Neurologic Clinical, Electrophysiologic, and Pathologic Characteristics of Primary vs Secondary Neurolymphomatosis.

BACKGROUND AND OBJECTIVES: Neurolymphomatosis (NL) is characterized by lymphomatous infiltration of the peripheral nervous system presenting as the initial manifestation of a lymphoma (primary NL [PNL]) or in relapse of a known lymphoma (secondary NL [SNL]). This report details and compares the neurologic clinicopathologic characteristics of these 2 groups. METHODS: This retrospective study was performed on patients diagnosed with pathologically confirmed NL in nerve between January 1, 1992, and June 31, 2020. Patient clinical characteristics, neurologic examination, imaging studies, EMG, and nerve biopsy data were collected, analyzed, and compared between PNL and SNL. RESULTS: A total of 58 patients were identified (34 PNL and 24 SNL). Time from neurologic symptom onset to diagnosis was longer in PNL at 18.5 months compared with 5.5 months in SNL (p = 0.01). Neurologic symptoms were similar in both patient groups and included primarily sensory loss (98%), severe pain (76%), and asymmetric weakness (76%). A wide spectrum of EMG-confirmed different neuropathy patterns were observed, but patients with SNL had increased numbers of mononeuropathies (n = 8) compared with PNL (n = 1, p = 0.01). MRI studies detected NL more frequently (86%) compared with fluorodeoxyglucose (FDG)-PET CT imaging studies (60%) (p = 0.007). Nerve biopsies revealed B-cell lymphoma (PNL n = 32, SNL n = 22), followed by T-cell lymphoma (PNL n = 2, SNL n = 2), with increased demyelination in both groups and increased axonal degeneration (p = 0.01) and multifocal myelinated fiber loss (p = 0.04) significant in SNL vs PNL. Identifying SNL resulted in patient treatment modifications but a worse prognosis compared with PNL (p = 0.025). DISCUSSION: While PNL and SNL are both primarily painful and asymmetric neuropathies with axonal and demyelinating features on EMG and nerve biopsy, SNL presents somewhat differently than PNL with fulminant, asymmetric often mononeuropathies better detected on MRI than FDG-PET/CT. The focal pattern of SNL is likely a result of residual cancer cells that evaded initial chemotherapy, which does not cross the blood-nerve barrier, and these cells can later recur and result in fulminant disease. Although still resulting in a poorer prognosis, identifying SNL is important because this changed treatment and management in every SNL case.

Primary neurolymphomatosis with MAG antibody: a case report.

Neurolymphomatosis (NL) is a rare neurologic manifestation of non-Hodgkin lymphoma (NHL) with poor prognosis. Investigations including MRI, PET/CT, nerve biopsy and cerebrospinal fluid (CSF) analysis can aid the diagnosis of NL. In this study, we presented a case of NL with co-existing myelin-associated glycoprotein (MAG) antibody. The patient first presented with symptoms of peripheral neuropathy involving multiple cranial nerves and cauda equina, and later developed obstructive hydrocephalus and deep matter lesions. He also had persistently positive MAG antibody, but did not develop electrophysiologically proven neuropathy and monoclonal immunoglobulin. The final brain biopsy confirmed diffuse large B cell lymphoma.

Clinical Presentation, Management, and Outcome in Neurolymphomatosis: A Systematic Review.

BACKGROUND AND OBJECTIVES: Neurolymphomatosis (NL) refers to lymphomatous infiltration of the peripheral nervous system (PNS). NL diagnosis and treatment are challenging given the broad differential diagnosis of peripheral neuropathy, the lack of larger cohorts, and the subsequent unavailability of prognostic factors or consensus therapy. This study aimed to define characteristics and prognostic factors of NL. METHODS: A systematic review of the literature (2004-2023) was performed using PubMed and Scopus databases and reported following PRISMA guidelines. Studies reporting individual patient data on cases with definitive NL diagnosis were included. Clinical, radiologic, pathologic, and outcome information were extracted. Univariable and multivariable survival analyses were performed using log-rank tests and Cox proportional hazard models. RESULTS: A total of 459 NL cases from 264 studies were accumulated. NL was the first manifestation of malignancy (primary NL) in 197 patients. PNS relapse of known non-Hodgkin lymphoma (secondary NL) occurred in 262 cases after a median 12 months. NL predominantly presented with rapidly deteriorating, asymmetric painful polyneuropathy. Infiltrated structures included peripheral nerves (56%), nerve roots (52%), plexus (33%), and cranial nerves (32%). Diagnosis was established at a median of 3 months after symptom onset with substantial delays in primary NL. It mainly relied on PNS biopsy or FDG-PET, which carried high diagnostic yields (>90%). Postmortem diagnoses were rare (3%). Most cases were classified as B-cell (90%) lymphomas. Tumor-directed therapy was administered in 96% of patients and typically consisted of methotrexate or rituximab-based polychemotherapy. The median overall survival was 18 months. Primary NL without concurrent systemic disease outside the nervous system (hazard ratio [HR]: 0.44; 95% CI 0.25-0.78; p = 0.005), performance status (ECOG <2, HR: 0.30; 95% CI 0.18-0.52; p < 0.0001), and rituximab-based treatment (HR: 0.46; 95% CI 0.28-0.73; p = 0.001) were identified as favorable prognostic markers on multivariable analysis when adjusting for clinical and sociodemographic parameters. DISCUSSION: Advances in neuroimaging modalities, particularly FDG-PET, facilitate NL diagnosis and offer a high diagnostic yield. Yet, diagnostic delays in primary NL remain common. Rituximab-based therapy improves NL outcome. Findings may assist clinicians in early recognition, prognostic stratification, and treatment of NL.

Lymphomatosis cerebri caused by adult T cell leukemia/lymphoma: a differential diagnosis for depression: a case report.

BACKGROUND: Primary central nervous system lymphoma is rare, and primary central nervous system T cell lymphoma is relatively uncommon, contributing to < 5% of all cases. Lymphomatosis cerebri, a rare subtype of primary central nervous system lymphoma, is characterized by extensive white-matter lesions on magnetic resonance imaging and nonspecific symptoms, such as cognitive decline and depression. Reports of lymphomatosis cerebri in adult T cell leukemia/lymphoma are limited. CASE PRESENTATION: A 49-year-old Japanese man gradually developed insomnia, anorexia, and weight loss over a 2-month period following work-related promotion. Initially diagnosed with depression, his condition rapidly deteriorated with cognitive decline and motor dysfunction. Despite various treatments, his symptoms persisted within a month. Upon admission, the presence of neurological abnormalities suggestive of a central nervous system disorder raised suspicion of a cerebral lesion. Diagnostic tests revealed extensive brain lesions on imaging and the presence of atypical lymphocytes (flower cells) in the cerebrospinal fluid. The patient was diagnosed with lymphomatosis cerebri due to adult T cell leukemia/lymphoma, a rare presentation in the literature. Due to irreversible brainstem damage and poor neurological prognosis, aggressive treatment was not initiated, and the patient died, with an autopsy confirming the diagnosis. CONCLUSION: Lymphomatosis cerebri with adult T cell leukemia/lymphoma is very rare. It is crucial to promptly consider lymphomatosis cerebri as a differential diagnosis, particularly in cases of rapid cognitive decline and poor treatment response. Recognition of lymphomatosis cerebri as an important differential diagnosis for cognitive decline, and depression is necessary for timely intervention and management. Further research is required to better understand this unique and rare presentation in adult T cell leukemia/lymphoma.

The role of 18F-FDG PET/CT in Neurolymphomatosis: A Comprehensive Imaging Approach.

Neurolymphomatosis (NL) is an uncommon and rare neurologic disorder characterised by extranodal lymphoma, where the tumour cells invade the cranial nerves, nerve plexus, nerve root, spinal nerve roots, trunk nerves or peripheral nerves. MRI is the modality of choice, but is often challenging in detection of early recurrence, assessing residual disease and response evaluation. 18FFDG PET/CT has superior diagnostic performance compared with body CT in the evaluation of NL. 18F-FDG PET-CT is helpful in evaluation of disease extent and potential to guide biopsy. 18F-FDG PETCT is a highly sensitive technique for early localisation of NL than MRI or CT alone. Besides diagnostic and prognostic value in NL, it might be very helpful in response assessment.

Neurolymphomatosis diagnosed after a recurrence of facial palsy.

Neurolymphomatosis (NL) is a rare complication of non-Hodgkin's lymphoma, characterized by the infiltration of lymphoma cells into the peripheral nerves. A 54-year-old woman initially presented with right facial palsy without any other significant symptoms and was diagnosed with Bell's palsy. Despite initial improvement, her condition recurred, prompting further evaluation. Magnetic resonance imaging (MRI) revealed contrast enhancement from the tympanic segment to the surface of the masseter muscle along the right facial nerve and an adjacent mass lesion. Biopsy of the mass revealed a diagnosis of T-cell/histiocyte-rich large B-cell lymphoma. Chemotherapy resulted in complete resolution of facial palsy. Follow-up MRI confirmed the absence of contrast enhancement along the facial nerve. Facial palsy was considered to be caused by NL. This case was classified as that of primary NL because the facial palsy was the first manifestation of a hematologic malignancy. Recurrent facial palsy, which is atypical in Bell's palsy, led to further evaluation with MRI, which finally resulted in the diagnosis of malignant lymphoma. In cases of recurrent facial palsy, clinicians should consider various diagnoses, including that of NL, and advocate early imaging tests and biopsy, if possible, for accurate diagnosis and improved outcomes.

Neurolymphomatosis as primary presentation of extra-nodal NK/T-cell lymphoma, nasal type.

Neurolymphomatosis (NL) describes an infiltration of cranial and peripheral nerves by lymphoma cells, most frequently in non-Hodgkin B-cell lymphoma. This clinical entity is rare and poses a challenging diagnosis. We describe a case of a 64-year-old female patient with NL associated with extra-nodal NK/T-cell lymphoma (ENKTL), nasal type, presenting as a painful progressive mononeuropathy multiplex with an oral cavity lesion. ENKTL is usually associated with Epstein-Barr virus (EBV) infection and rarely affects the central and peripheral nervous system. Lumbar puncture, magnetic resonance imaging (MRI), nerve biopsy, and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) help to establish the diagnosis. Thereby, NL should be considered in the differential diagnosis of painful progressive multiple neuropathies, even in patients without previous history of cancer.

Primary adrenal lymphoma presenting as neurolymphomatosis: A case report.

RATIONALE: Primary adrenal lymphoma (PAL) is a very rare and highly aggressive disease. Neurolymphomatosis (NL) is a rare manifestation of lymphoma characterized by the infiltration of lymphoma cells into peripheral nerves, resulting in neurological symptoms. To date, there have been very few reported cases of PAL with NL. By reviewing the entire treatment process of the patient, we aim to enhance recognition of PAL complicated with NL and guide clinicians to pay attention to the diagnosis of such diseases. Early recognition and diagnosis of NL are crucial for appropriate management and treatment decisions. PATIENT CONCERNS: We report a case of PAL in a 64-year-old female whose initial symptoms were pain and weakness in the left leg, which progressively worsened. In the half month before admission, the patient also showed signs of cranial nerve damage, such as diplopia and facial asymmetry. DIAGNOSIS: Computed tomography of the abdomen revealed an occupying lesion in the left adrenal region. Electromyography and somatosensory evoked potential examination of the extremities suggested left lumbar plexus damage and complete damage to the right facial nerve. Adrenal biopsy confirmed diffuse large B-cell lymphoma. INTERVENTIONS: The patient was treated with the R-CHOP scheme (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) combined with lenalidomide. OUTCOME: After 6 rounds of chemotherapy, the symptoms improved slightly. However, the condition progressed, and the patient passed away 1 year later. LESSONS: Due to the nonspecific clinical presentation, patients with neurological damage should be alerted to the possibility of PAL and need to be evaluated thoroughly.

Primary neurolymphomatosis diagnosed by spinal nerve root biopsy.

Primary neurolymphomatosis is the direct infiltration of lymphomatous neoplastic cells into nerve roots and/or peripheral nerves. A 67-year-old man had a 24-month history of progressive and severe left lower limb neuropathic pain, ipsilateral ankle dorsiflexion weakness and gait disturbance. Gadolinium-enhanced MRI showed thickening and enhancement of the cauda equina, L5, S1 and S2 nerve roots. 18Fluorodeoxyglucose positron emission tomography showed concordant hypermetabolism. L5 nerve root biopsy confirmed diffuse large B-cell lymphoma. One cycle of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) chemotherapy resulted in remission, but this was not sustained. Primary neurolymphomatosis is rare and diagnostically challenging, and often the diagnosis is delayed. While biopsy is the gold standard for diagnosis, neuroimaging helps to characterise lesions and to determine the feasibility of biopsy.

Nerve biopsy in T-cell lymphoma with neurolymphomatosis: where and when.

Peripheral T-cell lymphomas are rare heterogeneous haematological malignancies that may also involve peripheral nerves in a very small subset of cases. We report a patient with a diagnostically challenging cutaneous T-cell lymphoma and multifocal mononeuropathies in whom a targeted nerve biopsy identified lymphomatous infiltration of nerves and expedited combination treatment with chemotherapy and an autologous stem cell transplant. She showed an excellent response with a complete metabolic response on positron emission tomography imaging and significant clinical improvement, maintained 5 years post-treatment.

Pronator syndrome and anterior interosseous nerve palsy due to neurolymphomatosis: a case report.

Pronator syndrome is a median nerve entrapment neuropathy that can be difficult to diagnose due to its variable presentation and objective findings. Neurolymphomatosis is an uncommon disease in which malignant lymphocytes infiltrate central or peripheral nerve endoneurium and is often missed for prolonged periods prior to diagnosis. We present a rare case of pronator syndrome and anterior interosseous nerve palsy due to neurolymphomatosis that was occult on initial MRI in spite of the presence of a median nerve mass discovered intra-operatively during neurolysis. This case demonstrates the value of ultrasound for the examination of peripheral nerve pathology and illustrates its utility as an adjunct to MRI, in part due to the ability to screen a large region.

Primary cauda equina lymphoma confirmed by autopsy: A case report.

Compared with those involving the central nervous system, lymphomas involving the peripheral nervous system, namely neurolymphomatosis, are extremely rare. Neurolymphomatosis is classified as primary or secondary; the former is much rarer than the latter. Herein, we present an autopsied case of primary cauda equina lymphoma (PCEL), a type of primary neurolymphomatosis, with a literature review of autopsied cases of PCEL as well as primary neurolymphomatosis other than PCEL (non-PCEL primary neurolymphomatosis). A 70-year-old woman presented with difficulty walking, followed by paraplegia and then bladder and bowel disturbance. On magnetic resonance imaging, the cauda equina was diffusely enlarged and enhanced with gadolinium. The brainstem and cerebellum were also enhanced with gadolinium along their surface. The differential diagnosis of the patient included meningeal tumors (other than lymphomas), lymphomas, or sarcoidosis. The biopsy of the cauda equina was planned for a definite diagnosis, but because the patient deteriorated so rapidly, it was not performed. Eventually, she was affected by cranial nerve palsies. With the definite diagnosis being undetermined, the patient died approximately 1.5 years after the onset of disesase. At autopsy, the cauda equina was replaced by a bulky mass composed of atypical B-lymphoid cells, consistent with diffuse large B-cell lymphoma (DLBCL). The spinal cord was heavily infiltrated, as were the spinal/cranial nerves and subarachnoid space. There was metastasis in the left adrenal. The patient was finally diagnosed postmortem as PCEL with a DLBCL phenotype. To date, there have been a limited number of autopsied cases of PCEL and non-PCEL primary neurolymphomatosis (nine cases in all, including ours). The diagnosis is, without exception, B-cell lymphoma including DLBCL, and the histology features central nervous system parenchymal infiltration, nerve root involvement, and subarachnoid dissemination (lymphomatous meningitis). Metastases are not uncommon. All clinicians and pathologists should be aware of lymphomas primarily involving the peripheral nervous system.

Neurolymphomatosis as an Initial Presentation of Non Hodgkins Lymphoma: A Case Report.

Neurolymphomatosis (NL) is a rare clinical disease where neoplastic cells invade the cranial nerves, roots, plexus, or other peripheral nerves in patients with hematologic malignancy mainly Non-Hodgkins Lymphoma(NHL). Primary NL occurs as the first manifestation of a hematologic malignancy. We report a 68-year male who presented to us with low backache and burning paraesthesia in the back of both lower limbs followed by a left foot drop. The clinical and electrophysiological examination was suggestive of bilateral lumbosacral radiculopathy involving L2-S1 roots. Plain MRI of the lumbosacral spine was normal. F18FDG PET CT Scan revealed increased uptake in both L5 and left L3 roots. Contrast-enhanced MRI of the lumbosacral spine showed marked fusiform thickening and enhancement of both L5 and left L3 roots CT-guided Biopsy from left L5 root, lymph node, and bone marrow was suggestive of large B cell lymphoma-germinal center cell type. The diagnosis was neurolymphomatosis secondary to NHL.

COVID-19 associated Bell's Palsy and lumbosacral neurolymphomatosis in a patient with B-cell lymphoma-Case Report.

This is a case of acute onset unilateral Bell's Palsy during COVID-19 illness, coinciding with development of progressive leg pain, weakness, and sensation change. The patient was ultimately found to have a large B-cell lymphoma mass invading the sciatic nerve, lumbosacral plexus and the spinal canal with compression of cauda equina consistent with neurolymphomatosis. Although COVID-19 infection has been associated with Bell's palsy, Bell's palsy has also been reported with lymphoid malignancy. We review current literature on the association of Bell's palsy with COVID-19 infection and lymphoid malignancy, as well as review the diagnostic challenges of neurolymphomatosis. Providers should be aware of the possible association of Bell's palsy as harbinger of lymphoid malignancy.

Neurolymphomatosis: involvement of peripheral nervous system revealing hematologic malignancy, a report of nine cases.

BACKGROUND AND AIM: Neurolymphomatosis is defined as an infiltration of the peripheral nervous system (PNS) by malignant lymphoma cells. It is a rare entity and diagnosis is complicated especially when PNS involvement is the initial and leading symptom. To improve knowledge of the disorder and shorten the time to diagnosis, we report a series of nine patients without a history of hematologic malignancy, who were diagnosed with neurolymphomatosis after evaluation and workup of peripheral neuropathy. METHODS: The patients were included from the Department of Clinical Neurophysiology at Pitié Salpêtrière and Nancy Hospitals over a period of 15 years. Diagnosis of neurolymphomatosis was confirmed by histopathologic examination for each patient. We characterized their clinical, electrophysiological, biological, imaging, and histopathologic features. RESULTS: The neuropathy was characterized by pain (78%), proximal involvement (44%) or of all four limbs (67%), asymmetrical or with multifocal distribution (78%), abundant fibrillation (78%), a tendency to worsen rapidly, and significant associated weight loss (67%). Neurolymphomatosis was diagnosed principally on nerve biopsy (89%) identifying infiltration of lymphoid cells, atypical cells (78%), a monoclonal population (78%), and supported by fluorodeoxyglucose-positron emission tomography, spine or plexus MRI, cerebrospinal fluid analysis, and blood lymphocyte immunophenotyping. Six patients had systemic disease and three impairment limited to the PNS. In the latter case, progression could be unpredictable and may be diffuse and explosive, sometimes occurring years after a seemingly indolent course. INTERPRETATION: This study provides better knowledge and understanding of neurolymphomatosis when neuropathy is the initial presentation.

Thiotepa-based high-dose chemotherapy with autologous stem cell transplantation for neurolymphomatosis.

Neurolymphomatosis (NL) is a rare clinical entity characterized by lymphomatous infiltration of the peripheral nervous system. According to recent retrospective data, consolidative high-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) may be beneficial for NL. However, few reports to date have discussed optimal conditioning regimens. Herein, we report two cases of NL in patients with relapsed intravascular large B-cell lymphoma who received consolidative thiotepa-containing HDC-ASCT. Case 1: A 56-year-old woman who relapsed 2 months after the first complete remission (CR) and underwent ASCT. Case 2: A 65-year-old woman who relapsed 8 months after the first CR and underwent ASCT. Both patients engrafted. Time to neutrophil engraftment was 10 and 12 days after HDC-ASCT, and CR was sustained for 26 and 18 months, respectively, as of the last follow-up. Although there is little evidence supporting the utility of thiotepa-based HDC-ASCT in patients with NL, the results of this case report suggest that further studies are warranted to determine its efficacy in this setting.

Chimeric Antigen Receptor T-Cell Therapy of Neurolymphomatosis Monitored by FDG PET/CT.

ABSTRACT: 18 F-FDG PET/CT was performed to evaluate possible recurrent B-cell lymphoblastic lymphoma in a 34-year-old man. The images showed multiple foci of increased activity in the nerve root and peripheral nerve. A biopsy confirmed the diagnosis of neurolymphomatosis. After receiving chemotherapy, PET/CT showed progressive disease. The patient subsequently received the CD-19 chimeric antigen receptor T-cell therapy. A follow-up PET/CT acquired 30 days after chimeric antigen receptor T-cell therapy revealed no abnormal FDG activity.