(Adapted from Stein et al. ... [3] Stein H, Johrens K, Anagnostopoulos I. Non-mediastinal grey ... Differential Emu enhancer activity and expression of BOB.1/.
Hematology, 2005; 10 Supplement 1: 190 /192
LYMPHOMAS
Gray zone lymphomas
AHMET DOGAN Mayo Clinic, Rochester, MN, USA
The term gray zone lymphoma is mostly used for cases of malignant lymphoma which can not be reliably classified as Hodgkin lymphoma or nonHodgkin lymphoma [1 /3]. As this differential diagnosis has direct implications for management strategies, it is a major problem area for both pathologists and hemato-oncologists [4]. This difficulty is seen in three specific areas as shown in Figure 1. 1. Gray zone between Classical Hodgkin lymphoma (CHL) and diffuse large B-cell lymphoma (DLBCL), in particular primary mediastinal large B-cell lymphoma (MLBCL). 2. Gray Zone between CHL and ALK negative anaplastic large cell lymphoma (ALCL) and/or peripheral T-cell lymphoma (PTCL). 3. Gray zone between CHL or nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and T-cell/histiocyte-rich large B-cell lymphoma (TRLBCL)
CHL versus MLBCL will be straight forward where as in the middle, it may be impossible (Figure 2) There are limited number of tools for the pathologist to make this differential diagnosis. In the absence of a well-characterized genetic abnormality, the diagnosis rests on morphological and immunophenotypical analysis. Virtually all cases of CHL, like MLBCL or DLBCL are of B-cell origin and are composed of large cells. However in CHL, the B-cell phenotype of the neoplastic cells (RS cells and variants) is often incomplete, lacking expression of some pan-B-cell surface markers, B-cell associated transcription factors and immunoglobulin [8,9]. The phenotypic features that are useful in histological diagnosis are listed in Table I. The best clinical approach for the patients diagnosed as having a gray zone lymphoma is not clear. Some investigators prefer to treat these patients with protocols appropriate for DLBCL adding rituximab for those cases expressing CD20 [7].
Gray zone between CHL and DLBCL
Gray zone between CHL and ALK negative ALCL
This is the most frequent problem area in gray zone lymphomas. Typically these cases occur in the mediastinum but also, occasionally, in extra-mediastinal sites. In the mediastinum both the CHL and MLBCL are thought to arise from a common precursor, the thymic B-cell. Recent gene expression profiling studies revealed that gene expression profile of MLBCL were distinct from DLBCL occuring at extra-mediastinal sites, but appeared very similar to CHL cell lines [5,6]. This suggests that there is a close biological realtionship between these two entities and the pathological features which respresent the phenotype will overlap. The presence of both CHL and MLBCL in the same biosy or consecutive biopsies from the same patient supports this view [7]. Therefore one would expect that at either end of the phenotypical spectrum, differential diagnosis of
Another problem area for diagnosis of CHL is the differential diagnosis with ALCL that does express ALK. Although there is histological overlap, immunophenotyping is extremely helpful. ALCL is now considered to be exclusively of T or null cell origin and does not express B-cell lineage markers, especially pax-5 which is present in most CHL [3,10].
ISSN 1024-5332 print/ISSN 1607-8454 online # 2005 Taylor & Francis DOI: 10.1080/10245330512331389827
Gray zone between CHL or NLPHL and TRLBCL CHL may morphologically overlap with TRLBCL. In TRLBCL, large B cells may occasionally display the morphologic characteristics of Reed-Sternberg cells, Hodgkin’s cells, or variants, but the background cells usually do not include eosinophils, a distinctive feature of CHL. Immunophenotypically, the strong and consistent expression of pan-B-cell markers
Gray zone lymphomas
DLBCL
191
PTCL ALCL ALK+ CHL
MLBCL
NLPHL
ALCL ALK-
TRLBCL
Figure 1. Gray zone lymphomas. CHL: Classical Hodgkin lymphoma, DLBCL: Diffuse large B-cell lymphoma, MLBCL: Primary mediastinal large B-cell lymphoma, NLPHL: Nodular lymphocyte predominant Hodgkin lymphoma, TRLBCL: T-cell/histiocyte-rich large B-cell lymphoma, PTCL: Peripheral T-cell lymphoma, ALCL: Anaplastic large cell lymphoma. (Adapted from Stein et al. Eur J Hematol 2005) (3)
Figure 2. Phenotypic spectrum of CHL and MLBCL.
CD20, CD79a, and OCT2, the uniform expression of BCL6, the presence of immunoglobulin heavy or light chain expression, the absence or variable weak expression CD30, the lack of CD15 expression, and the absence of EBV gene products should be adequate to establish the diagnosis. Perhaps more difficult is the differential diagnosis between NLPHL and TRLBCL. Although architecTable I. Features helpful in differential diagnosis of CHL versus MLBCL/DLBCL CHL Morphology RS cells and All variants Nodular Most sclerosis Inflammatory All background Phenotype CD30 / CD15 // / CD45 / Fascin / CD20 /// CD79a / Bcl-6 // /, variable Pax-5 /, variable Oct-2 /// B ob-1 /// PU.1 / EBV // / immunoglobulin /
MLBCL
DLBCL
Occasional
Rare
Occasional
Rare
Occasional
Rare
tural nodularity and presence of a background of small B-cells favor NLPHL over TRLBCL, in later stages of NLPHL these features are usually lost and the accurate diagnosis may be only possible with clinical parameters. The immunophenotypic markers for differential diagnosis of CHL or NLPHL and TRLBCL are summarised in Table II [11/13].
References [1] Rudiger T, Jaffe ES, Delsol G, et al. Workshop report on Hodgkin’s disease and related diseases (‘grey zone’ lymphoma). Ann Oncol 1998;9:S31 /38. /
Table II. Immunophenotype of TRLBCL, CHL and NLPHL
Phenotype /// /// / / / / /, uniform /, uniform / / // / / ///
/// / / / / / // /, uniform // /, uniform / / // / /// // /
/
CD20 CD79a CD3 CD21 CD10 BCL-6 OCT-2 CD30 CD15 EMA EBV clg
TRLBCL
CHL
NLPHL
Centroblasts, L&H-like cells, RS-like cells
Rs cells, Hodgkin cells
L&H cells
/ / / / / / / /// / /// / /
/// /// / ///(FDC) / /// /// / // / / /// /
/ / / /(FDC) / / / / / / / /
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A. Dogan
[2] Poppema S, Kluiver JL, Atayar C, et al. Report: workshop on mediastinal grey zone lymphoma. Eur J Haematol 2005;75: 45 /52. [3] Stein H, Johrens K, Anagnostopoulos I. Non-mediastinal grey zone lymphomas and report from the workshop. Eur J Haematol 2005;75:42 /44. [4] Fisher RI. Treatment of grey zone lymphomas. Ann Oncol 1998;9:S121 /123. [5] Savage KJ, Monti S, Kutok JL, et al. The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. Blood 2003;102:3871 /3879. [6] Rosenwald A, Wright G, Leroy K, et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med 2003;198:851 /862. [7] Calvo KR, Traverse-Glehen A, Pittaluga S, et al. Molecular profiling provides evidence of primary mediastinal large B-cell lymphoma as a distinct entity related to classic Hodgkin lymphoma: implications for mediastinal gray zone lymphomas as an intermediate form of B-cell lymphoma. Adv Anat Pathol 2004;11:227 /238. [8] Pileri SA, Gaidano G, Zinzani PL, et al. Primary mediastinal B-cell lymphoma: high frequency of BCL-6 mutations and consistent expression of the transcription factors OCT-2, /
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BOB.1, and PU.1 in the absence of immunoglobulins. Am J Pathol 2003;162:243 /253. Loddenkemper C, Anagnostopoulos I, Hummel M, et al. Differential Emu enhancer activity and expression of BOB.1/ OBF.1, Oct2, PU.1, and immunoglobulin in reactive B-cell populations, B-cell non-Hodgkin lymphomas, and Hodgkin lymphomas. J Pathol 2004;202:60 /69. Torlakovic E, Torlakovic G, Nguyen PL, et al. The value of anti-pax-5 immunostaining in routinely fixed and paraffinembedded sections: a novel pan pre-B and B-cell marker. Am J Surg Pathol 2002;26:1343 /1350. Dogan A, Burke JS, Goteri G, et al. Micronodular T-cell/ histiocyte-rich large B-cell lymphoma of the spleen: histology, immunophenotype, and differential diagnosis. Am J Surg Pathol 2003;27:903 /911. Boudova L, Torlakovic E, Delabie J, et al. Nodular lymphocyte-predominant Hodgkin lymphoma with nodules resembling T-cell/histiocyte-rich B-cell lymphoma: differential diagnosis between nodular lymphocyte-predominant Hodgkin lymphoma and T-cell/histiocyte-rich B-cell lymphoma. Blood 2003;102:3753 /3758. Rudiger T, Ott G, Ott MM, et al. Differential diagnosis between classic Hodgkin’s lymphoma, T-cell-rich B-cell lymphoma, and paragranuloma by paraffin immunohistochemistry. Am J Surg Pathol 1998;22:1184 /1191. /
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