Blood Res 2013; 48(2):
Published online June 25, 2013
https://doi.org/10.5045/br.2013.48.2.156
© The Korean Society of Hematology
1Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
2Department of Pathology, University of Ulsan College of Medicine, Ulsan, Korea.
3Departments of Hematology and Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Correspondence to : Jooryung Huh. Department of Pathology, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. jrhuh@amc.seoul.kr
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Lymphoma diagnosis is based on histomorphology, immunophenotyping, flow cytometry, and molecular studies. Lymphomas are broadly classified as being of the B-cell and T-cell lineages, using immunohistochemistry and/or flow cytometry. Among the markers to determine B- and T-cell lineages, CD20 and CD3 are the most commonly used. T-cell lymphomas with aberrant expression of the B-cell marker CD20 or B-cell lymphomas with aberrant expression of T-cell associated antigens such as CD5, CD43, CD7, CD2, CD4, and CD8 have been reported [1-5]. However, cases of B-cell lymphoma with CD3 co-expression are extremely rare [6, 7]. Herein, we report a case of diffuse large B-cell lymphoma (DLBCL) in an elderly patient, with an aberrant co-expression of the T-cell associated antigen CD3 and cytotoxic molecule TIA-1, an infection with EBV, and a dual rearrangement of the immunoglobulin heavy chain (
A 72-year-old, HIV-negative Korean female presented with easy fatigue and epigastric discomfort, which had been gradually worsening over a period of 4 months, and weight loss of 3 kg over a period of 1 month. She had a history of stroke, hypertension, and osteoporosis with spinal fractures. Laboratory tests on admission revealed an elevated serum lactate dehydrogenase level (489 IU/L; reference range, 120-250 IU/L) with a slightly decreased serum hemoglobin level (10.2 g/dL; reference range, 12-16 g/dL). Computed tomography (CT) scans of the neck, chest, and abdomen showed multiple lymph node enlargements in the left supraclavicular area and the retroperitoneum, with a 7.5 cm cystic lesion in the left perirenal space. A 2 cm-sized gastric mass with central ulceration was noted during esophagogastroduodenoscopy (EGD). A biopsy of the left supraclavicular lymph node showed a partial effacement of the nodal architecture with diffuse infiltration by large atypical tumor cells separated by collagenous septae (Fig. 1). There were also multiple foci of geographic necrosis. These cells had pleomorphic nuclei, vesicular chromatin, prominent macronucleoli, and numerous mitotic figures, with many bizarre Reed-Sternberg (RS)-like multinucleated cells. Admixed with the tumor cells were small numbers of mature small lymphocytes and macrophages. A gastric biopsy also revealed similar findings. Immunohistochemistry showed that the tumor cells were positive for CD20, CD79a, CD3, MUM-1, BCL-2, TIA-1, CD43, OCT-2, and BOB-1, weakly positive for PAX-5, but negative for CD2, CD5, CD4, CD8, granzyme B, TCR-β F1, TCR-γ receptor, BCL-6, CD10, ALK-1, CD30, CD15, myeloperoxidase, and CD163. In the background, there were only a few scattered T cells, some of which were positive for TIA-1.
Non-Hodgkin lymphomas (NHL) are assigned to B-cell and T-cell lineages based on immunoprofiling, flow cytometry, and molecular studies. We describe a case of a large cell lymphoma with the hybrid expression of both B- and T-cell markers, monoclonal gene arrangement of both lineages, and EBV infection. This case illustrates the difficulty of determining of the lineage of non-Hodgkin lymphoma using only pan-B-cell or pan-T-cell markers.
Based on the histopathologic features, the age of the patient, and the expression of EBER, CD20, MUM-1, BCL-2, OCT-2, and BOB-1, a diagnosis of EBV-positive DLBCL of the elderly was favored, despite the cytoplasmic expression of CD3 and TIA-1. Because classical Hodgkin lymphoma (cHL) in older patients is also often associated with EBV infection, it should be included as a major differential diagnosis. In EBV-positive DLBCL of the elderly, tumor cells are often positive for CD30; consequently, CD30 expression is not helpful for differential diagnosis. A strong, homogenous expression of CD20 in more than 50% of the RS-like cells in combination with the expression of B-cell specific transcription factors such as OCT-2 and BOB-1 support a diagnosis of EBV-positive DLBCL. In addition, the finding that over 30% of the cytotoxic T-cells in the background infiltrate expressed TIA-1 favors EBV-positive DLBCL over EBV-positive cHL.
However, in the present case, the expression of CD3, the most specific surface antigen for mature T-lymphocytes in pleomorphic large cells, led to a diagnostic dilemma. Although several reports describe aberrant expression of the B-cell marker CD20 in T-cell NHL or aberrant expression of T-cell-associated antigens such as CD2, CD4, CD7, and/or CD8 in B-cell NHL (B-NHL) [1-5], there are only 3 reports (9 cases in all) of CD3-positive B-NHL [6, 7]. Several mechanisms have been proposed to explain the aberrant expression of T-cell antigens by neoplastic B cells: 1) neoplastic transformation leading to the consequent derepression of genetic material, 2) neoplastic transformation of stem/progenitor cells, and 3) neoplastic expansion of a subpopulation of B cells which normally express T-cell antigens [6]. Another hypothesis is associated with the transcription factor encoded by the
Another dilemma encountered in the diagnosis of this case resulted from the observation that there were dual rearrangements in both cell lineages. Dual or aberrant rearrangements, in which B- or T-cell phenotype lymphomas show monoclonality of both cell lineages (so-called "lineage infidelity") have been reported [11-15]. The percentage of aberrant rearrangement is between 5% and 29% for both B- and T-cell lymphomas. Garcia et al. reported that 21% of B-NHL cases showed a monoclonal pattern in one of the
Though the tumor in the present study showed a hybrid phenotype, the patient received R-CHOP therapy, with almost complete remission seen on a follow-up PET scan. The patient's response to R-CHOP treatment also supports the initial diagnosis of EBV-positive DLBCL with an aberrant expression of CD3 and TIA-1.
To the best of our knowledge, this is the first case of EBV-positive DLBCL with an aberrant expression of CD3, TIA, and dual monoclonal rearrangement of the
This tumor demonstrates dual rearrangement (red arrows) of
Blood Res 2013; 48(2): 156-160
Published online June 25, 2013 https://doi.org/10.5045/br.2013.48.2.156
Copyright © The Korean Society of Hematology.
Miji Lee1, Hee Jeong Cha2, Dok Hyun Yoon3, Cheolwon Suh3, and Jooryung Huh1*
1Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
2Department of Pathology, University of Ulsan College of Medicine, Ulsan, Korea.
3Departments of Hematology and Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Correspondence to: Jooryung Huh. Department of Pathology, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. jrhuh@amc.seoul.kr
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Lymphoma diagnosis is based on histomorphology, immunophenotyping, flow cytometry, and molecular studies. Lymphomas are broadly classified as being of the B-cell and T-cell lineages, using immunohistochemistry and/or flow cytometry. Among the markers to determine B- and T-cell lineages, CD20 and CD3 are the most commonly used. T-cell lymphomas with aberrant expression of the B-cell marker CD20 or B-cell lymphomas with aberrant expression of T-cell associated antigens such as CD5, CD43, CD7, CD2, CD4, and CD8 have been reported [1-5]. However, cases of B-cell lymphoma with CD3 co-expression are extremely rare [6, 7]. Herein, we report a case of diffuse large B-cell lymphoma (DLBCL) in an elderly patient, with an aberrant co-expression of the T-cell associated antigen CD3 and cytotoxic molecule TIA-1, an infection with EBV, and a dual rearrangement of the immunoglobulin heavy chain (
A 72-year-old, HIV-negative Korean female presented with easy fatigue and epigastric discomfort, which had been gradually worsening over a period of 4 months, and weight loss of 3 kg over a period of 1 month. She had a history of stroke, hypertension, and osteoporosis with spinal fractures. Laboratory tests on admission revealed an elevated serum lactate dehydrogenase level (489 IU/L; reference range, 120-250 IU/L) with a slightly decreased serum hemoglobin level (10.2 g/dL; reference range, 12-16 g/dL). Computed tomography (CT) scans of the neck, chest, and abdomen showed multiple lymph node enlargements in the left supraclavicular area and the retroperitoneum, with a 7.5 cm cystic lesion in the left perirenal space. A 2 cm-sized gastric mass with central ulceration was noted during esophagogastroduodenoscopy (EGD). A biopsy of the left supraclavicular lymph node showed a partial effacement of the nodal architecture with diffuse infiltration by large atypical tumor cells separated by collagenous septae (Fig. 1). There were also multiple foci of geographic necrosis. These cells had pleomorphic nuclei, vesicular chromatin, prominent macronucleoli, and numerous mitotic figures, with many bizarre Reed-Sternberg (RS)-like multinucleated cells. Admixed with the tumor cells were small numbers of mature small lymphocytes and macrophages. A gastric biopsy also revealed similar findings. Immunohistochemistry showed that the tumor cells were positive for CD20, CD79a, CD3, MUM-1, BCL-2, TIA-1, CD43, OCT-2, and BOB-1, weakly positive for PAX-5, but negative for CD2, CD5, CD4, CD8, granzyme B, TCR-β F1, TCR-γ receptor, BCL-6, CD10, ALK-1, CD30, CD15, myeloperoxidase, and CD163. In the background, there were only a few scattered T cells, some of which were positive for TIA-1.
Non-Hodgkin lymphomas (NHL) are assigned to B-cell and T-cell lineages based on immunoprofiling, flow cytometry, and molecular studies. We describe a case of a large cell lymphoma with the hybrid expression of both B- and T-cell markers, monoclonal gene arrangement of both lineages, and EBV infection. This case illustrates the difficulty of determining of the lineage of non-Hodgkin lymphoma using only pan-B-cell or pan-T-cell markers.
Based on the histopathologic features, the age of the patient, and the expression of EBER, CD20, MUM-1, BCL-2, OCT-2, and BOB-1, a diagnosis of EBV-positive DLBCL of the elderly was favored, despite the cytoplasmic expression of CD3 and TIA-1. Because classical Hodgkin lymphoma (cHL) in older patients is also often associated with EBV infection, it should be included as a major differential diagnosis. In EBV-positive DLBCL of the elderly, tumor cells are often positive for CD30; consequently, CD30 expression is not helpful for differential diagnosis. A strong, homogenous expression of CD20 in more than 50% of the RS-like cells in combination with the expression of B-cell specific transcription factors such as OCT-2 and BOB-1 support a diagnosis of EBV-positive DLBCL. In addition, the finding that over 30% of the cytotoxic T-cells in the background infiltrate expressed TIA-1 favors EBV-positive DLBCL over EBV-positive cHL.
However, in the present case, the expression of CD3, the most specific surface antigen for mature T-lymphocytes in pleomorphic large cells, led to a diagnostic dilemma. Although several reports describe aberrant expression of the B-cell marker CD20 in T-cell NHL or aberrant expression of T-cell-associated antigens such as CD2, CD4, CD7, and/or CD8 in B-cell NHL (B-NHL) [1-5], there are only 3 reports (9 cases in all) of CD3-positive B-NHL [6, 7]. Several mechanisms have been proposed to explain the aberrant expression of T-cell antigens by neoplastic B cells: 1) neoplastic transformation leading to the consequent derepression of genetic material, 2) neoplastic transformation of stem/progenitor cells, and 3) neoplastic expansion of a subpopulation of B cells which normally express T-cell antigens [6]. Another hypothesis is associated with the transcription factor encoded by the
Another dilemma encountered in the diagnosis of this case resulted from the observation that there were dual rearrangements in both cell lineages. Dual or aberrant rearrangements, in which B- or T-cell phenotype lymphomas show monoclonality of both cell lineages (so-called "lineage infidelity") have been reported [11-15]. The percentage of aberrant rearrangement is between 5% and 29% for both B- and T-cell lymphomas. Garcia et al. reported that 21% of B-NHL cases showed a monoclonal pattern in one of the
Though the tumor in the present study showed a hybrid phenotype, the patient received R-CHOP therapy, with almost complete remission seen on a follow-up PET scan. The patient's response to R-CHOP treatment also supports the initial diagnosis of EBV-positive DLBCL with an aberrant expression of CD3 and TIA-1.
To the best of our knowledge, this is the first case of EBV-positive DLBCL with an aberrant expression of CD3, TIA, and dual monoclonal rearrangement of the
This tumor demonstrates dual rearrangement (red arrows) of
This tumor demonstrates dual rearrangement (red arrows) of