Introduction

Proliferations of Epstein-Barr virus (EBV)-positive large B cells as a component of T cell lymphomas are being increasingly recognized [1,2,3,4,5]. This phenomenon has been described in association with lymphomas derived from follicular helper T cells like peripheral T cell lymphoma not otherwise specified (PTCL NOS) and angioimmunoblastic T cell lymphoma (AITL) [1, 4]. The follicular helper T cells may facilitate the expansion of abnormal B cells through an immunological blockade [4]. The marked immunosuppression in T cell lymphoma may be the cause of EBV-positive B cell proliferation. The transformed B cells vary in morphology, immunophenotype, and genotype. The diagnosis of T cell lymphoma complicated by a proliferation of large B cells depends on extensive immunophenotypic and molecular evaluation. This large B cell-rich T cell lymphoma should not be mistaken for a large B cell lymphoproliferative disorder [2]. Because of the presence of large B and T cells along with positivity for EBV, there is a chance for misdiagnosis as a reactive process. The awareness of the phenomenon and the use of immunohistochemistry and molecular studies will help to render an accurate diagnosis.

Case report

An 82-year-old female patient presented with cervical lymph node enlargement of 3-month duration. Excision biopsy of the node was done in an outside center. We reviewed the slides. Histopathological examination showed diffusely arranged small- to medium-sized atypical cells with irregular nuclei (Fig. 1). There was another population of large atypical lymphoid cells with moderate amount of cytoplasm, round/slightly indented nuclei, and eosinophilic nucleoli. The large cells were immunoblast-like cells and were seen intermingled with the small atypical cells. On immunohistochemical evaluation, the small- to medium-sized atypical cells were CD20 negative, CD10 negative, BCL6 negative, CD3 positive, and CD5 positive and showed downregulation of CD7 (Fig. 2). These cells showed positivity for CD25 and showed a high MIB 1 labelling index. The large cells were positive for CD20, CD30, and EBV-encoded small nuclear RNA (EBER) and were CD15 negative (Fig. 3). On further detailed evaluation, the patient gave a history of small hyperpigmented lesions in the skin. There were multiple enlarged cervical lymph nodes. Peripheral smear showed very few atypical lymphocytes with convoluted nuclei. A diagnosis of adult T cell leukemia/lymphoma was confirmed by positive serum HTLV-1 estimation. In this point, we could not ascertain the nature of B cell proliferation. To differentiate between a composite lymphoma and a B cell proliferation associated with T cell lymphoma, molecular studies were advised which showed TCR gene rearrangement and polyclonal B cell population. With these findings, a diagnosis of adult T cell leukemia/lymphoma with associated proliferation of large B cells was given.

Fig. 1
figure 1

Microscopy showing an admixture of small- to medium-sized atypical lymphocytes and large cells with prominent nucleoli (H&E, × 200)

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Fig. 2
figure 2

The small- to medium-sized atypical cells showing CD3 positivity (a), CD5 positivity (b) with loss of CD7 (c). The cells are CD25 positive (d) (IHC, × 400). The large cells are negative for all the markers

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Fig. 3
figure 3

The large cells are CD20 positive (a) and CD30 positive (b) and show EBER positivity (c) (IHC, × 400)

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Discussion

Proliferation of Epstein-Barr virus (EBV)-positive B cells is being increasingly recognized in T cell lymphomas [1, 2, 4]. When there is florid proliferation of large B cells, there is a greater chance of these neoplasms being misdiagnosed as large B cell lymphoma and the diagnosis of a T cell lymphoma is made only on recurrence. As the clinical management is entirely different in T cell and B cell lymphomas, the awareness of this phenomenon is very important. On the other end of the spectrum, the histological appearance and immunoprofile showing a mixture of T cells and CD30-positive large B cells, a misdiagnosis of a reactive lymphoid proliferation is a possibility.

The phenomenon of large B cell proliferation in T cell lymphomas is commonly seen in lymphomas derived from T follicular helper cells (TFH cells) [1,2,3,4,5]. TFH cells are a unique subset of T cells found in normal germinal center. These cells provide help to B cells in germinal center reactions and express markers such as BCL6, CD10, CD4, PD-1, SAP, and IL-2. TFH cells produce a chemokine receptor CXCR5 and chemokine CXCL13 which cause induction and proliferation of FDC [4]. It facilitates the adhesion of B cells to high endothelial venule and is involved in the recruitment of B cells to the lymph node. TFH cells play critical role in T cell-dependent B cell response. These cells promote the expansion of B cells in immune response. The continuing TFH cell help in TFH cell lymphomas may aberrantly expand the B cells outside normal physiological control. TFH-derived neoplasms such as angioimmunoblastic T cell lymphoma, follicular variant of PTCL NOS, and primary cutaneous small/medium CD4-positive T cell lymphomas are often associated with atypical B cell proliferation [4]. Polyclonal hypergammaglobulinemia and polyclonal plasmacytosis are often observed in AITL cases. Rarely, the marked B cell or plasma cell expansion can obscure the underlying T cell neoplasm [6]. EBV-positive B cells with immunoblastic features are nearly always found in the background of AITL cases [5]. In their series of AITL with a large B cell proliferation, Lome-Maldonado et al. noted that the presence of large B cells made no prognostic impact and they proposed AITL with large B cell proliferation as a specific subset of AITL [7]. A dramatic increase in the number of large cells has been reported in cases of PTCL NOS and is termed PTCL complicated by a proliferation of large B cells [1, 5, 7].

In most of the cases, the large B cell population is EBV infected [2, 4]. The expansion of EBV-positive B cells may be related to the defective immune surveillance secondary to T cell lymphomas. The relatively immunocompromised status in T cell lymphomas may facilitate EBV reactivation that subsequently lead to transformation of EBV-infected B cells through a polyclonal-oligoclonal-monoclonal program as in post-transplant lymphoproliferative disorder [3, 4]. It is postulated that in EBV-negative cases, the neoplastic T cells function as helper cells to promote the B cell proliferation.

EBV-negative clonal or monocytic B cell proliferations in patients with PTCL range from plasma cell proliferation to overt lymphomas. In their series, Balague et al. describe EBV-negative clonal plasma cell proliferation and lymphomas in 15 PTCL cases [8]. They observed clonal or monocytic plasma cell proliferations in eight cases, clonal or monocytic B cell proliferations in four cases, and B cell lymphoma with plasmacytic or plasmablastic differentiation in three cases.

B cell proliferation in cases of HTLV-1-positive adult T cell leukemia/lymphoma (ATLL) is an extremely rare phenomenon [9, 10]. In ATLL, there is a marked impairment of the immune system and these patients have a 25 fold increased risk of opportunistic infections compared to other types of non-Hodgkin lymphomas. ATLL has been linked to the Treg cells, which are a special type of regulatory T cells that suppresses the immune response and this explains the marked immunosuppression associated with ATLL. This marked defect in immune surveillance may be the reason for the proliferation of EBV-positive large B cells in ATLL cases [10]. Katsuki et al. demonstrated defective cytotoxic T lymphocytes (CTL) in ATLL patients. In their study, CTL obtained from nine EBV-seropositive ATLL patients were unable to induce regression of foci of EBV-transformed cells in vitro. The same assay using CTL from 10 healthy EBV-seropositive patients resulted in regression of the foci [11].

In majority of the cases of T cell lymphomas with proliferation of large B cells, the large cells have morphology similar to immunoblasts or Hodgkin cells. The numbers of large cells also vary and most of the authors require more than 25% of the background cells to be the large cells to call a significant large B cell proliferation [1, 7]. The EBV-infected Hodgkin-like cells will express CD30 mimicking classical Hodgkin lymphoma [4]. But the B cell program is most often preserved and will show strong expression of CD20 and PAX5, which facilitate to differentiate from classical Hodgkin lymphoma.

The B cells may show polyclonal, oligoclonal, or monoclonal immunoglobulin heavy chain rearrangement [1, 5]. If there are no overt features of B cell lymphoma like sheeting of the large B cells and architectural destruction, it is recommended to label the cases as PTCL complicated by a proliferation of large B cells and note the immunoglobulin gene rearrangement findings [1]. Cases showing architectural destruction and sheeting of B cells along with monoclonality should be classified as composite lymphoma. Rare cases of concurrent angioimmunoblastic T cell lymphoma and large B cell lymphoma, and the occurrence of B cell lymphoma after AILT has been reported [1, 12].

The phenomenon of marked proliferation of large B cells in T cell lymphomas can be diagnostically challenging. It can be mistaken as a reactive process when there is proliferation of EBV-positive large B cells with immunoblastic morphology, as Hodgkin lymphoma when the B cells show a Hodgkin cell-like morphology along with positivity for CD30 and EBER, or as a T cell-rich large B cell lymphoma when there is a clustering of large B cells. Extensive morphologic, immunophenotypic, and molecular evaluation along with the awareness of the entity will help to render an accurate diagnosis.