Diffuse large B-cell lymphoma with central nervous system symptoms during the maintenance therapy of acute lymphoblastic leukemia: a case report and literature review

Introduction

In the recent decades, the prognosis of patients with acute lymphoblastic leukemia (ALL) has improved due to refined risk stratification, intensive chemotherapy, immunotherapy, and hematopoietic stem cell transplantation (1). The 5-year survival rate of ALL exceeds 90% (2). However, secondary malignant neoplasms (SMNs) remain extremely serious complications and contribute to the deterioration of the primary ALL disease.

A multicenter retrospective analysis showed that the incidence of non-Hodgkin lymphoma (NHL) secondary to childhood and adolescent ALL was approximately 0.1%, with 5-year survival rates of 68.5%±6.4% (3). Nevertheless, the central nervous system (CNS) involvement of secondary NHL is seldom reported.

In this report, we describe an atypical case of a child who developed Epstein-Barr virus (EBV)-related diffuse large B-cell lymphoma (DLBCL) during the maintenance therapy of ALL with CNS symptoms as the first sign. We present this article in accordance with the CARE reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-24-2/rc).

Case presentation

A 12-year-old boy was initially admitted to Shenzhen Children’s Hospital on April 5, 2019, with the main complaint of pain in his legs and an abdominal mass for 2 months. Peripheral blood examination at the initial visit showed simultaneous peripheral blood cell reduction of the ternary systems, and bone marrow cytology revealed that the proportion of lymphoblasts was 94.2%. Flow cytometric analysis showed that the abnormal B lymphoid tumor cell population accounted for 84.20%, which were mainly positive for CD10, CD19, CD58/33, CD34, and negative for sIgM, kappa, and lambda. Cytogenetic analysis showed a normal karyotype of 46, XY[20]. Fluorescence in situ hybridization (FISH) revealed ETV6-RUNX1 rearrangement. In terms of imaging examination, the boy’s abdominal ultrasound showed diffuse space-occupying lesions in the rectal wall (6.0 cm × 1.6 cm). Additionally, there was no leukemia cells infiltration in the extramedullary evaluation.

This child was treated with the South China Children’s Leukemia Group-2016 (SCCLG-ALL-2016) protocol after being diagnosed as intermediate-risk ALL (4). The patient responded very well to induction therapy with prednisone. The patient achieved minimal residual disease (MRD) <0.01% according to the bone marrow cytology on day 15 and day 33. However, he was further evaluated as the high-risk group before the consolidation therapy, because the abdominal mass shrank less than 1/3 of the original volume. An abdominal mass biopsy was performed under general anesthesia on August 6, 2019, before consolidation therapy. However, the result of the abdominal mass biopsy before consolidation chemotherapy was negative (immunohistochemical CD19-, PAX5-, CD45-). Subsequently, the child entered maintenance chemotherapy on April 13, 2020. At that time, the patient underwent an abdominal enhanced magnetic resonance imaging (MRI) and the result showed that the abdominal mass has vanished.

On December 13th, 2021, when he was still in maintenance therapy of ALL, he was admitted to our hospital again with chief complaints of dizziness and vomiting for one week. On physical examination, the patient had pathological signs of the nervous system, including cervical resistance, Kernig sign (+), and Brudzinski’s sign (+). However, the blood routine examination, bone marrow cytology, bone marrow biopsy and tumor markers (alpha-fetoprotein, carcinoembryonic antigen, human chorionic gonadotropin, and neuron specific enolase) were negative, which meant the boy was still in complete remission (CR) for ALL. Unexpectedly, we detected the presence of EBV DNA in the child’s peripheral blood (2.82×10³/L). In the cerebrospinal fluid (CSF), EBV DNA concentration was 4.16×10³/L, and no tumor cells were found. Tumor markers were all negative in CSF. We also detected a dramatic decrease of T cells, B cells, NK cells and low level of immunoglobulin in his peripheral blood compared to that before the ALL treatment, indicating the immunosuppression. Head MRI showed that there was midbrain aqueduct occlusion, supratentorial ventricle dilated hydrocephalus, multiple metastases at the base of the third ventricle and the cerebellar vermis and multiple interstitial cerebral edema in the paraventricular cerebellum, brain stem, and dorsal thalamus (Figure 1A). Abdominal MRI showed lymph node enlargement in the left inguinal area, bilateral adrenal gland, and infiltration in the prostate. We performed a biopsy of his inguinal lymph nodes to further clarify the diagnosis. The histopathological picture of his lymph nodes featured with a neoplasm of large B-cells arranged in a diffuse pattern. The immunohistochemistry analysis of lymph nodes was positive for CD19, CD20, CD45, CD79a, CD2, CD3, CD4, CD5, CD7, CD30, Ki-67 (50% positive), PAX-5, C-myc, Bcl-6, Bcl-2, and P53, and negative for CD10, CD21, CD99, MPO, TdT, ALK, EMA, CD1, and CD57 (Figure 1B). The IgH, IgK and IgL rearrangement test were negative in the bone marrow and pathological section. The result of FISH and next negation sequencing test was negative except for the ETV6-RUNX1 rearrangement. Finally, this patient was diagnosed with EBV-positive DLBCL with a T-cell/histiocyte-rich large B-cell lymphoma-like pattern (stage IV, high risk, CNS involvement). We immediately stopped the maintenance therapy of ALL and gave him the chemotherapy based on the South China Children’s Cancer Group Non-Hodgkin Lymphoma Group (SCCCG-NHL-2017) protocol (5). Meanwhile, he received right external ventricular drain surgery to release the high pressure in his brain. After completing the induction phase of chemotherapy, the size of intracranial lesions significantly decreased. The re-examination of head MRI showed that his hydrocephalus was obviously diminished, and the range of multiple intracranial metastatic tumors was significantly reduced. Due to the financial reason, the patient did not receive hematopoietic stem cell transplantation after CR. Nowadays, this patient has been free from the recurrence of ALL or DLBCL for 20 months. All procedures performed in this study were in accordance with the ethical standards of the Human Ethics Committee of Shenzhen Children’s Hospital and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the parent and/or legal guardian of the patient for publication of this case report and accompanying image. A copy of the written consent is available for review by the editorial office of this journal.

Figure 1 The head MRI and histopathology slide of lymph node biopsy at the occurrence of DLBCL. (A) The MRI of head; (B) histopathological picture of bone marrow (hematoxylin and eosin stain) and inguinal lymph nodes (hematoxylin and eosin stain). BM, bone marrow; MRI, magnetic resonance imaging; DLBCL, diffuse large B-cell lymphoma.

Discussion

Data reported so far (1990–2022) indicated that few cases with ALL who developed NHL after ALL treatment have been reported. Table 1 summarizes these patients’ presentation, interval from ALL, immunophenotype, treatment, and prognosis. Among them, only 2 cases with ALL developed DLBCL, and none of them showed CNS involvement. At the end of follow-up, only one patient with DLBCL died and other 3 patients reached disease free survival or CR. See Table 1 for a summary of the cases.

The most common reason for secondary DLBCL may involve infection, immunodeficiency, genetic susceptibility, and treatment. A comprehensive study demonstrated 85 patients developed NHL after ALL between 1980–2018, and 65% was associated with immunodeficiency, generally EBV-related (10). It is reported that the pathogenesis of EBV associated lymphoma involves the complex interaction between viral gene expression patterns and cellular genetic changes (11). Thus, it can be easily envisaged how it contributes to the development of B-cell lymphomas because EBV persists in the B cells of the asymptomatic host. Unfortunately, we have not found the direct relationship between EBV infection and DLBCL as reported in relevant literature.

Immunosuppression is responsible for the deficiency of immune surveillance, which provides conditions for the proliferation of cancer cells. Studies have shown that an individual who repeatedly suffers from malignant tumors may be associated with potential genetic defects involved with primary immunodeficiency (12,13). Nevertheless, no patients with congenital immunodeficiency were reported in the cases we reviewed. The most common type of secondary immunodeficiency (SID) is a decreased antibody level occurring due to a side effect of medications used to treat hematological malignancies. SID can develop as a consequence of B-cell lymphoproliferative diseases (14,15). In this study, we detect a dramatic decrease of immune cells and immunoglobulin in the occurrence of DLBCL. More evidence is needed to confirm the correlation between ALL and DLBCL from the perspective of immune deficiency.

It should not be underestimated that radiation and chemotherapy can increase the risk of secondary lymphoma. Turcotte et al. reported that chemotherapy-only survivors had a 2.8-fold increased secondary malignancies risk rate compared with the general population. The elevated risk rate is associated with higher-dose alkylating agent and topoisomerase II inhibitors exposure (16). A study also indicated that NUDT15 variants may confer risk for SMNs after 6-mercaptopurine (6-MP) treatment in patients with ALL (17). In all the cases we sorted from the literature, alkylating agents or topoisomerase II inhibitors were involved in the treatment, but radiotherapy was not included. Therefore, further investigations in the future are required to explore pharmacokinetics effects on secondary lymphoma.

In this case, we detect a dramatic decrease of immune cells and immunoglobulin in the occurrence of DLBCL. We inferred that the ALL chemotherapy induced immune cells and antibody deficiency may be the reason for EBV infected secondary lymphoma. But more genetic tests were needed to confirm the correlation between ALL and secondary DLBCL in the present of immunodeficiency.

Conclusions

This case presented here is interesting as it provides many learning points. First, the clinical presentation of secondary lymphoma can be rather latent. It is difficult to recognize before some severe symptoms present. Second, it highlights the detection of EBV DNA in the peripheral blood and CSF during the full course of ALL therapy. Third, more genetic tests were needed to confirm the correlation between ALL and secondary DLBCL in the present of immunodeficiency.

Acknowledgments

Funding: This research was funded by The Medical Science and Technology Foundation of Guangdong Province (No. A2023335), Sanming Project of Medicine in Shenzhen (No. SZSM201512033), Guangdong Medical Science and Technology Research Project (No. A2020101), Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties (No. SZGSP012), Shenzhen Key Medical Discipline Construction Fund (No. SZXK034), Shenzhen Healthcare Research Project (No. SZLY2018015).

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-24-2/rc

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-24-2/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-24-2/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the Human Ethics Committee of Shenzhen Children’s Hospital and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the parent and/or legal guardian of the patient for publication of this case report and accompanying image. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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