Chromosomal Abnormalities as a Predisposition to Secondary Neurolymphomatosis in Patients with Diffuse Large B-Cell Lymphoma: A Report of Two Cases and a Literature Review

Abstract

Introduction

Neurolymphomatosis (NL) is a rare condition characterized by the infiltration of malignant lymphoma cells into the peripheral nervous system. The optimal treatment for NL remains unclear, and patients with secondary NL have a poor prognosis. Although early recognition of NL may contribute to successful treatment, the predictive factors for secondary NL are yet to be established.

Case Presentation

Here, we present our investigation on the predictive factors for secondary NL, and report two cases of secondary NL with a literature review. We analyzed chromosomal abnormalities in patients with secondary NL and found a common deletion of chromosome 10 and add(11)(p11). The chromosomal abnormalities might be a predictive factor for secondary NL; therefore, confirmation of chromosomal abnormalities can possibly give a hint for early detect of secondary NL. Prompt histopathological examination or imaging techniques can lead to early diagnosis of secondary NL in patients with diffuse large B-cell lymphoma (DLBCL).

Conclusion

When neurological symptoms manifest in patients with DLBCL and there are chromosomal abnormalities, the possible development of secondary NL should be considered.

Introduction

Neurolymphomatosis (NL) is a rare condition characterized by the infiltration of malignant lymphoma cells into the peripheral nervous system [1]. NL can manifest at the time of diagnosis, or as a secondary manifestation following the diagnosis of malignant lymphoma. The optimal treatment for NL remains unclear, and the overall survival of secondary NL is significantly worse than that of primary NL [2]. Early diagnosis of NL may contribute to successful treatment; however, predictive factors for secondary NL have yet to be established [3]. Here, we present our investigation into the predictive factors of secondary NL and report 2 cases of secondary NL, with a literature review.

Case Report

Patient 1

A 60-year-old female presented with fever, weight loss, and lymphadenopathy and was admitted to our hospital. The patient was diagnosed with diffuse large B-cell lymphoma (DLBCL), confirmed by biopsy of the left cervical lymph node. The results of the chromosomal analysis are shown in Table 1. Before chemotherapy, fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) did not reveal any findings indicating the presence of NL. Treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) was initiated. The patient experienced progressive lower-limb weakness after the first course of R-CHOP treatment. Drug-induced neuropathy was suspected, and vincristine was discontinued; however, the severity of the neurological symptoms did not improve. Guillain-Barré syndrome was suspected, and treatment with high-dose intravenous immunoglobulin was initiated. Nevertheless, the neurological symptoms progressed to the upper limbs and face, and the cause of the neuropathy could not be identified. Further treatment with antiviral agents (acyclovir) and high-dose steroid (1,000 mg methylprednisolone for 3 days) was ineffective. Due to a poor physical status associated with the neuropathy, FDG PET/CT could not be performed. The progressive loss of motor neurons led to respiratory failure, and the patient died on day 75. A postmortem examination was performed with the consent of the patient’s family. Following the autopsy, histopathological examination revealed abundant atypical lymphoid cells in the liver, kidneys, lymph nodes, spinal cord, nerve roots, and peripheral nerves (Fig. 1a, b). Immunohistochemical staining of the cauda equina nerves revealed lymphoid cell populations positive for CD20 (Fig. 1c), ultimately leading to the diagnosis of NL.

Table 1.

Chromosome analysis of patients with secondary NL

Author (Ref)	Age/sex	Histology	Diagnostic method for NL	Chromosome analysis
Tachibana et al. [4] (2007)	73/female	DLBCL	Autopsy	45, XX, add(1)(p13), add(2)(q33), −3, add(4)(q21), add(7)(q22), add(8)(q24), −10, add(11)(p11), add(12)(q13), der(14)t(14;18)(q32;q21), −15, ider(18)(q10)t(14;18), +der(?)t(?;1)(?;p13), +mar1 [5/20] 46, XX [15/20]
Our case 1	60/female	DLBCL	Autopsy	51, X, add(X)(q22), add(1)(p36.1), −4, −6, −6, +add(7)(q22), add(8)(p11.2), −10, −10, +11, +add(11)(p11.2), -16, -17, +18, −19, add(19)(q13.1), +9mar [1/20] 46, XX [3/20]
Our case 2	76/male	DLBCL	FDG PET/CT	94, XXYY, add(2)(p11.2)x2, +3, del(3)(q?)x2, +7, +7, add(8)(p11.2)x2, add(9)(p11)x2, −10, add(11)(p11.2)x2, −17, −17, der(17)(p?)x2, −18, −18, +mar1x2, +mar2x2 [1/20] 46, XY [18/20]

DLBCL, diffuse large B-cell lymphoma; FDG PET/CT, fluorodeoxyglucose positron emission tomography-computed tomography; NL, neurolymphomatosis.

Fig. 1.

Representative images of cauda equina nerves in secondary NL. a Cauda equina nerve, hematoxylin and eosin (H&E). b Cauda equina nerve, H&E. c Cauda equina nerve, CD20. d Cauda equina nerve, CD3. Scale bar is 1 mm (a). Scale bar is 200 μm (b–d).

Patient 2

A 76-year-old male with abnormal behavior and impaired consciousness was admitted to our hospital. Magnetic resonance imaging (MRI) of the brain and cerebrospinal fluid studies revealed no abnormalities. However, a skin biopsy of abdominal erythema revealed proliferation of large B-cells within the lumina of the blood vessels; therefore, the patient was diagnosed with intravascular large B-cell lymphoma (IVLBCL). Large B-cells positive for CD20 were observed in the bone marrow, as shown in the chromosome analysis in Table 1. Initiation of R-CHOP treatment followed by high-dose methotrexate treatment improved the impaired consciousness caused by IVLBCL; however, leg numbness and muscle weakness were experienced 8 months later. Images from MRI of the brain revealed subcortical masses in both temporal lobes and FDG PET/CT revealed an intensely avid cauda equina nerve. The patient was diagnosed with central nervous system progression of IVLBCL and secondary NL. Rituximab plus dexamethasone, high-dose cytarabine, and cisplatin was initiated as salvage chemotherapy and the neurological symptoms temporarily improved. However, after the fourth course of rituximab plus dexamethasone, high-dose cytarabine, and cisplatin, MRI of the brain showed subcortical tumor progression. Chemotherapy was discontinued and whole-brain radiotherapy was initiated. 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/10.1159/000541552).

Discussion

NL is a rare manifestation of malignant lymphoma and is observed in 0.85–2.9% of patients with non-Hodgkin’s lymphoma [5]. The prognosis for patients with secondary NL is poor [2]. Establishing predictive factors is imperative to improve overall survival of patients with secondary NL. To the best of our knowledge, this is the first study to investigate the predictive factors of secondary NL, focusing on chromosomal abnormalities, at the time of lymphoma diagnosis, in patients with DLBCL who developed NL. We conducted a MEDLINE database search through PubMed using a key word “neurolymphomatosis.” Full reading of 366 manuscripts was carried out. No limits were made concerning the published year of the manuscript, and the most recent PubMed search was conducted in May 2024 (Fig. 2). In the past, only one study has described chromosomal abnormalities in a patient with DLBCL and NL [4]. From the cytogenic results of 3 cases including our 2 cases at diagnosis, deletion of chromosome 10 and add(11)(p11) was observed (Table 1). Cigudosa et al. [6] reported that deletion of chromosome 10 was present in approximately 2% of 215 patients with DLBCL. Chromosomal abnormalities, such as add(11)(p11), are not frequently observed in patients with DLBCL [7]. On the other hand, deletion of chromosome 10 and add(11)(p11), at diagnosis, was observed in the 3 patients with secondary NL. Although there are no reports on the pathogenesis of add(11)(p11), another study reported that deletion of chromosome 10 affects the pathogenesis of nervous system tumors such as glioblastoma [8]. Therefore, together with our observations, we highlight the importance of confirming deletion of chromosome 10 and add(11)(p11) that may predict secondary NL in patients with DLBCL. Chromosomal abnormalities could possibly be a predictive factor for the development of NL. Although drug-induced neuropathy is frequently observed during chemotherapy for lymphoma, if neurological symptoms occur during the course of treatment, the possibility of NL should be considered. The diagnosis of NL remains a challenge. The importance of early examination using nerve biopsy or FDG PET/CT should be emphasized. Nerve biopsy is often difficult to perform because the nerves are inaccessible and the procedure can cause permanent neurological damage [9]. FDG PET/CT is a useful noninvasive imaging technique that exhibits high sensitivity and specificity [3, 10] as in case 2. Increasing importance of FDG PET/CT in the diagnosis of NL, secondary NL diagnosis is mostly guided by imaging techniques [11].

Fig. 2.

PRISMA flowchart.

Chromosomal abnormalities play critical roles in cancer pathogenesis. A deletion of chromosome 10 has been observed in several cancers, including glioblastoma, pancreatic neuroendocrine tumor, and prostate cancer [8, 12, 13]. Tumor suppressor genes such as NCOA4, CCDC6, PTEN, FAS, SUFU, and MXI1 are located on chromosome 10, and mutations in these genes are involved in tumorigenesis [14]. Among them, PTEN mutation especially plays a critical role in pathogenesis of glioblastoma [15]. More than 90% of glioblastomas lose chromosome 10 and half of these have PTEN mutation. The loss of PTEN function has been associated with therapeutic resistance, metastasis, and poor prognosis [16]. In addition, mutations in SUFU raise the risk of medulloblastoma and familial meningioma [17, 18]. As above, some genes on chromosome 10 have been reported to be involved in pathogenesis of cancers in the nervous system. Although the mechanism underlying development of secondary NL remains unclear, mutations in these genes may play a crucial role.

Conclusion

Although further studies are warranted, our observations suggest that a deletion of chromosome 10 and add(11)(p11) might predict the development of secondary NL in patients with DLBCL. Patients with deletions of chromosome 10 and add (11)(p11) could be considered at high risk of developing NL. Consequently, patients with DLBCL and chromosomal abnormalities require careful monitoring of their neurological symptoms, during treatment. The importance of early examination using nerve biopsy or FDG PET/CT should be emphasized.

Statement of Ethics

This study protocol was reviewed and approved by the Ethics Committee of the Juntendo University on June 2024 (JHS24-010). Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Conflict of Interest Statement

The authors state that they have no conflict of interest.

Funding Sources

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Author Contributions

Writing the manuscript: N.W.; data collection, analysis, and interpretation: N.W., S.H., S.S., Y.F., Y.T., K.Y., E.S., D.T., and N.H.; literature research: N.W., S.H., S.S., and D.T.; reviewing histology and immunohistochemistry: S.S., D.T., Y.T., and N.H.; revising the manuscript: E.S. and M.A.

Funding Statement

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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.