Successful Treatment of a Patient Presenting with Simultaneous Diffuse Large B-Cell Lymphoma and Hodgkin Lymphoma: A Case Report

Introduction

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma, which presents in nearly 30% of all non-Hodgkin lymphoma cases [1,2]. DLBCL occurs in approximately 3 to 7 per 100 000 people annually [3,4]. Hodgkin lymphoma (HL) accounts for 10% of all lymphomas, affecting 2 to 3 per 100 000 people [4,5]. DLBCL and HL theoretically belong to a continuous spectrum of B-cell malignant transformation. Thus, DLBCL and HL could develop in the same patient. In a retrospective study of 269 patients with a diagnosis of classical HL, 4 patients (1.5%) received a diagnosis of DLBCL after HL treatment [6]. However, simultaneously diagnosing DLBCL and HL is extremely rare, presenting unique clinical challenges. A report summarized about 20 cases over 50 years [7]. The standard treatment for each lymphoma is different. The rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone (R-CHOP) regimen is used as first-line therapy for patients with newly diagnosed DLBCL, whereas the doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) regimen is used for patients with HL [8,9]. DLBCL and HL are relatively rare diseases cancer types. Therefore, it is extremely rare for both lymphomas to occur simultaneously in one patient. Hence, establishing a strategy for treating both lymphoma subtypes at the same time is very difficult [10]. Generally, patients with newly diagnosed lymphoma who present with advanced disease can use doxorubicin-based cytotoxic combination chemotherapy and consider high-dose chemotherapy followed by autologous stem cell transplantation (auto-SCT). Herein, we present a successful treatment of a patient with a simultaneous diagnosis of advanced DLBCL and HL.

Case Report

A 20-year-old man visited the Nephrology Department because of severe proteinuria and suddenly increased creatinine level. Germinal center B-cell DLBCL was diagnosed through kidney biopsy (Figure 1, Table 1). No evidence of double- or triple-hit DLBCL was found. Owing to a palpable mass in his right neck, he also visited an otolaryngologist. Thus, HL (nodular sclerosis type) was diagnosed through a lymph node excisional biopsy (Figure 1, Table 2). In September 2020, the patient was transferred to the Hematology Department of Kyungpook National University Hospital after receiving a diagnosis of 2 different lymphomas simultaneously. The patient’s general condition was poor, with an Eastern Cooperative Oncology Group performance status of 3, fever above 38°C, unstable blood pressure, and tachycardia. He reported severe myalgia and generalized edema. Bodyweight loss of >10% in the last 1 month was identified. He had no specific past medical or family history of malignancy. Positron emission tomography/computed tomography (PET/CT) showed increased fluorodeoxyglucose uptake of the skull, mediastinum, spleen, both kidneys, right pelvic bone, and multiple lymph nodes (Figures 2, 3). A blood test revealed anemia, abnormal creatinine, and elevated lactate dehydrogenase (LDH). The chromosomal analysis of the bone marrow aspirate identified no cytogenetic abnormality. Next-generation sequencing was performed on the biopsied neck lymph node, kidney, bone marrow, and peripheral blood to find genetic singularity. However, no significant results could help in understanding and identifying this very rare condition of the patient (Tables 3, 4).

Six cycles of R-CHOP therapy were planned, and central nervous system prophylaxis by intrathecal administration of methotrexate was added because of high-risk features of central nervous system involvement (increased serum LDH, stage IV disease, >2 sites of extranodal involvements, and kidney involvement). After 2 cycles of chemotherapy, the follow-up PET/CT did not identify any evidence of abnormal hypermetabolic lesion suggesting lymphoma involvement. After completing 6 cycles of chemotherapy, without significant adverse events, and Deauville score of 1, complete remission was confirmed (Figure 4). Afterward, the patient decided to undergo consolidative auto-SCT. He received busulfan, cyclophosphamide, and etoposide conditioning regimen, followed by autologous stem cell rescue (CD34 count: 5.18×106) in April 2021. Engraftment of stem cells was done well, and no specific events other than mild neutropenic fever occurred. After auto-SCT, the patient was undergoing regular check-ups, including CT. He maintained a disease-free status for 40 months to date. The patient has not demonstrated any evidence of lymphoma recurrence during regular checkups. Hence, as a college student, he is leading a normal life, without psychophysiological problems.

Discussion

In this case report, we present a case of successfully treating a patient with a simultaneous diagnosis of DLBCL and HL. The R-CHOP regimen used as the first-line therapy was effective in both the DLBCL and HL, and the patient maintained a disease-free status for more than 40 months to date, without disease relapse after consolidative auto-SCT.

DLBCL is diagnosed through tissue biopsy, especially excisional biopsy specimens. Accurate classification is possible through tests such as immunohistochemistry, fluorescence in situ hybridization, and molecular testing, along with the morphological characteristics of the tissue [11]. According to the updated World Health Organization (WHO) classification, DLBCL, not otherwise specified (DLBCL, NOS) is the most common type. DLBCL is classified into germinal center B-cell and activated B-cell-like subtypes, and approximately 10% to 15% cases are unclassifiable [12]. These heterogeneous subtypes are assumed to arise from different stages of lymphoid differentiation, relying on the separate mechanisms, and compared with germinal center B-cell subtypes, inferior survival outcomes are identified with activated B-cell-like subtypes [13,14]. The germinal center B-cell subtype is associated with BCL6 and EZH2 gene expressions commonly identified in germinal center B cells [8], while the activated B-cell-like subtype is characterized by chronic B-cell receptor signaling and activation of nuclear factor κB [8,15,16]. Combination of anti-CD20 monoclonal antibody (rituximab) and CHOP has shown a significant improvement of survival as a first-line treatment [17]. Approximately 4% to 8% of patients with DLBCL, mainly the germinal center B-cell subtypes, present MYC rearrangement concurrent with a rearrangement in BCL2, BCL6, or both [18,19]. Patients with these double- or triple-hit lymphomas have shown poor treatment outcome after R-CHOP, and more intensive chemo-therapy consisting of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (DA-EPOCH-R) was associated with improved treatment outcomes [18,20]. Some previous studies have shown the benefits of consolidative upfront auto-SCT in terms of disease-free survival of progression-free survival (Table 5). However, auto-SCT is not currently recommended for all patients with DLBCL who achieved complete remission after R-CHOP, because it did not show statistical superiority in toxicity and long-term survival [21–24].

Patients with HL usually present with contiguously involved lymph node groups, and approximately 30% of patients have systemic symptoms, such as body weight loss, fever, and night sweats [9]. For accurate diagnosis, it is most important to identify malignant Reed-Sternberg cells of follicular center B-cell origin from appropriately biopsied tissue [25,26]. Based on the WHO classification, HL is divided into 2 distinct disease types: classical HL and nodular lymphocyte predominant HL [27]. Classic HL is more commonly diagnosed and is classified into nodular sclerosis, mixed cellularity, lymphocyte-depleted, and lymphocyte-rich subgroups. Among classical HL, nodular sclerosis is the most common subtype and is mainly diagnosed in adolescents and young adults. The malignant multinucleated giant Reed-Sternberg cell is the pathologic hallmark of classical HL. Recently, overexpression of programmed death-1 (PD-1) ligands with PD-L1 and PD-L2 was identified on Reed-Sternberg cells, which was associated with the occurrence and feature of HL [28–30]. In patients with advanced HL, the ABVD regimen showed significant clinical effect and decreased toxicity [31]. The dose-escalated regimen with doxorubicin, cyclophosphamide, etoposide, procarbazine, vincristine, prednisone, and bleomycin (BEACOPP), suggested by the German Hodgkin Study Group, also showed better treatment outcomes [32,33].

Incorporating a brentuximab vedotin, a CD30-directed antibody-drug conjugate, with doxorubicin, vinblastine, and dacarbazine (A+AVD) showed a survival advantage over ABVD for stage III or IV HL in the ECHELON-1 trial [34,35]. There was no additional survival benefit from upfront auto-SCT in patients with advanced unfavorable HL after achieving complete remission or partial remission [36]. However, high-dose chemotherapy followed by auto-SCT improved treatment outcomes in the salvage setting [37,38].

Although DLBCL and HL originate from B cells, both lymphomas develop into different diseases. The standard treatment and prognosis of both diseases are different. In the present case, genetic abnormalities by tissue next-generation sequencing from the kidney and neck lymph node were different, except for FAT4, which is unknown in lymphomas. Therefore, 2 lymphoma types were assumed to occur simultaneously, which is a very rare phenomenon. Fortunately, the patient could achieve complete remission after completing the R-CHOP regimen. In terms of HL, the ABVD or A-AVD (brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine) regimen could be selected as the first-line therapy. However, since aggressive DLBCL must be treated at the same time, R-CHOP was initially administered in our patient. According to previous studies, various regimens that include doxorubicin were effective for HL [9,36]. The CHOP regimen has also been well tolerated and effective in patients with newly diagnosed HL, even with advanced or unfavorable disease [39,40]. Additionally, we expected that rituximab would be effective in treating HL because of CD20 positivity in the immunohistochemistry of the HL tissue. CD20 is identified in most patients with lymphocyte-predominant HL, and only in a minority of patients with classical HL [41]. Interestingly, previous reports demonstrated that patients with HL and CD20-positive Reed Sternberg cells showed better responses to rituximab than did HL patients with CD20-negative cells [41,42]. In a recent randomized phase 2 study, outcomes of ABVD plus rituximab were superior to those of ABVD alone in patients with CD20-positive high-risk classical HL [43].

Because double primary lymphomas, such as DLBCL and HL, are extremely rare, only a few cases have been reported over decades [7,10,44]. In most cases, the first chemotherapy that patients received was for DLBCL, and both lymphomas responded well to the chemotherapy. In some cases, radiotherapy was added after chemotherapy, but consolidative SCT was rarely performed. For a deeper response of advanced lymphomas, consolidative high-dose chemotherapy followed by auto-SCT could be considered [45,46]. Although upfront auto-SCT in lymphomas is still controversial, some previous studies reported positive data regarding autologous transplantation in patients with DLBCL, particularly those with advanced disease [21–24]. Survival benefit of upfront auto-SCT in the treatment of HL has not been proven. Despite the advent of brentuximab vedotin, and checkpoint inhibitors, there may be a role for auto-SCT in patients with relapsed or refractory HL who have responded to salvage therapy [37,38].

Conclusions

In the treatment of double primary lymphomas, the initial therapy must be determined according to the malignant cell characteristics. Our case showed that the R-CHOP regimen was effective not only for DLBCL but also for HL. Notably, consolidative upfront auto-SCT should be considered for a deeper response. A well-designed prospective study is needed to support the rationale for our approach; however, the concomitant occurence of 2 different lymphomas is an extremely rare case.