Special Section2014 New Frontiers in Pathology

Reed-SternbergLike Cells in Non-Hodgkin LymphomasJuan C. Gomez-Gelvez, MD; Lauren B. Smith, MD

Large atypical cells with morphologic and immunopheno-typic features resembling Reed-Sternberg cells can be seen inthe background of reactive lymphadenopathies as well asnon-Hodgkin lymphomas. The presence of these cells is animportant diagnostic pitfall that must be recognized bypathologists who regularly interpret lymph node biopsies. Athorough evaluation of the morphologic and immunophe-notypic features of these cells and the cellular milieu iscrucial in achieving the correct diagnosis. In this review,examples of lymphomas presenting with Reed-Sternberglike cells will be provided. Additionally, a detailed descrip-tion of the common morphologic and immunophenotypicfeatures of these cells, as well as strategies that can be usedto distinguish them from the Reed-Sternberg cells of classicalHodgkin lymphoma, will be emphasized.(Arch Pathol Lab Med. 2015;139:12051210; doi:

10.5858/arpa.2015-0197-RA)

Non-Hodgkin lymphomas can occasionally present withmorphologic features that resemble classical Hodgkinlymphoma. The distinction between these 2 groups maybecome more challenging with the presence of scatteredlarge cells that morphologically and immunophenotypicallymimic the Reed-Sternberg cells of classical Hodgkinlymphoma. These cells, also known as Reed-Sternberglike(RS-like) cells, are commonly seen in high-grade lympho-mas, in which the neoplastic lymphocytes form sheets.However, rare cases of low-grade B-cell and T-celllymphomas can also present with scattered RS-like cells.13

In this context, they may represent a major diagnosticchallenge for the interpreting pathologist.

Among low-grade B-cell lymphomas, RS-like cells can beseen in chronic lymphocytic leukemia/small lymphocyticlymphoma (CLL/SLL), follicular lymphoma, or marginal zonelymphoma.2,49 In the setting of CLL/SLL, RS-like cells arescattered in the background of neoplastic cells. They maydisplay an activated B-cell immunophenotype characterizedby expression of CD20 and CD30 and are typically negative forCD15; however, in some cases, they may show expression of

both CD30 and CD15, making them virtually indistinguish-able from the true RS cell of classical Hodgkin lymphomas.9,10

In these cases, microdissection-based analysis has demon-strated that RS-like cells may or may not be clonally related tothe neoplastic B cells and are derived from germinal center Bcells given the presence of ongoing somatic hypermutation.6

Additionally, RS-like cells in CLL/SLL cases are frequentlypositive for Epstein-Barr virus, which may play a role in thepathogenesis of these cells, as well as in the transformation toHodgkin lymphoma variant of Richter syndrome.7,1114 WhenRS-like cells are seen in the context of CLL/SLL, this iscommonly referred to as CLL/SLL with HRS cells.

In the setting of follicular lymphomas, RS-like cells maybe few or numerous and can be seen between or within theneoplastic follicles.4,15 In these cases, the RS-like cells havebeen shown to have identical immunoglobulin heavy-chaingene rearrangements to those of the neoplastic centrocytesand centroblasts, suggesting a common cell of origin in spiteof their distinct morphology and immunophenotype.4 Asopposed to CLL/SLL cases, the RS-like cells seen infollicular lymphomas are not associated with Epstein-Barrvirus infection.4

In T-cell lymphomas, RS-like cells of B-cell lineage arecharacteristically seen in angioimmunoblastic T-cell lym-phoma and, more rarely, in peripheral T-cell lymphoma, nototherwise specified. The RS-like cells demonstrate expres-sion of CD30, CD20, and occasionally CD15.1,16 Addition-ally, RS-like cells are commonly associated with Epstein-Barr virus infection and may serve as the initiating event intransformation to diffuse large B-cell lymphoma. This rareoccurrence is believed to be related to the defective immunesurveillance secondary to the underlying T-cell malignan-cy.1723 More recently, the existence of RS-like cells of T-celllineage in the context of T-cell lymphomas has also beenreported. In these particular cases, the RS-like cells have notbeen associated with Epstein-Barr virus infection anddemonstrate expression of CD30 and CD15, at least oneT-cell marker, and a lack of B-cell markers.24

In the following examples, the presence of RS-like cellspresented a diagnostic challenge. Recommendations will beprovided on how to differentiate non-Hodgkin lymphomaswith RS-like cells from classical Hodgkin lymphomas, adistinction that is of vital importance for the managementand prognosis of patients.

RS-LIKE CELLS IN LOW-GRADEB-CELL NON-HODGKIN LYMPHOMAS

(FOLLICULAR LYMPHOMA)

Core needle biopsies are increasingly used for thediagnosis of lymphoproliferative disorders in daily practice.

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; September46, 2014; Ann Arbor, Michigan.Reprints: Lauren B. Smith, MD, Department of Pathology,

University of Michigan Medical School, 1301 Catherine St, AnnArbor, MI 48109 (e-mail: lbsmith@umich.edu).

Arch Pathol Lab MedVol 139, October 2015 Reed-SternbergLike Cells in Non-Hodgkin LymphomasGomez-Gelvez & Smith 1205

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,

follicular lymphomas often present with stromal fibrosis,

especially in retroperitoneal or perinephric locations. Their

neoplastic lymphoid infiltrate is composed of small cen-

trocytes with elongated and cleaved nuclei, and scattered

Figure 1. Follicular lymphoma with Reed-Sternberglike (RS-like) cells in a core biopsy. A, Vaguely nodular lymphocytic proliferation withprominent 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) (hematoxylin-eosin, original magnifications320 [A] and3400 [B]; original magnifications3400 [C through E], and3200 [F]).

1206 Arch Pathol Lab MedVol 139, October 2015 Reed-SternbergLike Cells in Non-Hodgkin LymphomasGomez-Gelvez & Smith

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

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

Figure 2. Follicular lymphoma with Reed-Sternberglike (RS-like) cells in an excisional biopsy. A, Nodal architecture effaced by neoplastic folliclesconsistent 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 magnifications320 [A] and3400 [B and C]; original magnification31000 [D through F and insets]).

Arch Pathol Lab MedVol 139, October 2015 Reed-SternbergLike Cells in Non-Hodgkin LymphomasGomez-Gelvez & Smith 1207

infiltrate. Nonetheless, they usually exhibit a more pro-

nounced polymorphic lymphoid population with variably

sized lymphocytes and overt cytologic atypia.

Immunohistochemical studies from the example illustrat-

ed in Figure 1 showed that both the small lymphocytes and

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

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 magnifications320 [A] and3400 [B]; original magnifications3400 [C through F], and31000 [insets]).

1208 Arch Pathol Lab MedVol 139, October 2015 Reed-SternbergLike Cells in Non-Hodgkin LymphomasGomez-Gelvez & Smith

follicular lymphoma. The immunophenotype did notsupport classical Hodgkin lymphoma, as the RS-like cellsexpressed CD45, CD20, and BCL-6 and were negative forfascin. This diagnosis was further corroborated by thepresence of a small paratrabecular lymphoid aggregate inthe staging bone marrow biopsy. Interestingly, the neo-plastic cells were CD10 positive on flow cytometric analysisof the bone marrow aspirate.

Although not a typical immunophenotype, it is importantto keep in mind that B-cell markers can be expressed onclassical RS cells. For example, CD20 and CD79a may bepresent in approximately 30% and 10% of cases, respective-ly.25,26 BCL-6, a B-cell transcription factor, can also be seen inapproximately 40% of cases.27 A useful clue for recognizingclassical RS cells versus RS-like cells is the pattern ofexpression of the different markers. On classical RS cells,CD30 is usually strong and homogeneous, whereas B-cellmarkers, when present, demonstrate a variable pattern ofexpression and are commonly weaker than CD30. Converse-ly, on RS-like cells, the B-cell markers tend to behomogenously expressed whereas CD30 is usually weaker.In this example, the expression of CD45, CD20, and BCL-6was strong and homogeneous, and CD30 was weaker.Additionally, fascin, a highly sensitive but poorly specificmarker for classical RS cells, was negative, which supportedour interpretation of RS-like cells.

In cases with RS-like cells expressing CD30 and CD15, thedifferential diagnosis includes not only classical Hodgkinlymphomas and non-Hodgkin lymphomas, but also com-posite lymphomas, especially when RS-like cells arenumerous. Figure 2, A through C, illustrates an exampleof a follicular lymphoma with numerous scattered RS-likecells. Immunohistochemical evaluation demonstrated ex-pression of CD30 and CD15 on the RS-like cells.Additionally, the RS-like cells also expressed CD45 (leuko-cyte common antigen), CD20, PAX-5, CD10, BCL-6, andBCL-2 (Figure 2, D through F). Although some of thesemarkers can be seen on classical RS cells, their concomitantand homogeneous expression would not be typical. PAX-5,for example, is typically weakly expressed by classical RScells, and strong expression would be more compatible witha B-cell non-Hodgkin lymphoma.28,29 The concomitantexpression of germinal center makers (ie, CD10 and BCL-6) is virtually never seen in classical RS cells and can be usedas convincing evidence of the presence of RS-like cells.30

Reed-Sternberglike cells, when associated with follicularlymphoma, may express CD10 and have identical immu-noglobulin heavy-chain gene rearrangements to those ofthe neoplastic germinal center cells.4 Of note, RS-like cellsare typically counted as centroblasts when grading follicularlymphomas.

Small B-cell lymphomas with RS-like cells can easily bemistaken for classical Hodgkin lymphomas in limitedsamples. Strict morphologic and immunophenotypic criteriamust be applied in order to reach the correct diagnosis inthese situations.

RS-LIKE CELLS IN PERIPHERAL T-CELL LYMPHOMAS

Peripheral T-cell lymphomas with RS-like cells representone of the most challenging differential diagnosis of classicalHodgkin lymphomas because of the characteristic mixedinflammatory background seen in both entities. Figure 3, Aand B, illustrates an excisional lymph node biopsy showing

distorted architecture with proliferation of an atypicalpolymorphous infiltrate including scattered RS-like cells.

In this example, immunohistochemical studies demon-strated that the RS-like cells were positive for CD30 andCD15 and negative for CD45 (leukocyte common antigen)and B-cell markers including CD20, PAX-5, CD10, andBCL-6. A subset of the RS-like cells also showed expressionof CD3 and CD4 (Figure 3, C through F). The vast majorityof the small lymphocytes in the background were CD3-positive lymphocytes with coexpression of CD4, CD5, andCD45 (weak). Importantly, CD7 was negative on themajority of these cells.

There are several clues that lead to the correct diagnosis inthis example. The absence of PAX-5 argues against classicalHodgkin lymphoma.31,32 The expression of CD3 and CD4 ona subset of the RS-like cells is consistent with a T-cellimmunophenotype. Furthermore, the presence of a mor-phologically and immunophenotypically abnormal lympho-cytic infiltrate is not characteristic of classical Hodgkinlymphoma. Angioimmunoblastic T-cell lymphoma wasdiagnosed given the increased vasculature and the expres-sion of BCL-6 and PD-1 in a subset of the background Tcells.

Reed-Sternberglike cells in T-cell lymphomas typicallypresent with a B-cell immunophenotype. More recently theyhave also been reported expressing T-cell markers whilelacking B-cell markers. This is an important pitfall torecognize because T-cell lymphomas and classical Hodgkinlymphomas frequently present with similar mixed inflam-matory infiltrates. Careful evaluation of the morphologicand immunophenotypic features of background lympho-cytes is important in reaching a correct diagnosis. T-cellreceptor gene rearrangement studies can be used to confirmthe morphologic and immunophenotypic impression.

CONCLUSIONS

Distinction between classical Hodgkin lymphoma andnon-Hodgkin lymphoma is crucial because of differences inprognosis and treatment. Reed-Sternberglike cells areoften seen in non-Hodgkin lymphomas and may lead tomisdiagnosis on small biopsies. Awareness of the morpho-logic and immunophenotypic features of these cells, alongwith a careful scrutiny of the background inflammatorymilieu, is essential in appropriate classification.

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