollicular versus interfollicular
PCD). Extra copies of BCL6 were present in 5 of 10 (50%) cases with
intrafollicular PCD, 2 of 4 (50%) cases with mixed intrafollicular/
interfollicular PCD, and in 2 of 9 (22%) cases with interfollicular
PCD. Five cases harbored extra signals of both BCL2 and BCL6, 4 of
which had predominantly intrafollicular PCD and none of which
had predominantly interfollicular PCD (p = 0.09). FISH did not
demonstrate an IRF4 gene rearrangement in the 3 cases that
showed strong IRF4/MUM1 staining (2 intrafollicular PCD cases
and 1 mixed intrafollicular/intrafollicular PCD case).
High throughput sequencing studies detected pathogenic/likely
pathogenic mutations in 24 of 25 cases, with a median of 2
mutations per case (range 0–7 mutations) (Fig. 3 and Supple-
mental Table 3). There was a trend toward a lower number of
mutations in intrafollicular PCD cases compared to interfollicular
PCD cases (p = 0.07). The most commonly mutated gene in FL-
PCD was KMT2D, which was mutated in 13 of 25 (52%) cases.
Other genes that were recurrently mutated included: TNFAIP3 and
TNFRSF14 in 5 cases; CREBBP and EZH2 in 4 cases; BCL10, CARD11,
CD79A, and EP300 in 3 cases; and ARID1A, BTG2, CD79B, GNA13,
POU2AF1, and SF3B1 in 2 cases each. BCL2, IRF8, and STAT6, which
are mutated in ≥10% of published FL13–22,29,33, were mutated in
only single cases of FL-PCD. A non-L265P MYD88 mutation was
identified in one case that showed interfollicular PCD. Differences
were identified in the mutational profile between interfollicular
and intrafollicular PCD cases (Fig. 4 and Supplemental Table 4).
Although 4 of 10 (40%) interfollicular PCD cases harbored a
CREBBP mutation, this gene was not mutated in the 11
intrafollicular PCD cases (p = 0.04). CREBBP mutations were also
not identified in the 4 cases with mixed intrafollicular/interfolli-
cular PCD, although this difference was not statistically significant.
KMT2D and TNFAIP3 mutations were more commonly mutated in
interfollicular PCD cases (70% and 30% of cases, respectively)
compared to cases with intrafollicular PCD (27% and 0% of cases,
respectively) (p = 0.09). Cases with mixed intrafollicular/interfolli-
cular PCD commonly harbored KMT2D (75% of cases) and TNFAIP3
(50% of cases) mutations.
Differences in the mutational profile of FL-PCD compared to
published FL and NMZL were noted (Fig. 4 and Supplemental
Table 4)13–26,33. FL-PCD overall showed a lower number of BCL2
mutations than what is typically reported in FL (48% of published
FLs; p = 0.0001). While CREBBP and KMT2D mutations, the most
common mutations in FL13–22,29,33, occurred at a similar frequency
in interfollicular PCD cases, intrafollicular PCD cases showed a
much lower frequency of these mutations (p ≤ 0.003). Cases with
interfollicular PCD had a higher frequency of CREBBP and KMT2D
mutations than is reported in NMZL (20% and 31% of published
NMZL, respectively; p ≤ 0.04)23–26. Intrafollicular PCD cases showed
a higher frequency of mutations in the tumor suppressor BTG2
compared to published FLs (2% of published FLs; p = 0.03)13–
22,29,33,34
. However, no significant differences in mutation
frequencies were found in cases of FL with intrafollicular PCD
when compared to published NMZL.
DISCUSSION
FLs are derived from GC B cells, but, unlike other lymphomas that
display a block in lymphoid maturation, FLs show evidence of
ongoing lymphocyte differentiation2,3,6,35. Similar to non-
neoplastic GC B cells, neoplastic follicular center cells often
demonstrate morphologic or immunophenotypic features asso-
ciated with differentiation to memory B cells when they exit the
follicle to interfollicular regions of the lymph node36. It is also well-
recognized that a subset of FLs displays overt MZD or PCD1,6–12. In
clinical practice, such cases may create diagnostic confusion with
MZL, and in fact previous studies have indicated that FLs with
MZD share some overlapping cytogenetic abnormalities with MZL,
in particular trisomy of chromosome 39,10. A prior study of FL-PCD
showed that these lymphomas consisted of two major subtypes,
with one subtype showing predominantly interfollicular PCD and a
second subtype harboring mostly intrafollicular plasma cells6.
Although these cases did not show distinct cytogenetic overlap
with MZL, with FISH studies showing no evidence of MALT1
rearrangements or trisomies of chromosomes 3 and 18 in the 13
cases tested, the subtype with predominantly intrafollicular

Modern Pathology (2022) 35:60 – 68

 S.E. Gibson et al.
66
plasma cells lacked the BCL2 rearrangement characteristic of FL6. It
is this subtype of FL with intrafollicular PCD that has been
postulated to share features with MZL with extensive follicular
colonization1,6.
The mutational profiles of FL and NMZL have been increasingly
investigated since the publication of this prior series of FL-PCD.
Although there are some overlaps in the mutational profiles of
these two types of lymphoma, FLs, in general, have more
prominent alterations in genes involved in epigenetic regulation
(e.g., KMT2D, CREBBP, EZH2, EP300, MEF2B, STAT6) and interaction
with the microenvironment (e.g., TNFRSF14)2. Similar alterations in
epigenetic regulators are also found in NMZL, but at lower
frequencies, and these lymphomas additionally harbor mutations
targeting NF-κB (e.g., TNFAIP3, BCL10, CARD11) and NOTCH (e.g.,
NOTCH2, SPEN) signaling pathways23,24. Based on this more recent
mutational data, we performed targeted high throughput
sequencing of 25 FL-PCD and completed an extensive morpho-
logic, immunophenotypic, cytogenetic FISH, and clinical evalua-
tion to determine if these lymphomas had any specific genetic or
other clinicopathologic characteristics, and to further clarify if the
subtype with intrafollicular PCD overlapped with NMZL.
The expanded cohort of FL-PCDs studied here did confirm that
cases could be divided into a subtype with predominantly
intrafollicular PCD and a subtype with predominantly interfolli-
cular PCD, with a smaller number of cases showing overlapping
features. Our search of the pathology archives at UPMC only
identified cases with PCD clearly documented at the time of
diagnosis; therefore, it is possible that FLs with more classic
features and only subtle PCD were missed. There were no
statistically significant differences in clinical features between the
subtypes nor in their histologic grade. Both subtypes included
several cases with associated diffuse large B-cell lymphoma.
Whether this truly represents a greater frequency in FL-PCD is
uncertain, but does suggest that it be considered in these cases
especially if one only has a small needle core biopsy. Although
there is only limited clinical data available from previously
reported FL-PCDs, one study published before the era of rituximab
found that patients commonly presented with disseminated
disease (67%) and had a median survival of 40 months37. This is
similar to our cohort, in which 88% of patients presented with
stage III-IV disease and 29% died with the disease at a median
follow-up of 5.7 years.
In contrast to the clinical features, morphologic differences were
identified between the two major subtypes, with the intrafollicular
PCD cases cytologically less like typical FL and with more
plasmacytoid features. This may lead to diagnostic confusion with
MZL with extensive follicular colonization, as well as create
difficulties in histologic grading6,38,39. The overlap with MZL is
further compounded by the lack of CD10 expression in about half
of the cases with intrafollicular PCD6,38. Additional immunohisto-
chemical stains, including BCL6, HGAL, MEF2B, and LMO2, are
useful to confirm the GC nature of the neoplastic cells in such
cases, as positivity for BCL6 and MEF2B was seen in all of the
CD10-negative cases and HGAL in almost three-quarters6,27,38,40.
However, the presence of more limited GC-associated markers in a
significant subset of the intrafollicular PCD cases does not exclude
the possibility of follicular colonization by a MZL, as upregulation
of at least BCL6 in colonized follicles is reported in MZLs, as
documented with IRTA1/BCL6 double staining41. Furthermore,
MEF2B is also expressed by plasmacytic cells27. Strong IRF4/
MUM1 staining in a subset of cases also raises the diagnostic
possibility of a large B-cell lymphoma with IRF4 rearrangement,
but negative FISH for IRF4 can help to exclude this diagnosis1.
IgM was more often expressed by the plasmacytic/plasmacytoid
cells in cases with intrafollicular PCD. In addition, while complete
PCD, including expression of CD138 and CD38, was present in all
cases with interfollicular PCD, intrafollicular PCD cases frequently
contained plasmacytoid cells that only showed IRF4/MUM1 and
cytoplasmic immunoglobulin expression. IRF4/MUM1 is first
expressed by a subset of B cells in the light zone of the GC and
is important, along with PRDM1 (BLIMP1) and XBP1, for further
differentiation of these cells into plasma cells1,42–44. CD38 is also
expressed by GC B cells, with higher expression noted throughout
the early to late stages of plasma cell differentiation1,43,45,46. In
contrast, CD138 identifies a more mature stage of plasma cell
differentiation1,43,45,46. The significance of the difference in the
degree of PCD noted between the two subtypes of FL with PCD is
uncertain. It is possible that the interfollicular PCD subtype of FL
more closely recapitulates normal post-follicular plasma cell
development, which generally occurs in extrafollicular
regions1,44,47. Cases with predominantly intrafollicular PCD may
reflect neoplastic B cells that are largely unable to effectively
differentiate beyond the pre-plasmablast or early plasmablast
stages of differentiation, or possibly B cells that represent
something other than classic GC cells1,43,44. These latter cases
may rarely still demonstrate some interfollicular plasmacytic cells
with complete PCD.
Similar to previous observations, all cases with predominantly
interfollicular PCD harbored a BCL2 rearrangement, an abnormality
strongly associated with classic FL1,2,6. Although a BCL2 rearrange-
ment was demonstrated in only 27% of cases with predominantly
intrafollicular PCD, 3 of the intrafollicular PCD cases that lacked a
BCL2 rearrangement did harbor a BCL6 rearrangement, which,
although not specific, may be detected in up to 15% of FLs and a
small proportion of nodal and extranodal MZLs1,4,5,48. Overall, 45%
of FLs with predominantly intrafollicular PCD and 75% of FLs with
mixed intrafollicular/interfollicular PCD lacked demonstrable BCL2
or BCL6 rearrangements, similar to our prior series6. One of the
cytogenetic hallmarks of MZL, although not specific, are trisomies,
especially of chromosomes 3 and 181. Although centromeric
probes were not used in this study, all cases with extra copies of
the BCL2 probe on chromosome 18 were among the subtype with
intrafollicular or mixed intrafollicular/interfollicular PCD, raising the
possibility that they had partial or complete trisomy 18. Extra
copies of the BCL6 probe, which would be consistent with
complete or partial trisomy 3, were also more common in the
intrafollicular or mixed intrafollicular/interfollicular PCD cases than
in the subtype with predominantly interfollicular PCD.
The mutational analysis further supported the distinction
between the two major subtypes of FL-PCD and showed that
while there might be some distinctive findings compared to other
FL, it was the group with intrafollicular PCD that was more similar
to NMZL. Similar to classic FL, cases with interfollicular PCD
frequently harbored alterations in epigenetic regulators including
CREBBP, EZH2, and KMT2D. Mutations in TNFRSF14, which is
mutated in approximately 33% of published FLs, were also found
in a similar proportion of cases with interfollicular PCD, but are
found in only about 10% of NMZLs5,13–26,33. When compared to
published FL and NMZL, the overall mutational profile of the
interfollicular PCD subtype was more similar to that of FL,
although it should be noted that TNFAIP3, which is more
frequently altered in NMZL, was mutated in 30% of interfollicular
PCD cases5,13–26,33. Additionally, BCL2, which is mutated in up to
half of the published FLs, was mutated in only one case with
interfollicular PCD13–22,29,33. Although the significant difference in
the mutation frequency of BCL2 may be related to the relatively
small size of our study cohort, it does raise the possibility that FL
with interfollicular PCD is genetically distinct from classic FL.
The intrafollicular PCD subtype had an overall mutational profile
that was more comparable to NMZL5,13–26,33. EZH2 and KMT2D
were less frequently mutated in this subtype, and no intrafollicular
PCD cases harbored a CREBBP mutation, which was statistically
Modern Pathology (2022) 35:60 – 68

significant. In looking more closely, the 5 cases with intrafollicular
PCD that lacked BCL2 and BCL6 rearrangements, also lacked
mutations in epigenetic regulators in all but one case, and in
contrast, 3 of the 5 showed mutations in genes implicated in NF-
κB or NOTCH signaling pathways. Four of these 5 cases were CD10
negative, but did express at least 2 other GC-associated markers,
contained plasmacytic/plasmacytoid cells that were IgM restricted,
and had plasmacytoid or small, round cell cytologic features.
These findings support the hypothesis that at least a significant
subset of cases with intrafollicular PCD has features often
associated with MZL and suggest a constellation of findings that
may help in their identification. Whether some or all of these cases
are better considered as a part of the heterogeneous category of
BCL2 non-rearranged FL or as MZL with prominent follicular
colonization remains uncertain, given their prominent follicular
growth pattern and expression of some GC-associated markers. It
might be that the subset that lacks BCL2 and BCL6 rearrangements
and has extra copies of these gene regions is the most like an
unusual MZL and should be segregated. Mutational studies may
provide additional support in some cases for this segregation.
Although it could be postulated that some FL-PCD composed of
bona fide GC cells lose their CD10 expression because of acquired
NF-κB activation, just as NF-κB activation leads to down-regulation
of CD10 expression in GCB-like diffuse large B-cell lymphoma cell
lines38,40,49,50, this would not explain why many of these cases lack
other features associated with classic FL.
The 4 cases with mixed intrafollicular/interfollicular PCD
identified in this study appeared to have overlapping features
with both of the major subtypes of FL-PCD. Similar to cases with
intrafollicular PCD, cases with mixed intrafollicular/interfollicular
PCD more commonly had follicle center cells with plasmacytoid
cytology, often lacked CD10 expression, and uniformly contained
plasmacytic/plasmacytoid cells that expressed IgM. Genetically
these cases also showed overlap with intrafollicular PCD cases,
including a frequent lack of BCL2 or BCL6 rearrangements,
presence of gains of BCL2 and/or BCL6, as well as mutations in
genes implicated in NF-κB signaling. However, mutations in genes
involved in epigenetic regulation were also commonly observed,
which more closely overlaps with the mutational profile of cases
with interfollicular PCD as well as classic FL. The limited number of
cases with mixed intrafollicular/interfollicular PCD in this study
precludes meaningful statistical analyses or a more definitive
conclusion on how to best regard this group.
In conclusion, this study confirms and expands the prior
observation that there are two main subtypes of FL-PCD, with
significant morphologic, immunophenotypic, and genetic differ-
ences, plus a small number of intermediate cases. The subtype
with predominantly interfollicular PCD, which generally retains
expression of CD10, harbors a BCL2 rearrangement, does not
commonly have extra copies of BCL2 or BCL6, and has a
mutational profile similar to other FLs, is clearly best considered
a type of classic FL. In contrast, the subtype with mostly
intrafollicular PCD, which often has follicles without many classic
centrocytes/centroblasts, frequently lacks CD10 expression, is
negative for BCL2 and/or BCL6 rearrangements in up to half of
the cases, commonly has FISH findings consistent with trisomies
of chromosomes 3 or 18, and has a mutational profile, while not
specific, that is indistinguishable from that found in NMZL.
Whether at least the subset of intrafollicular PCD cases lacking
BCL2 and BCL6 rearrangements would be better considered MZL
with extensive follicular colonization or just be considered a
distinct FL variant requires further study to determine if there are
any therapeutic or other clinical implications not discovered in the
current investigation. The findings also highlight the utility of a
multiparameter morphologic, immunophenotypic, and molecular/
genetic approach to categorizing the FL-PCD. From a practical
perspective, a more routine evaluation of BCL2 and BCL6 by FISH
Modern Pathology (2022) 35:60 – 68
S.E. Gibson et al.
67
would be of interest to help identify those FL-PCD that should not
be considered canonical FLs.
DATA AVAILABILITY
All data generated or analyzed during this study are included in this published article
[and its supplementary information files].
REFERENCES
1. Swerdlow S. H., et al (Eds). WHO classification of tumours of haematopoietic and
lymphoid tissues (Revised 4th edition). Lyon: IARC; 2017.
2. Pasqualucci, L. Molecular pathogenesis of germinal center-derived B cell lym-
phomas. Immunol. Rev. 288, 240–261 (2019).
3. Milpied, P. et al. Human germinal center transcriptional programs are de-
synchronized in B cell lymphoma. Nat. Immunol. 19, 1013–1024 (2018).
4. Wlodarska, I. et al. Fluorescence in situ hybridization identifies new chromosomal
changes involving 3q27 in non-Hodgkin’s lymphomas with BCL6/LAZ3 rearran-
gement. Genes Chromosomes Cancer 14, 1–7 (1995).
5. Nann, D. et al. Follicular lymphoma t(14;18)-negative is genetically a hetero-
geneous disease. Blood Adv. 4, 5652–5665 (2020).
6. Gradowski, J. F. et al. Follicular lymphomas with plasmacytic differentiation
include two subtypes. Mod. Pathol. 23, 71–79 (2010).
7. Nathwani, B. N. et al. Clinical significance of follicular lymphoma with monocytoid
B cells. Non-Hodgkin’s Lymphoma Classification Project. Hum. Pathol. 30,
263–268 (1999).
8. Yegappan, S., Schnitzer, B. & Hsi, E. D. Follicular lymphoma with marginal zone
differentiation: microdissection demonstrates the t(14;18) in both the follicular
and marginal zone components. Mod. Pathol. 14, 191–196 (2001).
9. Goodlad, J. R., Batstone, P. J., Hamilton, D. & Hollowood, K. Follicular lymphoma
with marginal zone differentiation: cytogenetic findings in support of a high-risk
variant of follicular lymphoma. Histopathology 42, 292–298 (2003).
10. Torlakovic, E. E., Aamot, H. V. & Heim, S. A marginal zone phenotype in follicular
lymphoma with t(14;18) is associated with secondary cytogenetic aberrations
typical of marginal zone lymphoma. J. Pathol. 209, 258–264 (2006).
11. Keith, T. A., Cousar, J. B., Glick, A. D., Vogler, L. B. & Collins, R. D. Plasmacytic
differentiation in follicular center cell (FCC) lymphomas. Am. J. Clin. Pathol. 84,
283–290 (1985).
12. Matsumoto, Y. et al. A case of AL amyloidosis associated with follicular lymphoma
with plasmacytic differentiation. Int. J. Hematol. 111, 317–323 (2020).
13. Bodor, C. et al. EZH2 mutations are frequent and represent an early event in
follicular lymphoma. Blood 122, 3165–3168 (2013).
14. Li, H. et al. Mutations in linker histone genes HIST1H1 B, C, D, and E; OCT2
(POU2F2); IRF8; and ARID1A underlying the pathogenesis of follicular lymphoma.
Blood 123, 1487–1498 (2014).
15. Pasqualucci, L. et al. Genetics of follicular lymphoma transformation. Cell Rep. 6,
130–140 (2014).
16. Okosun, J. et al. Integrated genomic analysis identifies recurrent mutations and
evolution patterns driving the initiation and progression of follicular lymphoma.
Nat. Genet. 46, 176–181 (2014).
17. Pastore, A. et al. Integration of gene mutations in risk prognostication for patients
receiving first-line immunochemotherapy for follicular lymphoma: a retrospective
analysis of a prospective clinical trial and validation in a population-based reg-
istry. Lancet. Oncol. 16, 1111–1122 (2015).
18. Correia, C. et al. BCL2 mutations are associated with increased risk of transfor-
mation and shortened survival in follicular lymphoma. Blood 125, 658–667
(2015).
19. Louissaint, A. Jr. et al. Pediatric-type nodal follicular lymphoma: a biologically
distinct lymphoma with frequent MAPK pathway mutations. Blood 128,
1093–1100 (2016).
20. Schmidt, J. et al. Genome-wide analysis of pediatric-type follicular lymphoma
reveals low genetic complexity and recurrent alterations of TNFRSF14 gene.
Blood 128, 1101–1111 (2016).
21. Krysiak, K. et al. Recurrent somatic mutations affecting B-cell receptor signaling
pathway genes in follicular lymphoma. Blood 129, 473–483 (2017).
22. Bouska, A. et al. Combined copy number and mutation analysis identifies
oncogenic pathways associated with transformation of follicular lymphoma.
Leukemia 31, 83–91 (2017).
23. Spina, V. et al. The genetics of nodal marginal zone lymphoma. Blood 128,
1362–1373 (2016).
24. van den Brand, M. et al. Recurrent mutations in genes involved in nuclear factor-
kappaB signalling in nodal marginal zone lymphoma-diagnostic and therapeutic
implications. Histopathology 70, 174–184 (2017).
 S.E. Gibson et al.
68
25. Gurth, M., Bernard, V., Bernd, H. W., Schemme, J. & Thorns, C. Nodal marginal zone
lymphoma: mutation status analyses of CD79A, CD79B, and MYD88 reveal no
specific recurrent lesions. Leuk Lymphoma 58, 979–981 (2017).
26. Pillonel, V. et al. High-throughput sequencing of nodal marginal zone lymphomas
identifies recurrent BRAF mutations. Leukemia 32, 2412–2426 (2018).
27. Moore, E. M., Swerdlow, S. H. & Gibson, S. E. Comparison of myocyte enhancer factor
2B versus other germinal center-associated antigens in the differential diagnosis of
B-cell non-Hodgkin lymphomas. Am. J. Surg. Pathol. 42, 342–350 (2018).
28. Li, M. M. et al. Standards and guidelines for the interpretation and reporting of
sequence variants in cancer: a joint consensus recommendation of the associa-
tion for molecular pathology, american society of clinical oncology, and college
of american pathologists. J. Mol. Diagn 19, 4–23 (2017).
29. Adzhubei, I. A. et al. A method and server for predicting damaging missense
mutations. Nat. Methods 7, 248–249 (2010).
30. Choi, Y. & Chan, A. P. PROVEAN web server: a tool to predict the functional effect
of amino acid substitutions and indels. Bioinformatics 31, 2745–2747 (2015).
31. Tate, J. G. et al. COSMIC: the catalogue of somatic mutations in cancer. Nucleic
Acids Res. 47, D941–D947 (2019).
32. Vaser, R., Adusumalli, S., Leng, S. N., Sikic, M. & Ng, P. C. SIFT missense predictions
for genomes. Nat. Protoc. 11, 1–9 (2016).
33. Barasch, N. J. K. et al. The molecular landscape and other distinctive features of
primary cutaneous follicle center lymphoma. Hum. Pathol. 106, 93–105 (2020).
34. Yuniati, L., Scheijen, B., van der Meer, L. T. & van Leeuwen, F. N. Tumor sup-
pressors BTG1 and BTG2: beyond growth control. J. Cell Physiol. 234, 5379–5389
(2019).
35. Vago, J. F., Hurtubise, P. E., Redden-Borowski, M. M., Martelo, O. J. & Swerdlow, S.
H. Follicular center-cell lymphoma with plasmacytic differentiation, monoclonal
paraprotein, and peripheral blood involvement. Recapitulation of normal B-cell
development. Am. J. Surg. Pathol. 9, 764–770 (1985).
36. Dogan, A. et al. Follicular lymphomas contain a clonally linked but phenotypically
distinct neoplastic B-cell population in the interfollicular zone. Blood 91,
4708–4714 (1998).
37. Frizzera, G., Anaya, J. S. & Banks, P. M. Neoplastic plasma cells in follicular lym-
phomas. Clinical and pathologic findings in six cases. Virchows Arch A Pathol Anat
Histopathol 409, 149–162 (1986).
38. Chapman, J. R. et al. Unusual variants of follicular lymphoma: case-based review.
Am. J. Surg. Pathol. 44, 329–339 (2020).
39. Naresh, K. N. Nodal marginal zone B-cell lymphoma with prominent follicular
colonization - difficulties in diagnosis: a study of 15 cases. Histopathology 52,
331–339 (2008).
40. van den Brand, M. et al. Immunohistochemical differentiation between follicular
lymphoma and nodal marginal zone lymphoma-combined performance of
multiple markers. Haematologica 100, e358–e360 (2015).
41. Falini, B. et al. IRTA1 is selectively expressed in nodal and extranodal marginal
zone lymphomas. Histopathology 61, 930–941 (2012).
42. Falini, B. et al. A monoclonal antibody (MUM1p) detects expression of the MUM1/
IRF4 protein in a subset of germinal center B cells, plasma cells, and activated
T cells. Blood 95, 2084–2092 (2000).
43. Sanz, I. et al. Challenges and opportunities for consistent classification of human
B cell and plasma cell populations. Front. Immunol. 10, 2458 (2019).
44. Klein, U. & Dalla-Favera, R. Germinal centres: role in B-cell physiology and
malignancy. Nat. Rev. Immunol. 8, 22–33 (2008).
45. Jego, G. et al. Reactive plasmacytoses are expansions of plasmablasts retaining
the capacity to differentiate into plasma cells. Blood 94, 701–712 (1999).
46. Bataille, R. et al. The phenotype of normal, reactive and malignant plasma cells.
Identification of “many and multiple myelomas” and of new targets for myeloma
therapy. Haematologica 91, 1234–1240 (2006).
47. Nathwani, B. N., Winberg, C. D., Diamond, L. W., Bearman, R. M. & Kim, H. Mor-
phologic criteria for the differentiation of follicular lymphoma from florid reactive
follicular hyperplasia: a study of 80 cases. Cancer 48, 1794–1806 (1981).
48. Ye, H. et al. Chromosomal translocations involving BCL6 in MALT lymphoma.
Haematologica 93, 145–146 (2008).
49. Poveda, J. et al. Expression of germinal center cell markers by extranodal mar-
ginal zone lymphomas of MALT type within colonized follicles, a diagnostic pitfall
with follicular lymphoma. Leuk Lymphoma 62, 1116–1122 (2021).
50. Thompson, R. C., Herscovitch, M., Zhao, I., Ford, T. J. & Gilmore, T. D. NF-kappaB
down-regulates expression of the B-lymphoma marker CD10 through a miR-155/
PU.1 pathway. J. Biol. Chem. 286, 1675–1682 (2011).
AUTHOR CONTRIBUTIONS
S.E.G and S.H.S conceived and designed the study, acquired, analyzed, and
interpreted the data, and wrote and edited the paper; Y-C.L helped analyze the
mutational data, and reviewed and edited the manuscript; S.A.Y acquired some of the
FISH data, and reviewed and edited the paper; N.J.B helped acquire clinical data,
performed a subset of the meta-analysis, and reviewed the paper.
ETHICS APPROVAL AND CONSENT TO PARTICIPATE
The study was approved by the University of Pittsburgh Institutional Review Board
(STUDY20070099) with a waiver of consent. It was performed in accordance with the
Declaration of Helsinki.
COMPETING INTERESTS
The authors declare no competing interests.
ADDITIONAL INFORMATION
Supplementary information The online version contains supplementary material
available at https://doi.org/10.1038/s41379-021-00938-z.
Correspondence and requests for materials should be addressed to Sarah E. Gibson.
Reprints and permission information is available at http://www.nature.com/
reprints
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims
in published maps and institutional affiliations.
Modern Pathology (2022) 35:60 – 68