Lacunar and Reed-Sternberg–Like Cells in Follicular Lymphomas

Hematopathology / FOLLICULAR LYMPHOMA WITH HODGKIN AND REED-STERNBERG–LIKE CELLS

Lacunar and Reed-Sternberg–Like Cells in Follicular Lymphomas Are Clonally Related to the Centrocytic and Centroblastic Cells as Demonstrated by Laser Capture Microdissection Michael G. Bayerl, MD,1 Gail Bentley, MD,2 Cristiana Bellan, MD,3 Lorenzo Leoncini, MD,3 W. Christopher Ehmann, MD,4 and Margarita Palutke, MD2 Key Words: Lymphoma; Follicular; Hodgkin; Immunoglobulin; Mutation; Transformation DOI: 10.1309/PMR86PHKK4J3RUH3

Abstract Two cases of follicular lymphoma (FL) with numerous large cells resembling the lacunar and Hodgkin and Reed-Sternberg (HRS) cells of classic Hodgkin lymphoma were studied to determine clonal relationships between the HRS-like cells and centrocytic and centroblastic (CCCB) cells. In both cases, CCCB cells were typical of FL; CD45RB, CD20, CD10, and bcl-2 positive. In case 1, the HRS-like cells were positive for CD45RB, CD20, CD10, CD30, OCT2, and BOB.1 and negative for CD15 and bcl-2. In case 2, the HRS-like cells were positive for CD30, fascin, CD20, OCT2, and BOB.1 and negative for CD45RB, CD10, CD15, and bcl-2. CCCB and single HRS-like cells were isolated by laser capture microdissection followed by polymerase chain reaction amplification and sequencing of immunoglobulin heavy chain gene rearrangements. In both cases, identical sequences were obtained from CCCB and HRS-like cells. These findings confirm that although the HRS cells and CCCB cells in these cases demonstrate morphologic and immunophenotypic divergence, they share a common cell of origin. These cases further highlight the potential diagnostic pitfall presented by FL with HRS-like cells.

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Lymphomas generally are divided into Hodgkin lymphomas (HLs) and non-Hodgkin lymphomas based on histologic features, immunophenotype, and clinical behavior. However, evidence indicates that the vast majority of HLs are derived from mature B cells.1-4 Occasionally, a lymphoma with histologic and immunophenotypic features of both HL and non-Hodgkin lymphoma in the same lymph node might develop in 1 person. This may occur as separate foci diagnostic of follicular lymphoma (FL) and classic HL, “composite lymphoma.” In contrast, FL might contain large cells with the morphologic features of Hodgkin and Reed-Sternberg (HRS) cells.5 In these cases, HRS-like cells may be few or numerous and are found surrounding and/or within the nodules of FL.6-9 HRS-like cells usually are CD30+ but lack expression of CD15. The background reactive cellularity and fibrosis of HL generally is absent. We evaluated 2 cases of FL with numerous large cells resembling the HRS cells of classic HL. Centrocytic and centroblastic (CCCB) cells and single HRS-like cells were isolated by using laser capture microdissection, followed by polymerase chain reaction (PCR) amplification and sequence analysis of immunoglobulin heavy chain (IGH) gene rearrangements. In each case, identical IGH rearrangements were obtained from CCCB cells and HRSlike cells. These results confirm that although the CCCB and HRS-like cells in these tumors are morphologically and immunophenotypically distinct, they share a common cell of origin. These cases also reinforce the diagnostic pitfall presented by FL with HRS-like cells.

© American Society for Clinical Pathology

Hematopathology / ORIGINAL ARTICLE

Materials and Methods Patient Selection Two cases of FL lymphoma with HRS-like cells were identified. In each case, an initial diagnosis of classic HL was considered. The lymph node in case 1 was obtained as the initial diagnostic biopsy material from a 77-year-old woman with right-sided inguinal lymphadenopathy. In case 2, right-sided inguinal lymph nodes were obtained from a 55-year-old woman with diffuse lymphadenopathy. At the time she came to our care, she was in her second relapse of lymphoma. She was given a diagnosis of FL at another institution 2.5 years earlier and treated with combination chemotherapy. At her first relapse, 1.5 years earlier, she was given a diagnosis of classic HL and treated with combination chemotherapy (doxorubicin, bleomycin, vinblastine, and dacarbazine) and local radiotherapy. Immunohistochemical Analysis Immunohistochemical analyses were performed on formalin- and/or B-5–fixed, paraffin-embedded tissue sections using the avidin-biotin-peroxidase method with the antibodies as listed ❚Table 1❚. Flow Cytometric Analysis In case 2, a fresh cell suspension derived from a lymph node was used for 3-color flow cytometric analysis (FACScan, Becton Dickinson, Mountain View, CA) using antibodies to CD2, CD4, CD5, CD7, CD8, CD10, CD19, CD20, CD22, CD23, κ light chain, and λ light chain (all Becton Dickinson). Case 1 was sent in consultation to one of us (M.P.), and no fresh tissue was available. Molecular Analysis For each case, 10 single Reed-Sternberg–like cells and 3 clusters of 3-4 CCCB cells each from follicular areas were

identified on H&E-stained sections and isolated by laser capture microdissection (Arcturus PixCell II, MWG-Biotech, Florence, Italy). Care was taken to specifically microdissect Reed-Sternberg–like cells only from T cell–rich regions away from the FL component. To control the sensitivity and specificity of this approach, at least 15 normal B cells were isolated from a paraffin-embedded section stained for CD20. The selected cells adhered to a Capsure (Arcturus, MWG-Biotech) transfer film. The Capsure transfer film carrier was placed directly onto a standard microcentrifuge tube containing digestion buffer (50 µL of buffer containing 0.04% Proteinase K, a 10-mmol/L concentration of tris(hydroxymethyl)aminomethane hydrochloride [pH 8.0], a 1-mmol/L concentration of EDTA, and 1% polysorbate 20). The tube was preheated upright in a 37°C oven for 5 minutes and then placed upside down so that the digestion buffer contacted the tissue on the cap. It was incubated overnight at 37°C and centrifuged for 5 minutes. The cap was removed. The reaction was heated to 95°C for 8 minutes to inactivate the Proteinase K and was used directly as a template for PCR amplification. A seminested PCR was performed in an Express thermal cycler (Hybaid, Teddington, England) using a wax barrier (Dynawax, Fynzyme, Espoo, Finland) to prevent nonspecific annealing of primers at low temperature. The first amplification was performed using an upstream consensus VH primer (FR2A) and a downstream JH primer (LJH). For the second amplification, the LJH primer was replaced by a nested consensus JH primer (VLJH), and an aliquot (1%) of the first PCR run was used as the template for the second round of amplification, which was performed in a total volume of 100 µL of PCR buffer and, with the exception of the internal JH primer, under the same conditions as the first round of PCR. The PCR conditions and primers have been described elsewhere.10

❚Table 1❚ Antibodies Used in Two Cases of Follicular Lymphoma Antibody CD45RB CD3 CD5 CD10 CD15 CD20 CD23 CD30 CD57 ALK1 Fascin bcl-2 OCT2 BOB.1

Case 1

Case 2

DAKO, Glostrup, Denmark Vector-Novocastra Laboratories, Burlingame, CA Vector-Novocastra Laboratories Vector-Novocastra Laboratories Becton Dickinson, San Jose, CA DAKO ND DAKO BioGenex, San Ramon, CA DAKO ND DAKO Santa Cruz Biotechnology, Santa Cruz, CA Santa Cruz Biotechnology

DAKO DAKO DAKO Vector-Novocastra Laboratories Becton Dickinson DAKO DAKO DAKO Immunotech, Marseille, France DAKO Cell Marque, Austin, TX DAKO Santa Cruz Biotechnology Santa Cruz Biotechnology

ND, not done.

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DOI: 10.1309/PMR86PHKK4J3RUH3

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Bayerl et al / FOLLICULAR LYMPHOMA WITH HODGKIN AND REED-STERNBERG–LIKE CELLS

and cloned according to the manufacturer’s instructions. Plasmid DNA was purified from clones containing gene inserts with Wizart Plus SV Minpreps kit (Promega, Madison, WI) following the manufacturer’s instructions, and cloned IgVH rearrangements were sequenced in both directions by an ABI Prism 373 A DNA sequencer (Applied Biosystems, Weiterstadt, Germany) using Sp6 reverse and T7 forward primers. Only the cases in which both sequences were completely homologous were compared against the GenBank database using the IgBlast algorithm (http://www.ncbi.nlm.nih.gov/igblast/).

❚Image 1❚ (Case 1) Nodular growth pattern (H&E, ×40).

In Situ Hybridization for Epstein-Barr Virus Formalin-fixed, paraffin-embedded tissue sections were assessed for Epstein-Barr virus (EBV) latency by in situ hybridization for EBV-encoded small nuclear RNAs (EBERs) using the supplier’s guidelines (DIG-AP Rembrandt for Epstein-Barr early RNAs kit, Zymed Laboratories, South San Francisco, CA).

Results

❚Image 2❚ (Case 1) Lacunar-like and Reed-Sternberg–like cells (H&E, ×400).

An aliquot of the second-round product was subjected to 2% agarose gel electrophoresis, and, following ethidium bromide staining, each amplicon deriving from single ReedSternberg cells and consisting of a single band was cut out, purified, and cloned before sequencing. The PCR products amplified from cell clusters (CCCB cells from follicular areas) and consisting of 2 bands of 277 base pairs (bp) and 245 bp in case 1 and 1 band of 269 bp in case 2 were cut out, purified, and cloned before sequencing. Cloning and Sequence Analysis The purified amplicons from single cells and cell clusters were ligated to the TA-cloning vector pCRII, used to transform interferon-αF cells (Invitrogen, Paisley, Scotland), 860

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In case 1, biopsy of an inguinal lymph node revealed a nodular lymphoid infiltrate completely effacing the nodal architecture and extending into perinodal adipose tissues ❚Image 1❚. In some areas, the infiltrate was composed of vague nodules typical of FL, predominantly centrocytes and a few centroblasts. There was focal, dense fibrosis forming bands encircling nodules. In some areas, there were abundant large cells morphologically resembling the lacunar cells of nodular sclerosis HL ❚Image 2❚. Only a few histiocytes, neutrophils, eosinophils, and plasma cells were present. By immunohistochemical analysis, the CCCB cells were typical of FL: positive for CD45RB, CD20, CD10, OCT2, BOB.1, and bcl-2 and negative for CD30 and CD15. Similarly, the HRS-like cells were positive for CD45RB, CD20 (strongly, diffusely), OCT2, BOB.1, and CD10. The HRS-like cells also were positive for CD30 and negative for CD15, bcl-2, and ALK1 ❚Table 2❚. No rosetting of CD57+ cells around the HRS-like cells was identified. EBERs were not detected by in situ hybridization. The CCCB component showed a double band (F1 = 277 bp, VH2-26-JH5 with 14 mutations and F2 = 245 bp, VH4-34-JH5 with 7 mutations), probably representing biallelic rearrangement. In 6 HRS-like cells, only 1 rearrangement, identical to F2 (VH4-34-JH5), was identified. No real intraclonal heterogeneity was observed. The F1 rearrangement is not functional, whereas the F2 rearrangement is functional ❚Table 3❚. For case 2, the patient's initial diagnostic left cervical lymph node biopsy specimen and staging bone marrow © American Society for Clinical Pathology


❚Table 2❚ Immunophenotypes in Two Cases of Follicular Lymphoma Immunophenotype Case No.

Cells

CD20

CD10

bcl-2

CD45RB

CD30

CD15

Fascin

OCT2

BOB.1

1

HRS CCCB HRS CCCB

+ + + +

+ + – +

– + – +

+ + – +

+ – + –

– – – –

ND ND + –

+ + + +

+ + + +

2

CCCB, centrocytic and centroblastic (follicular lymphoma); HRS, Hodgkin Reed-Sternberg–like cells; ND, not done.

❚Table 3❚ Results of Molecular Analysis in Two Cases of Follicular Lymphoma Case No. 1 2

No. of Cells

No. of PCR Bands Products Obtained Analyzed and Cloned (bp)

HRS, 10 CCCB, 3 clusters of 3-4 cells each HRS, 10 CCCB, 3 clusters of 3-4 cells each

6 6 5 8

245 245 277 269 269

No. of Clones Analyzed

PCR Products

Mutations

Shared

Unique

18 18

VH4-34-JH5 VH4-34-JH5 VH2-26-JH5 VH3-30-JH4 VH3-30-JH4

7 7 14 23 23

7

0 0

15 24

*

*

23

0 0

Intraclonal Diversity

Functional

No No No No No

Yes Yes No Yes Yes

bp, base pairs; CCCB, centrocytic and centroblastic (follicular lymphoma); HRS, Hodgkin Reed-Sternberg–like cells; PCR, polymerase chain reaction. * Not meaningful.

biopsy from May 1999 and biopsy specimen from a left cervical lymph node from May 2000 were obtained from outside institutions. The initial lymph node and bone marrow biopsies from 1999 revealed FL, grade 1, with the immunophenotype, CD45RB+, CD20+, CD10+, and bcl2+ and no large HRS-like cells. The lymph node biopsy specimen at first recurrence in 2000 was a small, fragmented incisional biopsy specimen with predominantly centrocytes, a few centroblasts, and a few large HRS-like cells. This tumor was diagnosed at the outside institution as classic HL. In November 2001, an excisional biopsy of several right inguinal lymph nodes was performed at our institution (Penn State M.S. Hershey Medical Center, Hershey, PA). These nodes showed complete architectural effacement by a nodular, lymphoid infiltrate ❚Image 3❚. The capsule was thickened and fibrotic, with fibrosis focally extending into and dividing the infiltrate into distinct nodules. The nodules were composed predominantly of centrocytes with small numbers of centroblasts, histiocytes, follicular dendritic cells, and large cells resembling the HRS cells of classic HL ❚Image 4❚. Pale zones between nodules contained more HRS-like cells than within the nodules with admixed small lymphocytes, high endothelial venules, abundant epithelioid histiocytes, and rare eosinophils. Immunoperoxidase staining showed that the CCCB cells of the nodules were typical of FL: positive for CD45RB, CD20, CD10, OCT2, BOB.1, and bcl-2 and

negative for CD30, CD15, and fascin. The HRS-like cells were positive for CD30 ❚Image 5❚, fascin, CD20 (strongly, diffusely), OCT2, and BOB.1 and negative for CD45RB, CD10, CD15, and ALK1. Small T cells, positive for CD3 and CD5, were found predominantly between nodules with only a few CD3+ and CD57+ cells in the nodules, not forming rosettes around HRS-like cells. EBERs were not detected by in situ hybridization.

❚Image 3❚ (Case 2) Nodular growth pattern with sclerosis (H&E, ×40).

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❚Image 4❚ (Case 2) Hodgkin Reed-Sternberg–like cell (H&E, ×1,000).

❚Image 5❚ (Case 2) CD30+ Hodgkin Reed-Sternberg–like cell (CD30 immunoperoxidase, ×200).

Flow cytometry performed on a fresh cell suspension from this specimen confirmed a predominant population of FL cells positive for CD45, CD19, CD20, CD22, and CD10 with monotypic surface λ light chain and negative for CD2, CD4, CD5, CD7, CD8, and CD23. One 269-bp PCR product was obtained from the CCCB cells and 5 HRS-like cells. The sequences showed identical VH3-30-JH4 rearrangements in the CCCB component and single HRS-like cells with 23 mutations in the FR3 and CDR2 portions. The rearrangement is functional. No real intraclonal heterogeneity was observed (Table 3).

overlap between FL and classic HL, these extended immunoprofiles support FL with HRS-like cells rather than classic HL. In particular, expression of CD20, OCT2, and BOB.1 in the HRS-like cells strongly supports FL with HRS-like cells rather than classic HL. In both cases studied, the HRS-like cells and CCCB cells obtained by laser capture microdissection contained identical IGH rearrangements, with identical somatic hypermutations and no intraclonal diversity. These results suggest that even though the HRS-like cells and CCCB cells have divergent morphologic features and immunophenotypes, they share a common cell of origin. The finding of a biallelic rearrangement in CCCB cells in case 1 and not in RS-like cells of the same case may be because this rearrangement could not be revealed by primers for the high mutations owing to the small amount of DNA obtained from single cells. In most FLs previously studied, intraclonal diversity of somatic hypermutations has been identified.11-14 This has been interpreted as evidence that the neoplastic cells retain enough of their germinal center identity to remain susceptible to the mechanisms of somatic hypermutations. In both of our cases, no intraclonal diversity was demonstrated in the CCCB or HRS-like cells. There are several possible explanations for this result. Susceptibility to somatic hypermutation might have been lost before the morphologic and immunophenotypic divergence of the CCCB and HRS-like cell populations. Failure to identify intraclonal diversity in case 2 also might be attributed to clonal restriction due to tumor evolution over time and/or treatment effect. Previous investigations have shown that chemotherapeutic treatment of FL and large cell transformation of FL might be associated with restriction of intraclonal diversity.11-14 Alternatively,

Discussion This report presents 2 cases of FL with numerous CD30+ HRS-like cells and compares morphologic, immunophenotypic, and molecular analysis of the CCCB component and single HRS-like cells. These cases also highlight the diagnostic pitfall of HRS-like cells in FL vs classic HL. In each case, the morphologic divergence of the CCCB and HRS-like cells was mirrored by immunophenotypic divergence. In both cases, the CCCB cells expressed the typical immunoprofile of FL, positive for CD20, CD10, and bcl-2 and negative for CD30. In both cases, the HRS-like cells expressed CD30. In case 2, HRS-like cells shared other antigenic features of the HRS cells of classic HL; specifically, they expressed fascin and did not express CD45RB. In case 1, the CD30+ HRS-like cells were more typical of FL, expressing CD20, CD10, and CD45RB. In both cases, the CCCB and HRS-like cells expressed OCT2 and BOB.1 and did not express CD15. Although there was some immunophenotypic 862

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lack of detection of intraclonal diversity might be due to the inherent limitations of our analysis such as mutations interfering with PCR amplification or limited sampling of the CCCB component.15 The mechanism of morphologic and immunophenotypic divergence of HRS-like cells found in FL is not understood. EBV has been associated with the HL variant of Richter syndrome in patients with chronic lymphocytic leukemia.16-19 In contrast, neither of our cases showed EBV latency by in situ hybridization for EBERs. The cases we have presented highlight the diagnostic dilemma presented by the occasional lymphoma with morphologic and immunophenotypic features overlapping FL and classic HL. In case 1, the initial diagnosis at the outside institution was nodular sclerosis HL based on nodularity, encircling fibrosis, and CD30+ HRS-like cells. However, the vague nodules of predominantly small cleaved lymphocytes extending into perinodal adipose tissue and lacking a polymorphous inflammatory background were morphologic clues that this might not be classic HL. In this case, immunohistochemical immunophenotyping conclusively confirmed the diagnosis of FL with HRS-like cells rather than classic HL. In case 2, the diagnostic dilemma was more challenging. This patient came to our institution with diagnoses of grade 1 FL given 2.5 years earlier and classic HL given 1.5 years earlier. The subsequent biopsy specimen obtained at our institution indeed had some morphologic and immunophenotypic features of both FL and classic HL. Most of the tumor was composed of follicles quite typical of FL. Focally, dense fibrous bands extended from the thickened capsule and encircled tumor nodules, suggesting nodular sclerosis HL or “composite” FL and classic HL. There was a distinct population of HRS-like cells within and surrounding the follicles that were CD30+ and fascin+ and CD45RB– and CD15–. Taken in isolation, the HRS-like cells might have been compatible with the HRS cells of classic HL at the morphologic and immunophenotypic levels. In this case, the typical FL diagnosed 2.5 years earlier, diffuse lymphadenopathy, background nodules typical of FL, intimate admixture of the HRS-like cells within and around the nodules of FL, and expression of CD20, OCT2, and BOB.1 by the HRS-like cells suggested that FL with HRS-like cells was the most parsimonious explanation for the HRS-like cells.

Conclusion FL with abundant HRS-like cells is a potential diagnostic pitfall, particularly in the absence of adequate tissue sampling and immunophenotyping. In particular, expression of CD20,

OCT2, and BOB.1 in HRS-like cells argues strongly for FL with HRS-like cells rather than classic HL. Although HRSlike and CCCB cells in each case showed divergent morphologic features and immunophenotypes, molecular analysis confirmed that the HRS-like cells were related clonally to the CCCB cells. The mechanism of morphologic and immunophenotypic divergence of the CCCB and HRS-like cells in these tumors remains to be elucidated. From the Departments of 1Pathology and 4Internal Medicine, Hematology/Oncology, Penn State University School of Medicine, M.S. Hershey Medical Center, Hershey, PA; 2Pathology, Wayne State University School of Medicine, Detroit, MI; and 3Human Pathology and Oncology, University of Siena, Siena, Italy. Address reprint requests to Dr Bayerl: Dept of Pathology H179, Penn State Hershey Medical Center, 500 University Dr, Hershey, PA 17033. Acknowledgments: We acknowledge the assistance of the technical staff of the histology and immunohistochemistry sections of Harper University Hospital, Detroit, MI, and the Penn State M.S. Hershey Medical Center, Hershey, PA.

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Lacunar and Reed-Sternberg–Like Cells in Follicular Lymphomas

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