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Reed-Sternberg-Like Cells in Non-Hodgkin Lymphomas.

Non-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-Sternberg-like (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. (1-3) 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. (2,4-9) 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 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. (7,11-14) 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 Epstein-Barr 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. (17-23) 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. 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 centrocytes with elongated and cleaved nuclei, and scattered 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 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 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 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-Sternberg-like 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 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 CD3-positive 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-Sternberg-like 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-Sternberg-like 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.

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

References

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

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 4-6, 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).

Caption: Figure 1. Follicular lymphoma with Reed-Sternberg-like (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 X20 [A] and X400 [B]; original magnifications X400 [C through E], and X200 [F]).

Caption: Figure 2. Follicular lymphoma with Reed-Sternberg-like (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 X20 [A] and X400 [B and C]; original magnification X1000 [D through F and insets]).

Caption: Figure 3. Angioimmunoblastic T-cell lymphoma with Reed-Sternberg-like cells. A, Distorted nodal architecture with a diffuse polymorphic infiltrate. B, Reed-Sternberg-like cells scattered in a lymphohistiocytic background showing expression of CD3 (C), CD4 (D), CD30 (E), and CD15 (F) (hematoxylin-eosin, original magnifications X20 [A] and X400 [B]; original magnifications X400 [C through F], and X1000 [insets]).
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Title Annotation:Special Section--2014 New Frontiers in Pathology
Author:Gomez-Gelvez, Juan C.; Smith, Lauren B.
Publication:Archives of Pathology & Laboratory Medicine
Date:Oct 1, 2015
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