Special Section2014 New Frontiers in Pathology

Reed-SternbergLike Cells in Non-Hodgkin Lymphomas

Juan C. Gomez-Gelvez, MD; Lauren B. Smith, MD

 Large atypical cells with morphologic and immunophenotypic features resembling Reed-Sternberg cells can be seen in
the background of reactive lymphadenopathies as well as
non-Hodgkin lymphomas. The presence of these cells is an
important diagnostic pitfall that must be recognized by
pathologists who regularly interpret lymph node biopsies. A
thorough evaluation of the morphologic and immunophenotypic features of these cells and the cellular milieu is
crucial in achieving the correct diagnosis. In this review,
examples of lymphomas presenting with Reed-Sternberg
like cells will be provided. Additionally, a detailed description of the common morphologic and immunophenotypic
features of these cells, as well as strategies that can be used
to distinguish them from the Reed-Sternberg cells of classical
Hodgkin lymphoma, will be emphasized.
(Arch Pathol Lab Med. 2015;139:12051210; doi:
10.5858/arpa.2015-0197-RA)

on-Hodgkin lymphomas can occasionally present with

morphologic features that resemble classical Hodgkin
lymphoma. The distinction between these 2 groups may
become more challenging with the presence of scattered
large cells that morphologically and immunophenotypically
mimic the Reed-Sternberg cells of classical Hodgkin
lymphoma. These cells, also known as Reed-Sternberglike
(RS-like) cells, are commonly seen in high-grade lymphomas, in which the neoplastic lymphocytes form sheets.
However, rare cases of low-grade B-cell and T-cell
lymphomas can also present with scattered RS-like cells.13
In this context, they may represent a major diagnostic
challenge for the interpreting pathologist.
Among low-grade B-cell lymphomas, RS-like cells can be
seen in chronic lymphocytic leukemia/small lymphocytic
lymphoma (CLL/SLL), follicular lymphoma, or marginal zone
lymphoma.2,49 In the setting of CLL/SLL, RS-like cells are
scattered in the background of neoplastic cells. They may
display an activated B-cell immunophenotype characterized
by expression of CD20 and CD30 and are typically negative for
CD15; however, in some cases, they may show expression of
Accepted for publication June 1, 2015.
From the Department of Pathology, University of Michigan
Medical School, Ann Arbor.
The authors have no relevant financial interest in the products or
companies described in this article.
Presented in part at the New Frontiers in Pathology: An Update for
Practicing Pathologists meeting; University of Michigan; September
46, 2014; Ann Arbor, Michigan.
Reprints: Lauren B. Smith, MD, Department of Pathology,
University of Michigan Medical School, 1301 Catherine St, Ann
Arbor, MI 48109 (e-mail: lbsmith@umich.edu).
Arch Pathol Lab MedVol 139, October 2015

both CD30 and CD15, making them virtually indistinguishable from the true RS cell of classical Hodgkin lymphomas.9,10
In these cases, microdissection-based analysis has demonstrated that RS-like cells may or may not be clonally related to
the neoplastic B cells and are derived from germinal center B
cells given the presence of ongoing somatic hypermutation.6
Additionally, RS-like cells in CLL/SLL cases are frequently
positive for Epstein-Barr virus, which may play a role in the
pathogenesis of these cells, as well as in the transformation to
Hodgkin lymphoma variant of Richter syndrome.7,1114 When
RS-like cells are seen in the context of CLL/SLL, this is
commonly referred to as CLL/SLL with HRS cells.
In the setting of follicular lymphomas, RS-like cells may
be few or numerous and can be seen between or within the
neoplastic follicles.4,15 In these cases, the RS-like cells have
been shown to have identical immunoglobulin heavy-chain
gene rearrangements to those of the neoplastic centrocytes
and centroblasts, suggesting a common cell of origin in spite
of their distinct morphology and immunophenotype.4 As
opposed to CLL/SLL cases, the RS-like cells seen in
follicular lymphomas are not associated with Epstein-Barr
virus infection.4
In T-cell lymphomas, RS-like cells of B-cell lineage are
characteristically seen in angioimmunoblastic T-cell lymphoma and, more rarely, in peripheral T-cell lymphoma, not
otherwise specified. The RS-like cells demonstrate expression of CD30, CD20, and occasionally CD15.1,16 Additionally, RS-like cells are commonly associated with EpsteinBarr virus infection and may serve as the initiating event in
transformation to diffuse large B-cell lymphoma. This rare
occurrence is believed to be related to the defective immune
surveillance secondary to the underlying T-cell malignancy.1723 More recently, the existence of RS-like cells of T-cell
lineage in the context of T-cell lymphomas has also been
reported. In these particular cases, the RS-like cells have not
been associated with Epstein-Barr virus infection and
demonstrate expression of CD30 and CD15, at least one
T-cell marker, and a lack of B-cell markers.24
In the following examples, the presence of RS-like cells
presented a diagnostic challenge. Recommendations will be
provided on how to differentiate non-Hodgkin lymphomas
with RS-like cells from classical Hodgkin lymphomas, a
distinction that is of vital importance for the management
and prognosis of patients.
RS-LIKE CELLS IN LOW-GRADE
B-CELL NON-HODGKIN LYMPHOMAS
(FOLLICULAR LYMPHOMA)
Core needle biopsies are increasingly used for the
diagnosis of lymphoproliferative disorders in daily practice.

Reed-SternbergLike Cells in Non-Hodgkin LymphomasGomez-Gelvez & Smith 1205

Figure 1. Follicular lymphoma with Reed-Sternberglike (RS-like) cells in a core biopsy. A, Vaguely nodular lymphocytic proliferation with
prominent stromal fibrosis. B, Higher magnification demonstrates small lymphocytes with cytologic atypia intermixed with numerous RS-like cells,
which demonstrate homogeneous expression of CD20 (C) and BCL-6 (D), variable expression of CD30 (E), and negative CD15 (F) (hematoxylineosin, original magnifications 320 [A] and 3400 [B]; original magnifications 3400 [C through E], and 3200 [F]).

Figure 1, A and B, illustrates a core needle biopsy from a

retroperitoneal mass showing a dense lymphocytic infiltrate
with cytologic atypia, prominent stromal fibrosis, and
numerous RS-like cells. Among non-Hodgkin lymphomas,
1206 Arch Pathol Lab MedVol 139, October 2015

follicular lymphomas often present with stromal fibrosis,

especially in retroperitoneal or perinephric locations. Their
neoplastic lymphoid infiltrate is composed of small centrocytes with elongated and cleaved nuclei, and scattered

Reed-SternbergLike Cells in Non-Hodgkin LymphomasGomez-Gelvez & Smith

Figure 2. Follicular lymphoma with Reed-Sternberglike (RS-like) cells in an excisional biopsy. A, Nodal architecture effaced by neoplastic follicles
consistent with follicular lymphoma. B and C, Higher magnification demonstrates scattered RS-like cells (black arrows) positive for CD20 (D), CD30
(E), and CD15 (F) (hematoxylin-eosin, original magnifications 320 [A] and 3400 [B and C]; original magnification 31000 [D through F and insets]).

centroblasts with open chromatin and membrane-bound

nucleoli. Classical Hodgkin lymphomas should also be
considered in limited biopsies with RS-like cells. Classical
Hodgkin lymphoma is often associated with prominent
fibrosis, but the inflammatory infiltrate is characteristically
Arch Pathol Lab MedVol 139, October 2015

composed of a mixed population of eosinophils, plasma

cells, histiocytes, and small lymphocytes without cytologic
atypia. Finally, a peripheral T-cell lymphoma should also be
considered given the presence of cytologic atypia in the
small lymphocytes and the prominent mixed inflammatory

Reed-SternbergLike Cells in Non-Hodgkin LymphomasGomez-Gelvez & Smith 1207

Figure 3. Angioimmunoblastic T-cell lymphoma with Reed-Sternberglike cells. A, Distorted nodal architecture with a diffuse polymorphic infiltrate.
B, Reed-Sternberglike cells scattered in a lymphohistiocytic background showing expression of CD3 (C), CD4 (D), CD30 (E), and CD15 (F)
(hematoxylin-eosin, original magnifications 320 [A] and 3400 [B]; original magnifications 3400 [C through F], and 31000 [insets]).

infiltrate. Nonetheless, they usually exhibit a more pronounced polymorphic lymphoid population with variably
sized lymphocytes and overt cytologic atypia.
Immunohistochemical studies from the example illustrated in Figure 1 showed that both the small lymphocytes and
1208 Arch Pathol Lab MedVol 139, October 2015

the RS-like cells were positive for CD20, BCL-6, and CD45
(leukocyte common antigen) and negative for CD10 (Figure
1, C and D). Additionally, the RS-like cells were positive for
CD30 and negative for CD15 and fascin (Figure 1, E and F).
In spite of the lack of CD10, BCL-6 supported a diagnosis of

Reed-SternbergLike Cells in Non-Hodgkin LymphomasGomez-Gelvez & Smith

follicular lymphoma. The immunophenotype did not

support classical Hodgkin lymphoma, as the RS-like cells
expressed CD45, CD20, and BCL-6 and were negative for
fascin. This diagnosis was further corroborated by the
presence of a small paratrabecular lymphoid aggregate in
the staging bone marrow biopsy. Interestingly, the neoplastic cells were CD10 positive on flow cytometric analysis
of the bone marrow aspirate.
Although not a typical immunophenotype, it is important
to keep in mind that B-cell markers can be expressed on
classical RS cells. For example, CD20 and CD79a may be
present in approximately 30% and 10% of cases, respectively.25,26 BCL-6, a B-cell transcription factor, can also be seen in
approximately 40% of cases.27 A useful clue for recognizing
classical RS cells versus RS-like cells is the pattern of
expression of the different markers. On classical RS cells,
CD30 is usually strong and homogeneous, whereas B-cell
markers, when present, demonstrate a variable pattern of
expression and are commonly weaker than CD30. Conversely, on RS-like cells, the B-cell markers tend to be
homogenously expressed whereas CD30 is usually weaker.
In this example, the expression of CD45, CD20, and BCL-6
was strong and homogeneous, and CD30 was weaker.
Additionally, fascin, a highly sensitive but poorly specific
marker for classical RS cells, was negative, which supported
our interpretation of RS-like cells.
In cases with RS-like cells expressing CD30 and CD15, the
differential diagnosis includes not only classical Hodgkin
lymphomas and non-Hodgkin lymphomas, but also composite lymphomas, especially when RS-like cells are
numerous. Figure 2, A through C, illustrates an example
of a follicular lymphoma with numerous scattered RS-like
cells. Immunohistochemical evaluation demonstrated expression of CD30 and CD15 on the RS-like cells.
Additionally, the RS-like cells also expressed CD45 (leukocyte common antigen), CD20, PAX-5, CD10, BCL-6, and
BCL-2 (Figure 2, D through F). Although some of these
markers can be seen on classical RS cells, their concomitant
and homogeneous expression would not be typical. PAX-5,
for example, is typically weakly expressed by classical RS
cells, and strong expression would be more compatible with
a B-cell non-Hodgkin lymphoma.28,29 The concomitant
expression of germinal center makers (ie, CD10 and BCL6) is virtually never seen in classical RS cells and can be used
as convincing evidence of the presence of RS-like cells.30
Reed-Sternberglike cells, when associated with follicular
lymphoma, may express CD10 and have identical immunoglobulin heavy-chain gene rearrangements to those of
the neoplastic germinal center cells.4 Of note, RS-like cells
are typically counted as centroblasts when grading follicular
lymphomas.
Small B-cell lymphomas with RS-like cells can easily be
mistaken for classical Hodgkin lymphomas in limited
samples. Strict morphologic and immunophenotypic criteria
must be applied in order to reach the correct diagnosis in
these situations.
RS-LIKE CELLS IN PERIPHERAL T-CELL LYMPHOMAS
Peripheral T-cell lymphomas with RS-like cells represent
one of the most challenging differential diagnosis of classical
Hodgkin lymphomas because of the characteristic mixed
inflammatory background seen in both entities. Figure 3, A
and B, illustrates an excisional lymph node biopsy showing
Arch Pathol Lab MedVol 139, October 2015

distorted architecture with proliferation of an atypical

polymorphous infiltrate including scattered RS-like cells.
In this example, immunohistochemical studies demonstrated that the RS-like cells were positive for CD30 and
CD15 and negative for CD45 (leukocyte common antigen)
and B-cell markers including CD20, PAX-5, CD10, and
BCL-6. A subset of the RS-like cells also showed expression
of CD3 and CD4 (Figure 3, C through F). The vast majority
of the small lymphocytes in the background were CD3positive lymphocytes with coexpression of CD4, CD5, and
CD45 (weak). Importantly, CD7 was negative on the
majority of these cells.
There are several clues that lead to the correct diagnosis in
this example. The absence of PAX-5 argues against classical
Hodgkin lymphoma.31,32 The expression of CD3 and CD4 on
a subset of the RS-like cells is consistent with a T-cell
immunophenotype. Furthermore, the presence of a morphologically and immunophenotypically abnormal lymphocytic infiltrate is not characteristic of classical Hodgkin
lymphoma. Angioimmunoblastic T-cell lymphoma was
diagnosed given the increased vasculature and the expression of BCL-6 and PD-1 in a subset of the background T
cells.
Reed-Sternberglike cells in T-cell lymphomas typically
present with a B-cell immunophenotype. More recently they
have also been reported expressing T-cell markers while
lacking B-cell markers. This is an important pitfall to
recognize because T-cell lymphomas and classical Hodgkin
lymphomas frequently present with similar mixed inflammatory infiltrates. Careful evaluation of the morphologic
and immunophenotypic features of background lymphocytes is important in reaching a correct diagnosis. T-cell
receptor gene rearrangement studies can be used to confirm
the morphologic and immunophenotypic impression.
CONCLUSIONS
Distinction between classical Hodgkin lymphoma and
non-Hodgkin lymphoma is crucial because of differences in
prognosis and treatment. Reed-Sternberglike cells are
often seen in non-Hodgkin lymphomas and may lead to
misdiagnosis on small biopsies. Awareness of the morphologic and immunophenotypic features of these cells, along
with a careful scrutiny of the background inflammatory
milieu, is essential in appropriate classification.
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