Case 3 -

Peripheral T-cell Lymphoma, Simulating Hodgkin Lymphoma, with CD30+ and CD15+ RS-like Cells Stefania Pittaluga Laboratory of Pathology NIH, NCI

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Clinical History: 83 yo male who presented with generalized adenopathy, night sweats, and fatigue; he was treated with hyper-CVAD. A complete remission was obtained, but he recurred four months later with adenopathy in the right neck. Submitted for review: Lymph node, right inguinal (pre- treatment) Case 3 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 3 - Figure 1 - Effaced nodal architecture with scattered Reed-Sternberg-like cells in an inflammatory background, H&E. Case 3 - Figure 2 - Cytological features of the RS-like cells are best appreciated at higher magnification, H&E. Case 3 - Figure 3 - Mild cytologic atypia of background lymphocytes is noted with admixed eosinophils and plasma cells. Case 3 - Figure 4 - CD3 - The RS-like cells and background lymphocytes are both positive for CD3; the cytologic atypia of background lymphocytes is best appreciated with the CD3 immunostain. Case 3 - Figure 5 - CD3 - The RS-like cells and background lymphocytes are both positive for CD3; the cytologic atypia of background lymphocytes is best appreciated with the CD3 immunostain. Case 3 - Figure 6 - CD15 - The RS-like cells are positive for CD15 (membranous and golgi), while background lymphocytes show a golgi pattern of staining. Case 3 - Figure 7 - CD30 - The RS-like cells are positive for CD30; background lymphocytes are largely negative. Case 3 - Figure 8 - Pax-5 - The RS-like cells show weak positivity for PAX-5. Case 3 - Figure 9 - CD10 - A subset of background lymphoid cells stain positively for CD10. Case 3 - Figure 10 - CD21 - CD21 stains dendritic meshworks, which are not only related to residual B-cell areas, but are also associated with high endothelial venules. Histological Features The lymph node biopsy shows effacement of the nodal architecture by an atypical lymphoid proliferation associated with scattered large cells with Reed-Sternberg (RS)-like features. Some cells have a mummified appearance. There is a mixed inflammatory background with the lymphocytes showing a mild to moderate degree of cytological atypia. Immunohistological Features. The Hodgkin-like cells are positive for CD15, CD30, CD3 and CD4, while a subset express PAX-5. The large atypical cells are negative for CD5, CD8, CD10, CD20, CD79a, and BCL-6. The CD45 stain was difficult to interpret in the RS-like cells. The background lymphoid cells are positive for CD3, CD4, CD5, variably CD10 + and express CD15 with a perinuclear Golgi pattern; they are negative for CD30, CD57, TIA-1. CD21 stains extrafollicular dendritic meshworks which are associated with the high endothelial venules. In situ hybridization for Epstein Barr virus is negative with an adequate U6 control. Flow cytometry: 16% aberrant T cells with down-regulation of CD3 and CD7. Other markers: CD2 moderately positive; CD5 moderately positive, CD8 negative, CD13/33 negative, CD19 negative, CD20 negative, CD22 negative, CD23 negative, CD38 variably positive, CD56 negative, kappa negative, lambda negative Molecular studies: Southern blot analysis using EcoRI, BamH1+HindIII, XbaI using TCR beta (constant region and J2) showed rearranged bands in all three digestions (by report). TCR gamma PCR: Clonal rearrangement detected IgH PCR: Polyclonal pattern detected. Differential Diagnosis Classical Hodgkin Lymphoma, mixed cellularity subtype Peripheral T-cell lymphoma, unspecified Angioimmunoblastic T-cell lymphoma Peripheral T-cell lymphoma with CD30+CD15+ RS-like cells Final Diagnosis: Peripheral T-cell lymphoma, simulating Hodgkin Lymphoma, with CD30+ and CD15+ RS-like cells Clinical Follow-Up: Not available Discussion Classical Hodgkin lymphoma (CHL) is characterized by the presence of Reed-Sternberg (RS) cells and their variants in an inflammatory background composed of eosinophils, plasma cells, lymphocytes and histiocytes. The RS cells are usually positive for CD30, CD15, weakly for PAX-5, and lack CD45. The expression of B-cell markers, such as CD19, CD20, CD22 and CD79a, is variable and is reported in about 20-30% of cases. However, most of the cases (98%) show immunoglobulin heavy chain gene rearrangement when using isolation of single RS cells. Thus, these findings support a B-cell derivation for the majority of CHL cases. A small subset of CHL cases express B-lineage-inappropriate markers, including antigens that can be seen on T cells, dendritic cells and histiocytes; i.e.CD2, CD3, CD4,CD5, CD8, granzyme-B, TIA-1, fascin and restin. Tzankov et al (2006) in a recent review identified the expression of one (CD2) or more than one T-cell marker in about 5% of CHL; however, T-cell receptor gene rearrangements were detectable in less than 1% of cases tested. These findings confirm previous studies in which most cases of CHL with a T-cell phenotype were genotypically B-cell derived. The evaluation of the expression of T-cell markers in RS cells is difficult and subject to great individual interpretation, due to the rosetting of T cells around the RS-cells. When reviewing the immunohistochemical stains, the possibility of antigen shedding and binding should be considered, and only cells with continuous and complete membranous staining should be considered as positive. In addition, some of the T-cell markers that are more frequently observed (i.e. CD2 and CD4) are not considered "truly" lineage specific, and the RS-cells in such cases often maintain PAX-5 expression. The presence of T-cell markers in rare cases of CHL, besides having implications for the histogenesis of CHL, leads to serious, if not impossible, differential diagnostic difficulties with peripheral T cell lymphoma, unspecified (PTCL) and with angioimmunoblastic T-cell lymphoma (AIL-T). Some PTCL contains large atypical cells that resemble RS cells in a mixed inflammatory background often rich in eosinophils and plasma cells. The distinction between CHL and PTCL can be made based on the careful examination of the background lymphocytes, which often will display a cytological atypia only in the latter PTCL group. Additional phenotypic studies identifying an aberrant T-cell phenotype also support a diagnosis of PTCL over CHL. Moreover, the RS-like cells in such cases, if they are of T-cell lineage, rarely show positivity for both CD30 and CD15. Molecular studies from whole sections further aid in supporting a diagnosis of PTCL. The distinction between PTCL and CHL is further complicated by the occurrence of some cases of PTCL, most commonly AIL-T, in which RS-like cells of B-cell lineage are admixed among the neoplastic T-cells. In such cases the RS cells are of B cell origin, display a classic phenotype (i.e. CD30+/CD15+/CD20+/-) and are Epstein-Barr virus (EBV) associated. Based on laser capture microdissection, Quintanilla-Martinez et al (1999) demonstrated that the RS cells were of B cell derivation and oligoclonal, while the underlying lymphoma had T-cell gene rearrangement. The possibility of a composite lymphoma was considered; however, none of the patients developed CHL and subsequent biopsies revealed the presence of a similar T-cell clone. It was then suggested that the presence of RS-like cells may have been an epiphenomenon and did not represent a "true" composite lymphoma. The possibility of the development of an EBV-induced Hodgkin lymphoma in a background of a PTCL was raised recently by Pajor et al (2006), due to the presence of a clonal B-cell rearrangement in the RS cells. The presence of large transformed EBV+ B-cells is a known phenomenon in PTCL, in particular in angioimmunoblastic T-cell lymphomas (AIL-T). Usually the lymph nodes show marked polyclonal plasmacytosis as well as frequent large immunoblasts, associated with residual B cell areas often without well-formed secondary follicles. The neoplastic T-cells have a clear cytoplasm. Another distinctive feature is represented by the presence of arborizing high endothelial venules with expansion of dendritic meshworks. The neoplastic cells in the majority of cases express CD4, a subset is also CD10 positive and sometimes BCL-6, these features are suggestive of a germinal center-based T-helper phenotype. This relationship is further supported by the partial expression of CXCL13 in AILT, a chemokine crucial for the germinal center formation. As previously mentioned, another distinguishing feature of AILT is the presence of EBV-positive B cells. The presence of these cells has been postulated to be secondary to decreased immune surveillance. In some instances, a progression to an EBV-positive lymphoproliferative disorder reminiscent of a polymorphic post-transplant lymphoproliferative disorder is observed. In other cases the EBV-positive cells resemble RS cells leading to an erroneous diagnosis of CHL (see above Quintanilla-Martinez cases). To further complicate the issue of PTCL simulating CHL, we have observed eleven cases of PTCL in which at least a subset of the neoplastic cells expressed CD30 and CD15 in conjunction with aberrant T-cell markers. Based on histology and phenotype, we divided the cases into two groups: one mimicking CHL and the others with more typical features of PTCL. In both groups in situ hybridization fro EBV was negative. In the first group, we considered helpful: 1) the cytological atypia of background lymphocytes, 2) the loss of 1 or more T-cell associated markers and 3) the expression of T-cell markers by the RS-like cells, and 4) the detection of T-cell receptor gene rearrangement using whole sections, a finding that should be absent in CHL. All of these features support the diagnosis of PTCL over CHL. The cases that resemble CHL but are of T-cell lineage raise the issue as to whether such cases should be considered "true CHL" of T-cell derivation. The existence of a T-cell variant of CHL is still controversial. By definition, in CHL the background lymphocytes are reactive and not part of the neoplastic process. Therefore, clonal TCR gene rearrangement should be identified only in the RS cells and not in the background T cells. The second group was characterized by sheets of atypical cells displaying marked cytological atypia and a more uniform expression of CD30 and CD15 by the neoplastic T cells. These cases were unlikely to be diagnosed as CHL. References (Selected): Al Saati T, Galoin S, Gravel S, lamant L, Roda D, Chittal SM, Delsol G: IgH and TcR-gene rearrangements identified in Hodgkin's disease by PCR demonstrate lack of correlation between genotype, phenotype and Epstein-Barr virus status. J Pathol 1997; 181:387-393. Barry TS, Jaffe ES, Sorbara L, Raffeld M, Pittaluga S: Peripheral T-cell lymphoma expressing CD30 and CD15. Am J Surg Pathol 2003; 27:1513-1522. Davis TH, Morton CC, Miller-Cassman R, Balk SP, Kadin ME: Hodgkin's disease, lymphomatoid papulosis, and cutaneous T-cell lymphoma derived from a common T-cell clone. N Engl J Med 1992; 326:1115-1122. Kadin ME, Muramoto L, Said J: Expression of T-cell antigens on Reed-Sternberg cells in a subset of patients with nodular sclerosing and mixed cellularity Hodgkin's disease. Am J Pathol 1988; 130:345- Kremer M, Sandherr M, Geist B, Cabras AD, Höfler H, Fend F: Epstein-Barr virus-negative Hodgkin's lymphoma after mycosis fungoides:molecular evidence for distinct clonal origin. Mod Pathol 2001; 14:91-97. Müschen M, Rajewsky K, Bräuninger A, Baur SA, Oudejans JJ, Roers A, Hansmann M-L, Küppers R: Rare occurrence of classical Hodgkin's disease as a T cell lymphoma. J Exp Med 2000; 191:387-394. Pajor I, Kajtár B, Jáksó P, Lacza Á, László R, Radványi G, Mórocz I, Tóth A, Varga A: Epstein-Barr-induced B-cell proliferation of Hodgkin's and Reed-Sternberg cell pheno- and genotype may develop in peripheral T-cell lymphomas. Histopathology 2006; 49:538-558 Quintanilla-Martinez L, Fend F, Moguel LR, Spilove L, Beaty MW, Kingma DW, Raffeld M, Jaffe ES: Peripheral T-cell lymphoma with Reed-Sternberg-like cells phenotype and genotype associated with Epstein-Barr virus infection. Am J Surg Pathol, 1999; 23: 1233-1240. Seitz V, Hummel M, Marafioti T, Anagnostopoulos I, Assaf C, Stein H: Detection of clonal T-cell receptor gamma chain gene rearrangements in Reed-Sternberg cells of classic Hodgkin disease. Blood 2000; 95:3020-3024. Tzankov A, Bourgau C, Kaiser A, Zimpfer A, Maurer R, Pileri SA, Went P, Dirnhofer S: Rare expression of T-cell markers in classical Hodgkin's lymphoma. Mod Pathol 2005; 18:1542-1549.