Primary large B-cell lymphoma of the central nervous system with positive NMDAR antibody: a case report

N-methyl-D-aspartate receptor (NMDAR) is an ionotropic glutamate (Glu) receptor that is widely expressed in the central nervous system (CNS), mainly in the hippocampus. NMDAR is involved in physiological processes such as learning and memory and synaptic plasticity [1]. Primary CNS lymphoma (PCNSL) is a rare type of non-Hodgkin’s lymphoma that affects the brain, spinal cord, and eyes and accounts for approximately 3–5% of intracranial tumors, 1% of all lymphomas, and less than 5% of non-Hodgkin’s lymphoma [2]. The clinical manifestations of PCNSL lack specificity and can be difficult to differentiate from those of diseases such as autoimmune encephalitis combined with cognitive impairment and psychiatric symptoms, thus leading to misdiagnosis; oftentimes, multiple biopsies are required to confirm the diagnosis. Previous studies have reported Hodgkin’s lymphoma combined with anti-NMDAR encephalitis [3], but primary diffuse large B-cell lymphoma (one of the non-Hodgkin lymphomas) of the CNS with anti-NMDAR antibody positivity has not been reported. In this case study, the patient had atypical clinical manifestations and was positive for anti-NMDAR antibodies, leading to the initial misdiagnosis of “anti-NMDAR antibody encephalitis.” The diagnosis was revised after 2 biopsies. The case is summarized herein, to further improve the understanding of PCNSL.

Autoimmune encephalitis is an autoimmune disease that has received extensive attention in recent years. Among them, anti-NMDAR encephalitis is the most common and is primarily mediated by NMDAR-targeting immunoglobulin G1 (IgG1) antibodies. There are three different subunits in NMDARs: NR1, NR2, and NR3 [4]. The NMDAR-IgG1 antibodies in cerebrospinal fluid mainly target the NR1 subunit of NMDAR on the postsynaptic membrane of neurons, which are distributed throughout the limbic system and in the basal ganglia and the brainstem. NMDAR-IgG1 antibodies reduce the density of NMDAR on the postsynaptic membrane and disrupt the interaction with ephrin receptor 2 (Ephs2), resulting in the excessive release of glutamate and excitotoxicity and causing characteristic clinical manifestations, i.e., mental and behavioral abnormalities, memory loss, seizures, autonomic dysfunction, and decreased levels of consciousness [5]. Animal experiments have shown that mice with reduced NR1 subunit expression or NR2A subunit deletion exhibit behavioral changes characteristic of schizophrenia [6].

Consistent with the diagnostic criteria for anti-NMDAR encephalitis [7], the clinical manifestations of this patient at admission were diplopia, memory loss, drowsiness, and anti-NMDAR antibody positivity (serum 1:32, cerebrospinal fluid 1:1 (CBA method)); brain tissue was normally based on pathology. Other diseases were excluded. This patient was initially diagnosed with “anti-NMDAR antibody encephalitis.” The patient’s condition improved after treatment with methylprednisolone therapy and intravenous gamma globulin, and a reexamination of the MRI indicated that the lesion area had decreased. After the decrease in methylprednisolone dose at discharge, the patient had recurrent symptoms, and cranial MRI revealed that the lesion in the head of the left caudate nucleus had enlarged significantly (Fig. 4). To confirm the diagnosis, a second stereotactic brain biopsy was performed, and the pathological report indicated PCNSL. The final diagnosis was primary diffuse large B-cell lymphoma of the CNS.

Primary diffuse large B-cell lymphoma of the CNS with anti-NMDAR antibody positivity, as in this case study, has not been reported. Previous studies have reported Hodgkin’s lymphoma and non-Hodgkin’s lymphoma combined with anti-NMDAR antibody encephalitis [8]. However, there is no relevant report on NMDAR antibody-positive PCNSL. PCNSL originates in the CNS. The pathogenesis of PCNSL is currently unclear but may be related to immunodeficiency [9]. The clinical manifestations of PCNSL, such as subacute onset, progressive cognitive impairment, and cranial nerve damage, lack specificity, leading to difficulty in differentiating PCNSL from other diseases, such as autoimmune encephalitis and intracranial primary granuloma. MRI can be normal or may demonstrate hippocampal and insular hyperintensities on T2 and FLAIR weighted images [10]. Fluorodeoxyglucose-positron emission tomography should be considered when MRI is normal. For example, for this patient, the presence of cognitive dysfunction combined with anti-NMDAR antibody positivity (serum, 1:32; cerebrospinal fluid, 1:1) led to an initial misdiagnosis of anti-NMDAR antibody encephalitis. Currently, there is no unified standard for the diagnosis of PCNSL. Although, some features are clues to the diagnosis: CNS lymphomas may present in varied forms, however, some findings can contribute to facilitating the differential diagnosis which includes gliomas, metastases, and inflammatory diseases. The finding of an expansile supratentorial solid lesion hypointense on T2-weighted images, with no signs of necrosis, lipids peak in the solid component, low perfusion, and diffusion restriction, favors the possibility of such diagnosis [11, 12]. In terms of anti-NMDAr encephalitis, most frequently, lesions in grey matter structures located in the limbic system (as the hippocampus) but also in cortical regions (frontal, temporal, parietal, and insular cortices) subcortical nuclei (thalamus, basal ganglia, brainstem) and also in the hemispheric white matter [10, 13]. The diagnosis requires a brain biopsy, and some patients even require multiple biopsies. In this case, the patient was diagnosed after 2 biopsies. The initial treatment with steroids and immunoglobulins may have led to atypical lesions, furthermore, the stereotactic brain biopsy may not precisely puncture the tumor tissue, resulting in normal brain tissue in the first biopsy. The second biopsy was performed two months later to confirm the diagnosis, including the lymph node biopsy. The major limitation of this case is that the follow-up period was relatively short and the intervention in the department of hematology was not recorded in detail. Furthermore, a bone marrow biopsy was not performed.

The following aspects of the case reported herein are worth discussing. (1) There are various imaging manifestations of PCNSL, and MRI manifestations: T1-weighted sequences are iso- or slightly hypointense, most T2-weighted sequences are iso- or slightly hyperintense, FLAIR sequences are slightly hyperintense, and DWI is iso- or slightly hyperintensity. The corresponding area of the ADC presents a low signal. After injection of contrast agent, either nodular and mass-like enhancement, or heterogeneous enhancement can be observed [14]. The MRI presented multiple lesions, with low T1 signal and high T2 signal in bilateral basal ganglia, thalamus, brainstem, and other parts, slightly high signal on FLAIR, and heterogeneous enhancement. When early PCNSL enhancement is atypical, differentiation from other immune-mediated diseases, such as limbic encephalitis, vasculitis, and systemic lupus erythematosus, is necessary. PCNSL is common in patients without immunodeficiency situations, like immunodeficiency virus (HIV), post-organ transplantation, and Epstein-Barr virus (EBV) [15]. Upregulated antigens and/or stimuli from the EBV gene may induce high-level somatic mutations in lymphoid tissues such as lymphocytes or germinal centers, and B cells from mutated lymphoid tissue can transform into lymphoma cells [16]. Victor et al. reported a case of herpes simplex encephalitis complicated with PCNSL in a distal right temporal lobe lesion [17]. It is speculated that the viral infection of neurons may lead to lymphocyte proliferation and mutation or produce local immune system changes, leading to the occurrence of large B-cell lymphoma. In a prospective study, autoantibodies against NMDA receptors were found in the cerebrospinal fluid of 60% of patients with recurrent herpes simplex virus (HSV) encephalitis [18]. Therefore, in this patient, the early immature B-cell-mediated antigen–antibody response may have generated an immune response against the NMDA receptors distributed on the surface of neurons in the temporal lobe, resulting in the production of NMDA receptor antibodies. (2) The importance of cerebrospinal fluid analysis was not fully recognized in the diagnosis of this patient. In the cerebrospinal fluid of this patient, there were 16 × 10⁶ white blood cells per liter, and a cytological examination was not performed. Fifteen percent of PCNSL patients can be diagnosed by detecting immature lymphocytes, with heterogeneous and pachychromatic nuclei, using cerebrospinal fluid cytology, and a biopsy can be avoided [19]. Flow cytometry immunophenotyping and immunoglobulin gene family analysis of cerebrospinal fluid can distinguish malignant and reactive B lymphocytes. Studies have found that potential PCNSL biomarkers include microRNAs (miR-21, miR-101, and 548b). Among them, miR-222 has a certain value for the early detection of diffuse large B-cell lymphoma [20], as do soluble CD19, interleukin (IL-10), and chemokine ligand 13 (CXCL13), but further validation and screening are required to replace brain biopsy [21, 22]. (3) In this case, the use of steroids and gamma globulin after the initial diagnosis may have caused atypical pathological changes that led to 2 biopsies for diagnosis [4]. This indicates that repeated biopsies may be required to confirm a diagnosis of PCNSL.

Finally, the initial misdiagnosis of this patient indicates that when using autoantibody positivity as part of the clinical diagnostic criteria, clinical manifestations, imaging characteristics, routine cerebrospinal fluid tests, and cytology should also be considered for a comprehensive diagnosis. A diagnosis based only on anti-NMDAR antibody positivity lacks comprehensive differentiation. In addition, the initial use of large doses of steroids and gamma globulin reduced the size range of lesions on cranial MRI, having a certain therapeutic effect, but masked the true condition, leading to repeated biopsies to confirm the diagnosis.

In conclusion, we report a case in which the patient had atypical clinical manifestations and was positive for anti-NMDAR antibodies. When the primary CNS diffuses large B-cell lymphoma associated with autoimmune encephalitis, it is very easy to be misdiagnosed. Therefore, in the diagnosis of immune diseases caused by nervous system infections, it is necessary to dynamically observe the evolution of the disease, perform differential diagnoses when necessary, and ultimately improve our understanding of the disease.