Diffuse large B-cell lymphoma relapse presenting as extensive neurolymphomatosis

Abstract

A 56-year-old woman with a history of diffuse large B-cell non-Hodgkin lymphoma (DLBCL-NHL) in remission for two years presented with weight loss and multifocal sensory/motor symptoms. Magnetic resonance imaging (MRI) of the neuraxis and whole-body FDG PET/CT led to a diagnosis of secondary neurolymphomatosis (NL). MRI demonstrated extensive thickening and enhancement of multiple cranial nerves and peripheral nerve plexuses with corresponding elevated metabolism on FDG PET/CT. Treatment with chemotherapy resulted in complete response on FDG PET/CT and subsequently she underwent autologous stem cell transplantation. NL is a rare manifestation of lymphoma affecting the peripheral nervous system. Nonspecific neuropathic symptoms make clinical diagnosis difficult. Though nerve biopsy is considered the gold standard, MRI and FDG PET/CT are accepted alternatives for making the diagnosis. We review imaging findings in NL, describe the differential diagnosis, and discuss the limitations of the imaging modalities.

Introduction

Neurolymphomatosis (NL), also known as nerve-seeking lymphoma, is a rare entity that characteristically involves the peripheral nervous system (PNS) including cranial nerves. The primary form, without previous documentation of lymphoma elsewhere in the body, is seen in 26% of NL patients,¹ whereas the more common secondary form presents as progression or relapse of lymphoma in the PNS. NL is distinct from leptomeningeal disease (lymphomatous meningitis) and perineural spread from epidural disease.² On histopathology, NL is characterized by lymphomatous infiltration of the connective-tissue layers of the nerve.³ NL is related to non-Hodgkin lymphoma (NHL) in 90% and to acute leukemia in 10%.¹ In 75% of the cases, NL is associated with diffuse large B-cell lymphoma (DLBCL), the most common and aggressive subtype of NHL.^1,4 But other subtypes like follicular lymphoma, mantle cell lymphoma, natural killer cell lymphoma, and peripheral T-cell lymphoma can also invade the PNS.¹

According to the presence of pain and involvement of single or multiple peripheral nerves and/or cranial nerves, four patterns of clinical presentation have been described.⁴ The symptoms and electrical findings in NL are nonspecific and mimic other neoplastic, inflammatory, and autoimmune neuropathies. Nerve biopsy is considered the gold standard for the diagnosis of NL but may not be possible. With recent advances in high-resolution imaging, magnetic resonance imaging (MRI) and ¹⁸F-fludeoxyglucose–positron emission tomography/computed tomography (FDG-PET/CT) are being considered as alternatives for diagnosing NL. MRI provides exquisite anatomic details on the extent of abnormalities. A reported including 50 patients by an international collaborative group found MRI positive in 77% of NL.¹ FDG PET/CT was more sensitive than MRI, with PET being positive in 84% and providing important metabolic information.¹ PET/CT can also help differentiate from other neuropathies that are generally hypometabolic.

We present pretreatment and posttreatment MRI and FDG PET/CT findings in a patient with extensive secondary NL from DLBCL. We discuss the differential diagnosis and illustrate the differentiating features from other causes of neuropathies in patients with lymphoma and nerve thickening.

Case report

A 56-year-old woman, in complete remission for two years after chemotherapy for stage IIIA DLBCL, presented with two-month history of progressive right hand numbness, bilateral leg paresthesia, and weakness. She also complained of poor appetite and weight loss. Examination revealed weakness of the distal right upper extremity and distal lower extremities, and antalgic gait due to left leg stiffness. Electrical studies demonstrated right C8 radiculopathy, left L3/L4 radiculopathy, and mild distal sensory axonopathy in lower extremities. Prolonged F-wave latencies of multiple nerves were also observed.

A CT of the chest and abdomen was negative for lymphadenopathy but revealed a left psoas mass (Figure 1(a) and (b)). A subsequent contrast enhanced MRI of the brain and entire spine revealed diffuse thickening and homogeneous enhancement of the multiple cranial nerves, and brachial and lumbosacral nerve roots (Figure 2(a) to (f)). The extradural segments of the nerve roots were predominantly involved. The left L3 nerve root mass demonstrated a fusiform morphology extending into the left psoas mass. The brachial and lumbosacral plexus nerves were mildly hyperintense on T2-weighted sequence with complete loss of the fibrillar pattern that is seen normally in presacral fat related to the lumbosacral nerve plexus. In the sacrum there was altered marrow signal and enhancement in the S2 to S3 vertebrae contiguous to the nerve root thickening within the sacral spinal canal. On the basis of the MRI findings, NL was considered the likely diagnosis. Other causes of multifocal nerve thickening such as hereditary neuropathy, chronic inflammatory demyelinating neuropathy (CIDP), neurosarcoidosis, and neurofibromatosis were in the differential diagnosis. A cerebrospinal fluid (CSF) analysis revealed abnormal CD19+ B cells on flow cytometry without expression of CD5+, CD10+, membrane, or cytoplasmic light chains, but with morphology suspicious for DLBCL.

Figure 1.

(a) Axial contrast-enhanced computed tomography and (b) coronal multiplanar reformation of the abdomen show a homogeneously enhancing elongated soft-tissue mass (arrow) extending from the left neural foramen into the left psoas muscle in the upper lumbar spine. This represents neurolymphomatosis of the lumbar nerve but in isolation mimics a neurogenic tumor.

Figure 2.

Diffuse thickening and homogeneous enhancement of multiple cranial nerves (yellow straight arrows) on axial and coronal postcontrast magnetic resonance imaging (MRI) of the brain—(a), right oculomotor nerve, (b) right mandibular nerve, and (c) vestibulocochlear nerves in the internal auditory canals. (b) Bilateral trigeminal ganglion are also involved (red asterisk). The enhancement in the vestibulocochlear nerves are nodular and are difficult to differentiate from leptomeningeal disease. Thickening and enhancement of (d) brachial and (e, f) lumbosacral plexus (red arrows) in sagittal and coronal MRI of the cervical and lumbar spine. (f) The left L3 extradural nerve root shows a mass-like fusiform morphology. An incidental left posterior communicating aneurysm (curved yellow arrow) was also identified and was successfully treated by coil embolization during follow-up.

A whole-body FDG PET/CT examination showed multifocal hypermetabolic activity (SUVmax 7 to 10 range) along the abnormally thickened mandibular division of the right trigeminal nerve, bilateral brachial, and lumbosacral nerve plexuses (Figure 3(a) and (b)). A linear to fusiform pattern of activity was observed in the plexuses. A mass-like region of activity was present in the midline sacrum from the involvement of the extradural segments of sacral nerve roots and contiguous infiltration of the S2 to S3 vertebrae. A focal hypermetabolic cutaneous lesion was also present in the right parasternal region. PET/CT was negative for hypermetabolic lymphadenopathy or visceral abnormalities. Biopsy of the right parasternal cutaneous nodule revealed high-grade DLBCL. Bone marrow involvement was negative on PET/CT and on aspirate.

Figure 3.

(a) Anterior and (b) lateral maximum intensity projections of initial ¹⁸F-fludeoxyglucose–positron emission tomography demonstrate multifocal sites of hypermetabolic activity (arrows) that correspond to neurolymphomatosis. Hypermetabolic activity is seen involving the mandibular branch of the right fifth cranial nerve at the skull base (red arrows), bilateral brachial plexuses (yellow arrows), lumbar plexuses (orange arrows),and a mass-like activity in midline sacrum (blue arrows) from a combination of sacral nerve roots and infiltrated S2/S3 vertebrae. A presternal cutaneous hypermetabolic focus (black arrows) represents site of biopsy-proven diffuse large B-cell lymphoma.

The patient underwent seven cycles of chemotherapy with rituximab, methotrexate, procarbazine, and vincristine and achieved complete remission with complete metabolic response demonstrated on posttreatment FDG PET/CT (Figure 4). On MRI, there was significant decrease in the thickness of the enhancing nerves. After three months, she underwent consolidative autologous stem cell transplantation. On follow-up, one year after transplant she remains symptom free and in remission by imaging.

Figure 4.

(a) Anterior and (b) lateral maximum intensity projections of posttreatment 18F-fludeoxyglucose (FDG)-positron emission tomography show resolution of the areas of abnormal FDG uptake indicative of complete metabolic response.

Discussion

The differential diagnosis for peripheral neuropathy is broad.⁵ In the setting of lymphoma, the causes can be grouped under direct neoplastic involvement including neurolymphomatosis, treatment-related neuropathy (chemotherapy or radiation), autoimmune or paraneoplastic process related to lymphoma or systemic disease, infections, and finally conditions that are unrelated to lymphoma (Table 1).^6,7 Though clinical exam and nerve conduction studies were able to demonstrate PNS abnormalities in our patient, CT and MRI revealed abnormalities that were suspicious of NL. PET/CT demonstrated hypermetabolic activity in the cranial nerves and plexuses that was highly suggestive of NL. PET/CT also revealed the hypermetabolic cutaneous lesion that was used as an alternative biopsy site instead of nerve biopsy. PET/CT was also important during posttreatment follow-up to demonstrate complete metabolic response and guided further management.

Table 1.

Differential diagnoses of peripheral neuropathy in lymphoma.

• Neoplastic infiltration

○  Neurolymphomatosis ○  Leptomeningeal disease ○ Perineural spread

• Radiation-related plexopathy

• Neurotoxicity from chemotherapeutic agents (e.g. vinca alkaloids)

• Autoimmune etiology ○ Vasculitis ○ Paraneoplastic

• Infections ○ Infective neuropathy (Herpes zoster) ○ Acquired immunodeficiency syndrome

• Miscellaneous conditions ○ Spinal cord or nerve root compression from adjacent mass ○ Inflammatory conditions (e.g. neurosarcoidosis, Lyme disease) ○ Chronic inflammatory demyelinating polyneuropathy ○ Guillain-Barré syndrome ○ Hereditary neuropathies ○ Paraproteinemia ○ Amyloidosis ○ Metabolic and nutrient deficiencies

CT, MRI, and PET/CT findings in NL, and differential diagnosis

NL most frequently involves peripheral nerves (up to 60% of cases) followed by spinal nerve roots, cranial nerves, and nerve plexuses.¹ A particular predilection to brachial and lumbar plexuses and trigeminal nerves has been observed.⁸ More than 50% have multifocal involvement of the PNS, and 20% have concurrent systemic disease at the time of presentation.^1,4 Neuroimaging has a high diagnostic yield in NL evaluation. A study conducted by the International Primary Central Nervous System (CNS) Lymphoma Collaborative Group reported sensitivity of 77%, 84%, 40%, and 88% for MRI, PET/CT, CSF cytology, and nerve biopsy respectively for detecting NL.¹ On high-resolution MRI, fusiform enlargement with or without nodularity, increased T2 signal, and moderate to marked enhancement of the nerves have been described as the typical findings in NL.^2,9,10 Contrast-enhanced CT can potentially demonstrate similar findings but has limited soft-tissue contrast. On FDG-PET/CT exam, intense linear uptake along the nerve or plexus is the characteristic finding for NL.^9–11 But less than 20% can be negative on FDG PET/CT.¹ This failure of PET to demonstrate NL could be due to low-grade or indolent lymphomas, which are known to demonstrate low metabolic activity, or due to low-volume disease.¹²

When the NL involvement is focal or restricted to a single cranial, peripheral nerve, or plexus, findings can be nonspecific and difficult to differentiate from nerve sheath tumors on MRI.¹³ Heterogeneous signal intensity of the mass generally favors a benign or malignant nerve sheath tumor.⁹ In our case, the enhancement of the nerves was homogeneous both in CT and MRI particularly in the left psoas mass, suggestive of NL. Radiation-related plexopathy can mimic NL but the degree of enlargement of the nerves is generally mild, T2 signal is variable from hypointense to hyperintense and with a “tram-track” pattern of enhancement.⁹ The FDG uptake on PET/CT is only minimal to mild in radiation-related plexopathy.⁹ Radiation-related plexopathy does not usually manifest before six months after therapy.⁷ Other inflammatory conditions such as Guillain-Barré syndrome and CIDP, which have increased incidence in patients with lymphoma, can also show nerve enlargement, T2 hyperintensity, and enhancement of cranial nerves and peripheral nerve roots.⁷ Generally, the thickening, enhancement, and FDG uptake are usually to a lesser degree compared to NL.⁹ On occasions, a nerve biopsy may be required because NL can be indistinguishable from inflammatory neuropathies, hereditary neuropathies, neurofibromatosis, or amyloidosis on MRI and FDG PET/CT.¹⁴

Advantages and limitations of imaging modalities

MRI has the advantage of superior soft-tissue contrast and spatial resolution compared to FDG PET/CT. It can possibly detect disease in patients with FDG-negative NL. However, MRI is relatively less sensitive than FDG PET/CT and may not be ideal to assess disease response following chemotherapy. MRI can underestimate the disease extent or fail to identify skip lesions.^9,10 It can also overestimate the disease because the nerve distal to the area of lymphomatous infiltration may demonstrate abnormal T2-hyperintense signal and enlargement due to associated reactive neuritis. Advanced MRI techniques such as diffusion and texture analysis have been reported to help differentiate primary CNS lymphoma from other neoplasms and inflammatory conditions.^15,16 But there are no reports of their utility in neurolymphomatosis. MRI can also be limited in patients with claustrophobia, implants, pacemaker, or severe renal insufficiency that prevents contrast administration.

The foremost advantage of FDG PET/CT in NL is the provision of pretreatment metabolic information that serves to assess response to treatment. In addition, FDG PET/CT helps to identify biopsy site, when required, to maximize diagnostic yield. The disadvantages are availability and exposure to radiation.

Conclusions

NL is a rare form of relapse of high-grade DLBCL. A high index of suspicion is necessary to avoid a delay in diagnosis because the clinical findings, nerve-conduction studies, and CSF analysis can be nonspecific. MRI and FDG PET/CT findings are highly suggestive in NL, but considerable overlap exists in the imaging findings of NL and other causes of neuropathy in patients with lymphoma. However, multifocal significant extradural nerve thickening of the peripheral nerve system, moderate to intense homogeneous enhancement, T2 hyperintensity, and intense hypermetabolic activity on FDG PET/CT are considered typical for NL. In the appropriate setting, an invasive nerve biopsy can potentially be avoided. Alternatively, PET/CT can guide to an alternative, more accessible biopsy site, as in our case, in which cutaneous biopsy confirmed the diagnosis of DLBCL NL.

Conflict of interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Prem P Batchala https://orcid.org/0000-0002-3744-7012