Diffuse Large B-Cell Lymphoma with Aberrant Coexpression of CD5 and CD8 T-Cell Markers

Abstract

Introduction

The expression of T-cell-associated antigens on diffuse large B-cell lymphoma (DLBCL) is uncommon. The coexpression of ≥2 T-cell-associated antigens on DLBCL is even rarer. This has been reported in the literature only a few times, most commonly coexpression of either CD5 or CD8 and a second, different T-cell marker.

Case Presentation

This case report features a patient who presented with a rapidly evolving head and neck mass that displayed coexpression of CD5 and CD8.

Conclusion

In this case report, we present the first case to our knowledge of DLBCL with coexpression of only CD5 and CD8.

Introduction

Diffuse large B-cell lymphoma (DLBCL) is a type of non-Hodgkin lymphoma (NHL) and is the most common type of lymphoma among adult patients. Immunophenotypic expression of neoplastic cells in DLBCL usually includes pan B-cell markers such as CD20, PAX5, and CD79a. Intracytoplasmic immunoglobulins are found in around 50% of cases as well, with IgM being the most common, followed by IgG and other isotypes [1]. Staining for cyclin D1 can also be observed and is positive in a minority of tumor cells. The proliferation index, evaluated through Ki-67, is high in more than 40–100% of cases. P53 is positive in 20–60% of cases. Expression of CD10, BCL6, and MUM1 is observed in DLBCL and is used for classification of cell of origin germinal center B-cell (GCB)-like DLBCL versus activated B-cell (ABC)-like DLBCL. CD10 and BCL6 are GCB markers, and MUM1 is a non-germinal cell maker. MYC and BCL2 can be expressed in DLBCL as well.

In general, lymphocytes normally are categorized into B, T, and natural killer cells based on their cell markers. B cells are normally characterized by the CD markers CD19, CD20, CD22, CD72, and CD74, while T-cell markers include CD2, CD3, CD4, CD5, CD6, CD7, CD8, and others [2]. Although CD5 is a T-cell marker, expression of CD5 in DLBCL is observed in 10% of cases [1]. CD5-positive DLBCL has been well studied and is found to be associated with worse prognosis than CD5-negative DLBCL cases [3].

Other aberrant expression of singular T-cell-associated antigens has also been previously described in the literature. However, coexpression of 2 or ≥2 T-cell-associated antigens on DLBCL is rare and has only been reported a few times. Kaleem et al. [4] described 2 cases with coexpression of CD7/CD8 and CD4/CD7. Inaba et al. [5] showed 3 cases of coexpression CD2/CD5, CD2/CD7, and CD5/CD7. Sangle et al. [6, 7] described a CD2/CD7-positive case and another CD4/CD5/CD8-positive case. Tsuyama et al. [8] showed 5 cases of aberrant coexpression of T-cell markers, with 2 cases of coexpression of CD5/CD7/CD8 but none with just CD5/CD8 markers [8]. In this report, we present the first case to our knowledge of DLBCL exhibiting coexpression of CD5 and CD8. The significance of coexpression of T-cell-associated antigens on B-cell lymphomas remains unclear due to the limited number of reported cases.

Case Presentation

A 56-year-old male with a history of alcohol-induced cirrhosis, a 46-pack-year smoking history, and chronic kidney disease stage 3a presented with three rapidly enlarging masses on his left cheek, mandible, and neck, along with associated facial swelling. He initially noticed a small mass on his cheek 3 weeks ago and was treated with clindamycin with no resolution. The mass progressively grew in size, and the patient developed two more masses near his left mandible and neck. At presentation to the hospital, the masses were non-fluctuant and non-mobile, with the largest measuring 7.5 by 8.3 cm on the cheek and extending to the left mandibular angle. Symptoms included tenderness to palpation of the cheek and mandible, difficulty and worsening pain with chewing, dysphagia, hoarse voice, sore throat, and left temple tenderness to palpation with radiation to the left ear.

Computed tomography of the head and neck revealed a well-circumscribed, enhancing mass in the left masticator space (7.5 × 8.3 cm), extending into left pharyngeal space medially and to the left infratemporal fossa (Fig. 1a–c). Similar masses were also noted in the premaxillary region (4.3 × 3.5 cm), neck (3.9 × 2.5 cm), and mediastinum. Computed tomography of the abdomen and pelvis showed scattered peritoneal, subcutaneous, and left chest wall masses compatible with metastases. Additionally, imaging showed diffuse left mediastinal, premaxillary, supraclavicular, and inguinal lymphadenopathy. Biopsy of the cheek mass showed CD5- and CD8-positive DLBCL. Treatment with R-CHOP was initiated, and the patient had significant reduction tumor size and pain over the next 4 days. The patient then developed Klebsiella gram-negative sepsis, complicated by refractory neutropenia and immunosuppression from chemotherapy, and passed away 12 days after diagnosis.

Fig. 1.

Computed tomography (CT) head without contrast (a, b) and soft tissue neck with contrast (c) shows an enhancing mass in the left masticator space and premaxillary region, along with extension to infratemporal fossa.

The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000536571).

Pathologic Findings

Biopsy revealed fragments of lymphoid tissue heavily infiltrated by large, atypical cells (Fig. 2a). A panel of immunohistochemical stains was performed, and atypical cells were positive for CD20 (Fig. 2b), PAX5 (Fig. 2c), CD5 (Fig. 2d), CD8 (Fig. 2e), CD10, BCL2, BCL6, cMYC (∼20%), and MUM1. The atypical cells were negative for CD3, CD4, CD23, CD30, cyclin D1, SOX11. The Ki-67 score showed a proliferation index of ∼100% (Fig. 2f). In situ hybridization for Epstein-Barr viral encoded RNA was negative. Flow cytometry showed atypical B lymphocytes that were positive for CD5 (Fig. 2g), CD8 (Fig. 2h), CD19 (Fig. 2g), CD20, CD22 (Fig. 2h), and was kappa light chain-restricted (Fig. 2i). Fluorescence in situ hybridization was positive for rearrangement of BCL6, but negative for rearrangement of MYC at the 8q24 locus and negative for double fusion involving t(14, 18) IgH/BCL2. Chromosomal microarray analysis was positive for loss of TP53.

Fig. 2.

Biopsy tissue revealed lymphoid tissue with large, atypical cells stained with hematoxylin and eosin stain (a). A panel of immunohistochemical strains was performed that stained positive for CD20 (b), PAX5 (c), CD5 (d), CD8 (e), and Ki-67 with a proliferation index of 100% (f). a–e are original magnification ×200. Flow cytometry of atypical cells was positive for CD5 (g), CD8 (h), CD19 (g), CD20, and CD22 (h), and was kappa light chain-restricted (i).

Discussion

The expression of T-cell-associated antigens on DLBCL is uncommon. Among these antigens, CD5 is the most frequently expressed with an estimated prevalence of 10% [1]. The expression of other T-cell antigens is less frequent. In one study analyzing the immunophenotype of 128 B-cell lymphoma patients, CD5 was expressed in 18% of cases, CD7 in 6.3% of cases, and CD2 in 2.3% of cases [5]. Another study showed 15% (31/225) frequency of CD5 marker expression in DLBCL cases [8].

A study by Tsuyama et al. [8] examined T-cell markers besides CD5 (CD8, CD7, CD2, and CD4) expression in 501 cases of mature B-cell lymphomas and found that only 5% (27/501) of cases expressed non-CD5 T-cell markers. Twenty-five of those cases were found in patients with DLBCL, which was significantly more common than other types of B-cell lymphoma. Another study examined 150 patients with B-cell lymphomas and found that 11 cases (7.3%) had associated T-cell antigens, with CD2 and CD7 being the most common ones [9]. CD8 expression was also found to be infrequent in B-cell NHL [8]. Carulli et al. [10] in a study with 951 B-cell NHL patients showed expression of CD8 in just 18 cases, with a 3% frequency of CD8 expression in B-CLL/SLL and 1.18% frequency in other B-cell lymphomas (3 follicular lymphoma cases, 2 DLBCL, and 1 lymphoplasmacytic lymphoma). In our patient’s case, the DLBCL cells exhibited coexpression of only CD5 and CD8, which to the best of our knowledge has not been reported in the literature.

The impact of T-cell antigen expression on the clinical course and prognosis of DLBCL remains uncertain for CD5 and CD8 coexpression. Many studies show poor survival outcomes in cases of DLBCL with CD5 expression [3, 8]. Prognosis for CD8 expression on NHL is controversial with mixed evidence from various studies. Some authors believe it is linked to aggressive disease, while other studies report that it is not [10]. However, the limited cases in the literature for coexpression of CD5/CD8 prevent our ability to draw conclusions on the significance of this aberrant phenotype. In our patient’s case, his DLBCL progressed rapidly, with enlargement over the span of 3 weeks, causing airway compromise and dysphagia. However, his disease also responded with significant reduction in tumor size after 3–4 days of R-CHOP treatment, indicating rapid clinical improvement and response until he had complications with treatment and passed away.

Our patient did not have a DLBCL with a particularly poor prognosis. His DLBCL expressed CD10; therefore via the Hans algorithm, his DLBCL is classified as a GBC DLBCL [11]. GCB DLBCLs have a better prognosis, compared to the other subtypes of DLBCL – namely, ABC DLBCLs and type 3 DLBCLs. The 5-year survival rate for GBC DLBCLs after R-CHOP is 60%, as opposed to 35% for ABC DLBCLs [11]. However, several features of our patient’s DLBCL may indicate a poor prognosis. Our patient’s DLBCL was positive for CD5 expression, which is known for a worse prognosis compared to CD5 negative DLBCLs, and a Ki-67 score of 100%, which also carries a very poor prognosis and is more indicative of triple-hit lymphomas [3, 12]. Yet, our patient’s DLBCL lacks the chromosomal rearrangements of the MYC gene and the BCL2 gene and cannot be classified as a triple-hit lymphoma. Additionally, a study by Inaba et al. [5] looked at 128 patients with B-cell non-Hodgkin’s lymphoma and found that lymphoma cells from 31 patients expressed aberrant T-cell-associated antigens and positive t-cell antigen expression was associated with a more aggressive clinical course, less favorable outcomes, and a higher chance of extranodal involvement. Therefore, it is possible that our patient’s T-cell markers may have been linked to our patient’s aggressive disease and death. Our patient also did have extranodal involvement, with scattered peritoneal, subcutaneous, and left chest wall masses compatible with metastases. Other studies by Tsuyama et al. [8] and Suzuki et al. [9] show no impact of T-cell markers on patient outcomes. However, the sample sizes for coexpression of 2 or more T-cell markers are small in those studies. Ultimately, it is difficult to give a definitive answer on what effect this DLBCL’s T-cell antigen coexpression may have had on his clinical course and prognosis, given his mixture of prognostic factors.

Furthermore, coexpression of two or more T-cell-associated antigens is rare, with only a few reported cases in the literature. In most instances, DLBCL coexpresses CD5 along with another T-cell-associated antigen. In the study examining 501 B-cell lymphoma cases by Tsuyama et al. [8], 5/31 DLBCL patients had aberrant coexpression of CD5 and another T-cell marker (3 cases coexpressed CD5/CD7/CD8 in DLBCL). Another example by Inaba et al. [5] reported three cases of coexpression in DLBCL: CD2/CD5, CD2/CD7, and CD5/CD7. Wu et al. [13] reported 2 cases of CD3/CD5 coexpression in DLBCL, and Kaleem et al. [4] reported one case of DLBCL with coexpression of CD4/CD7 Sangle described a CD2/CD7-positive DLBCL case and another CD4/CD5/CD8-positive DLBCL case [6, 7].

Under physiologic conditions, B cells normally do not express T-cell markers. Several hypotheses have been proposed to explain the presence of T-cell antigens in DLBCL. One hypothesis suggests that the deregulation of gene expression control in malignant B cells leads to the activation of normally silent or repressed genes associated with T-cell differentiation [4]. This hypothesis used the example of PAX5, a transcription factor that commits undifferentiated precursor cells to the B lymphoid lineage [14]. Another hypothesis associates EBV infection with aberrant T-cell expression. The mechanism behind this process proposes that EBV latent membrane protein-1 modulates the expression of cell surface molecules, along with cytoplasmic molecules, which can affect expression of T-cell-specific molecules [9]. However, our patient was negative for EBV. One possible etiology for T-cell antigen expression in this case is monoclonal expansion of the normally present CD5-positive B cells in the mantle zones of the lymph nodes [7]. Further neoplastic transformation may have led to derepression of normally silent T-cell antigen transcription factors, leading to expression of CD8 [5]. It has also been hypothesized by Kaleem et al. [4] that DLBCL that expresses CD8 may be clonal expansion of an unidentified subset of normally occurring B lymphocytes that express CD8. While multiple hypotheses have been put forward, none have yet been substantiated in the literature.

Histopathologically, DLBCL-expressing T-cell antigens exhibit the same features as DLBCL without T-cell antigens. Both types are present with typical characteristics, including sheets of large, atypical cells with oval, vesicular nuclei, and prominent nucleoli [1]. In our patient’s case, the tumor displayed sheets of atypical lymphocytes with enlarged pleomorphic nuclei, frequent mitotic figures, and apoptotic bodies, consistent with these findings.

Conclusion

In conclusion, a small proportion of DLBCL may express T-cell antigens. The prognostic significance of such DLBCLs is unclear; however, it is important for pathologists and oncologists to be aware of such cases to decrease the probability of diagnostic confusion and delay in diagnosis. This case contributes to the existing literature, serving as an example of DLBCL with coexpression of two T-cell antigens.

Statement of Ethics

This case report is exempt from Ethical Committee approval due to the nature of reporting based on daily clinical practice. This retrospective review of the patient’s data, imaging, and history did not require Ethical Committee approval in accordance with local/national guidelines. Written informed consent was obtained from the patient’s next of kin, his son, for publication of this case report and any accompanying images.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was not supported by any internal or external sponsor or funder.

Author Contributions

J.F. and S.T. were involved in data collection and writing the manuscript. V.O. was involved in data collection. B.J. was involved in editing and revising the manuscript.

Funding Statement

This study was not supported by any internal or external sponsor or funder.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.