Hematopathology Diagnoses Too Easy to Miss!
Malignant Lymphomas that Mimic Other Lymphomas of a Different Type with Very Different Clinical Implications (continued)
Marsha Kinney, James Cook and Steven Swerdlow
T-cell rich large B-cell lymphoma
The patient is a 43 year-old man who presented with
right cervical adenopathy. A biopsy was performed at an outside institution, where a diagnosis of
classical Hodgkin lymphoma was rendered. The patient was treated, and responded well. However, after 5
years, the patient relapsed, and a second biopsy was performed. At the time of relapse, the new and
original biopsies were reviewed in consultation, both of which showed identical findings. The slide
provided demonstrates the features in the original specimen.
The histologic sections demonstrated an essentially diffuse,
heterogeneous infiltrate composed of small lymphocytes, histiocytes, occasional large transformed cells,
and scattered large atypical cells with prominent nucleoli. Some of the large atypical cells were
binucleate or multinucleate.
Immunohistochemical stains showed the small lymphocytes
to consist predominantly of CD3 positive T-cells. The large atypical cells were strongly positive for
CD20 and CD45 (LCA), and coexpressed OCT2 and BOB1. The atypical cells were negative for CD30, but were
strongly positive for CD15. An EBER stain for Epstein-Barr virus was negative.
T-cell/Histiocyte-Rich Large B-cell Lymphoma (TCRLBCL):
TCRLBCL is defined as a diffuse proliferation of large neoplastic B-cells that represent <10% of the
Small B-cells are rare to absent. The majority of the infiltrate
consists of benign, small T-cells, usually with a prominent admixed histiocytic proliferation. The
neoplastic B-cells may display a variety of cytologic features. In some cases, the B-cells may be
predominantly of centroblastic or immunoblastic morphology. In some cases, Reed-Sternberg-like cells are
present. In still other cases, large multilobate cells are present that resemble that L&H cells
("popcorn cells") of nodular lymphocyte predominant Hodgkin lymphoma (nLPHL).
Phenotypic studies of TCRLBCL are best accomplished via immunohistochemistry, as the relatively rare
neoplastic B-cells may be difficult to characterize by flow cytometry.  Using immunostains,
most cases of TCRLBCL will be strongly positive for CD45 (LCA) and CD20,
and will show
expression of the B-cell transcription factors OCT2 and BOB1.  CD10 and BCL6 have been
described in a subset of cases. Although usually negative for CD30 and CD15, up to one third may be
positive for CD30 and rare CD15 positive cases have also been described, as seen in the case
In some cases, immunohistochemical stains for kappa and lambda light chains may
show monotypic staining.
Clinically, these patients typically present with advanced disease, with involvement of multiple lymph
node groups, spleen, and often bone marrow.
Due to the usual presentation at advanced
stage, patients with TCRLBCL often show an aggressive clinical course. However, at least some studies
have suggested that when adjusted for stage, T-cell rich large B-cell morphology is not an independent
The revised 2008 WHO classification recognizes TCRLBCL as a distinct subtype of DLBCL. 
These cases display characteristic morphologic and phenotypic findings that create diagnostic
difficulties for the lymph node pathologist. In particular, cases of TCRLBCL may be confused with
several others forms of lymphoma, including classical Hodgkin lymphoma, nLPHL and peripheral T-cell
lymphoma, unspecified (PTCLU).
TCRLBCL versus classical Hodgkin lymphoma:
In a subset of TCRLBCL, the
large atypical B-cells include a population of binucleate cells with large nucleoli
("Reed-Sternberg-like" cells). In conjunction with the non-neoplastic background that usually consists
of small T-cells and numerous admixed epithelioid histiocytes, these findings raise a differential
diagnosis with classical Hodgkin lymphoma. In particular, these findings may be suggestive of lymphocyte
rich classical Hodgkin lymphoma or, if eosinophils and plasma cells are prominent, mixed cellularity
This differential diagnosis is best addressed using a panel of immunohistochemical stains. Evaluation
of CD20 and CD45 (LCA) stains are particularly important. While CD20 and LCA may be seen on the
neoplastic cells of classical Hodgkin lymphoma in a minority of cases (approximately 25% in most
studies), these antigens will typically be found on only a minority of the neoplastic cells within the
case, and the intensity of staining is usually variable but weak overall.
the neoplastic cells of TCRLBCL are generally expected to show uniform and strong staining in the vast
majority of the neoplastic B-cells. CD30 and CD15 are typically absent in TCRLBCL, although as mentioned
above, occasional exceptions will occur.
Especially useful in this differential are the
B-cell transcription factors OCT2 and BOB1. Abnormalities in these transcription factors are frequent in
classical Hodgkin lymphoma, and are thought to contribute to the lack of functional immunoglobulin heavy
chain rearrangements in Reed-Sternberg cells. Nearly all cases of classical Hodgkin lymphoma will be
negative for either OCT2 or BOB1 or, in at least two thirds of cases, both of these markers; the
expression of both OCT2 and BOB1 is very rare in classical Hodgkin lymphoma.
contrast, most cases of TCRLBCL will show expression of both of these markers. 
TCRLBCL versus nodular lymphocyte predominant Hodgkin lymphoma:
cases of TCRLBCL contain large atypical multilobate cells that strongly resemble the L&H cells
(so-called "popcorn cells") associated with nLPHL. In fact, there may be an etiological relationship
between TCRLBCL and nLPHL,  as discussed below. The distinction between these two entities
is very important, as the two diagnoses suggest very different clinical outcomes. nLPHL is usually
localized, and is an especially indolent lymphoproliferative disorder, such that localized therapy alone
might be considered in some patients.  TCRLBCL, in contrast, is usually disseminated, and is
associated with an adverse clinical course that will typically be managed with multiagent chemotherapy,
similar to other diffuse large B-cell lymphomas. Distinguishing between these entities is therefore
critical for proper therapy.
By definition, all cases of nLPHL will display, at least focally, a nodular growth pattern. The
nodules are composed of large, expanded follicular dendritic cell meshworks that contain a predominance
of small B-cells, some with a germinal center cell phenotype, admixed with numerous CD57 positive
T-cells.  Large, multinucleate "popcorn cells" are present within the nodules, frequently
surrounded by rosettes of CD3 positive T-cells that usually coexpress CD57. Some cases will display
inter-nodular areas with scattered "popcorn cells." The inter-nodular areas in these cases strongly
resemble TCRLBCL.  Recognition of the nodular areas within nLPHL is essential for correct
diagnosis. Although the nodules are often apparent on routine H&E sections, immunohistochemical
stains for CD21 and CD57 may be very valuable in difficult cases. Expanded nodules of CD21 positive FDC
networks are expected in all cases of nLPHL, while such nodules should be rare if not completely absent
in TCRLBCL. CD57 positive T-cells are typically increased in nLPHL, and most cases will show rosettes
of CD57 positive T-cells around the "popcorn cells." CD57 positive cells are infrequent in most cases of
TCRLBCL, and only rarely form rosettes around large B-cells. 
It should be noted at this point that there clearly are cases of nLPHL that show, in subsequent
biopsies, evolution to a morphology consistent with TCRLBCL. In some cases, nLPHL and TCRLBCL may even
be identified within the same specimen.
A precise cutoff point at which to diagnose
nLPHL with a coexisting TCRLBCL, vs. nLPHL with expanded interfollicular areas, has not yet been
defined. However, it appears reasonable to reserve a diagnosis of concurrent TCRLBCL for cases with at
least large expanses of lymph node occupied by a proliferation with T-cell rich large B-cell morphology,
without admixed FDC nodules. These findings have led to a question of whether TCRLBCL represents a
"diffuse form" of nLPHL. In fact, comparative genomic hybridization studies performed on the
micro-dissected CD20 positive cells from nLPHL and TCRLBCL, do display some common cytogenetic findings,
supporting a pathogenetic relationship in at least some cases.  However, in the great
majority of cases, TCRLBCL presents as a clinical de novo lymphoma, without a prior diagnosis of nLPHL.
TCRLCL versus peripheral T-cell lymphoma:
Because the vast majority of the
infiltrate in cases of TCRLBCL is composed of T-cells, some cases are easily misdiagnosed as a peripheral
T-cell lymphoma, unspecified (PTCLU). The key to the correct diagnosis, usually accomplished by an
initial round of immunohistochemical stains, is recognition that the scattered large, atypical cells are
CD20 positive B-cells while the more numerous CD3 positive cells are cytologically unremarkable.
In difficult cases, such as those with a degree of atypia in the background T-cells, a panel of T-cell
immunostains should be employed in order to rule out an aberrant T-cell phenotype. PCR studies for a
T-cell receptor gamma chain rearrangement, may also be useful to ensure the T-cells represent a
polyclonal population. In approximately one half to two thirds of cases of TCRLBCL, a monoclonal
immunoglobulin heavy chain rearrangement may be detected.
The absence of a monoclonal
immunoglobulin rearrangement, however, never excludes the diagnosis of TCRLBCL as the primers employed
for immunoglobulin heavy chain analysis in most labs have a high false negative rate.
Lastly, it should also be remembered that some T-cell lymphomas will have coexisting large B-cell
In such cases, the large B-cells are frequently EBV-positive. EBER
stains may therefore also be of assistance, as most TCRLBCL would appear to be negative for
- Lim MS, Beaty M, Sorbara L, et al. T-cell/histiocyte-rich large B-cell lymphoma: a heterogeneous entity with derivation from germinal center B cells. Am J Surg Pathol 26: 1458-1466, 2002.
- Delabie J, Vandenberghe E, Kennes C, et al. Histiocyte-rich B-cell lymphoma. A distinct clinicopathologic entity possibly related to lymphocyte predominant Hodgkin's disease, paragranuloma subtype. Am J Surg Pathol 16: 37-48, 1992.
- Gatter KC, Warnke R, Diffuse Large B-cell Lymphoma. in Tumours of Haematopoietic and Lymphoid Tissues. Jaffe ES, Harris NL, Stein H, et al., [Eds.] IARC Press: Lyons. 2001, 171-174.
- Macon WR, Williams ME, Greer JP, et al. T-cell-rich B-cell lymphomas. A clinicopathologic study of 19 cases. Am J Surg Pathol 16: 351-363, 1992.
- Wang J, Sun NC, Chen YY, et al. T-cell/histiocyte-rich large B-cell lymphoma displays a heterogeneity similar to diffuse large B-cell lymphoma: a clinicopathologic, immunohistochemical, and molecular study of 30 cases. Appl Immunohistochem Mol Morphol 13: 109-115, 2005.
- Browne P, Petrosyan K, Hernandez A, et al. The B-cell transcription factors BSAP, Oct-2, and BOB.1 and the pan-B-cell markers CD20, CD22, and CD79a are useful in the differential diagnosis of classic Hodgkin lymphoma. Am J Clin Pathol 120: 767-777, 2003.
- Krishnan J, Wallberg K, Frizzera G. T-cell-rich large B-cell lymphoma. A study of 30 cases, supporting its histologic heterogeneity and lack of clinical distinctiveness. Am J Surg Pathol 18: 455-465, 1994.
- Bouabdallah R, Mounier N, Guettier C, et al. T-cell/histiocyte-rich large B-cell lymphomas and classical diffuse large B-cell lymphomas have similar outcome after chemotherapy: a matched-control analysis. J Clin Oncol 21: 1271-1277, 2003.
- Achten R, Verhoef G, Vanuytsel L, et al. T-cell/histiocyte-rich large B-cell lymphoma: a distinct clinicopathologic entity. J Clin Oncol 20: 1269-1277, 2002.
- De Wolf-Peeters C, Delabie J, Campo E, et al., T-cell/histiocyte-rich large B-cell lymphoma. in WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th Ed. Swerdlow SH, Campo E, Harris NL, et al., [Eds.] IARC Press: Lyons. 2008, 238-239.
- Zukerberg LR, Collins AB, Ferry JA, et al. Coexpression of CD15 and CD20 by Reed-Sternberg cells in Hodgkin's disease. Am J Pathol 139: 475-483, 1991.
- Schmid C, Pan L, Diss T, et al. Expression of B-cell antigens by Hodgkin's and Reed-Sternberg cells. Am J Pathol 139: 701-707, 1991.
- Stein H, Marafioti T, Foss HD, et al. Down-regulation of BOB.1/OBF.1 and Oct2 in classical Hodgkin disease but not in lymphocyte predominant Hodgkin disease correlates with immunoglobulin transcription. Blood 97: 496-501, 2001.
- Re D, Muschen M, Ahmadi T, et al. Oct-2 and Bob-1 deficiency in Hodgkin and Reed Sternberg cells. Cancer Res 61: 2080-2084, 2001.
- Rudiger T, Gascoyne RD, Jaffe ES, et al. Workshop on the relationship between nodular lymphocyte predominant Hodgkin's lymphoma and T cell/histiocyte-rich B cell lymphoma. Ann Oncol 13 Suppl 1: 44-51, 2002.
- Stein H, Delsol G, Pileri S, et al., Nodular Lymphocyte Predominant Hodgkin Lymphoma. in Tumours of Haematopoietic and Lymphoid Tissues. Jaffe ES, Harris NL, Stein H, et al., [Eds.] IARC Press: Lyons. 2001, 240-243.
- Fan Z, Natkunam Y, Bair E, et al. Characterization of variant patterns of nodular lymphocyte predominant hodgkin lymphoma with immunohistologic and clinical correlation. Am J Surg Pathol 27: 1346-1356, 2003.
- 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 102: 3753-3758, 2003.
- Huang JZ, Weisenburger DD, Vose JM, et al. Diffuse large B-cell lymphoma arising in nodular lymphocyte predominant Hodgkin lymphoma: a report of 21 cases from the Nebraska Lymphoma Study Group. Leuk Lymphoma 45: 1551-1557, 2004.
- Franke S, Wlodarska I, Maes B, et al. Comparative genomic hybridization pattern distinguishes T-cell/histiocyte-rich B-cell lymphoma from nodular lymphocyte predominance Hodgkin's lymphoma. Am J Pathol 161: 1861-1867, 2002.
- Hodges E, Hamid Y, Quin CT, et al. Molecular analysis reveals somatically mutated and unmutated clonal and oligoclonal B cells in T-cell-rich B-cell lymphoma. J Pathol 192: 479-487, 2000.
- Quintanilla-Martinez L, Fend F, Moguel LR, et al. Peripheral T-cell lymphoma with Reed-Sternberg-like cells of B-cell phenotype and genotype associated with Epstein-Barr virus infection. Am J Surg Pathol 23: 1233-1240, 1999.
- Higgins JP, van de Rijn M, Jones CD, et al. Peripheral T-cell lymphoma complicated by a proliferation of large B cells. Am J Clin Pathol 114: 236-247, 2000.
- Zettl A, Lee SS, Rudiger T, et al. Epstein-Barr virus-associated B-cell lymphoproliferative disorders in angloimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified. Am J Clin Pathol 117: 368-379, 2002.
- Lome-Maldonado C, Canioni D, Hermine O, et al. Angio-immunoblastic T cell lymphoma (AILD-TL) rich in large B cells and associated with Epstein-Barr virus infection. A different subtype of AILD-TL? Leukemia 16: 2134-2141, 2002.