By Michael Rubin, MD
Professor of Clinical Neurology, Weill Cornell Medical College
SYNOPSIS: Lymphoma that presents with peripheral neuropathy is a challenging diagnosis. Diagnosis and treatment often are delayed, but they can be facilitated by early consideration and imaging with fluorodeoxyglucose-positron emission tomography. Early diagnosis and hematologic treatment may be effective.
SOURCE: Ducatel P, Michaud M, Viala K, et al. Neurolymphomatosis: Involvement of peripheral nervous system revealing hematologic malignancy, a report of nine cases. J Peripher Nerv Syst 2023; Mar 1. doi: 10.1111/jns.12541. [Online ahead of print].
Usually of B cell origin but reported as well with primary central nervous system (CNS) lymphoma of T cell origin, neurolymphomatosis is a rare entity. It may present as a relapse of systemic or primary CNS lymphoma, or as a primary presentation when malignant lymphoma cells infiltrate any part of the peripheral nervous system (PNS). In patients with known lymphoma, diagnosis may be suspected, but in patients with no known hematologic malignancy, diagnosis is challenging and usually is delayed. What is the clinical profile of neurolymphomatosis that might facilitate early diagnosis?
Nine patients diagnosed with neurolymphomatosis at the Departments of Clinical Neurophysiology at Pitié Salpêtrière and Nancy Hospitals, France, between January 2005 and May 2020 were retrospectively reviewed, collecting demographic, clinical, electrophysiologic, biologic, imaging, nerve biopsy, and treatment data. Inclusion criteria required an initial evaluation for neuropathy, lymphocytic nerve infiltration without blood vessel injury, and nerve or tissue biopsy showing an abnormal cytologic aspect or major monoclonal population.
Fluorodeoxyglucose-positron emission tomography (FDG-PET) or magnetic resonance imaging (MRI) was used to confirm PNS involvement if lymphoma was not confirmed by nerve biopsy. Exclusionary criteria comprised a prior diagnosis of neuropathy, hematologic malignancy, autoimmune disease, neurosarcoidosis, neuroborreliosis, Hansen’s disease, amyloidosis, or cryoglobulinemia.
All patients had clinical assessment, including the Overall Neuropathy Limitations Scale, Modified Rankin Scale, and Numeric Pain Rating Scale. Nerve conduction studies (NCS), performed in standard fashion, were reported as symmetric sensory-motor axonal neuropathy, asymmetric sensory-motor axonal neuropathy if asymmetry was observed in only one motor or sensory nerve, or multiple mononeuropathy when asymmetry was observed in more than one motor or sensory nerve. Nerve biopsy, performed on the superficial peroneal nerve in all patients, was submitted for staining, immunolabeling, and molecular biology testing.
Among the nine patients, twice as many were men, with overall median age of onset of 71 years. Onset was chronic in seven patients and subacute in two patients, with pain reported in seven patients, described as severe and relentless. Among eight patients with leg weakness and six patients with both arm and leg weakness, the motor deficit was distal in four patients, proximal in one patient, and proximo-distal in three patients. One patient had no weakness, six patients had significant weight loss, and seven patients had sensory ataxia. Multiple mononeuropathy was the most frequent NCS pattern (n = 5), with two patients each showing symmetric or asymmetric sensory-motor axonal neuropathy.
Spontaneous activity in the form of fibrillation potentials or positive sharp waves was reported in seven patients, indicating axonal involvement, with no patient meeting criteria for definite chronic inflammatory demyelinating polyradiculoneuropathy. Cerebrospinal fluid protein levels were elevated in four patients, with a mean protein level of 0.73 g/L, and a high lymphocyte count in three patients, none showing the presence of a tumoral monotypic population despite undergoing a median of three spinal taps. Nerve biopsy was diagnostic in eight patients, with the remaining patient showing lymphoma on left testis biopsy, with MRI and FDG-PET confirming nerve root involvement. Hematologic treatment resulted in neurological stabilization in three patients, improvement in one patient, with four patients worsening despite chemotherapy. One patient’s data were missing.
COMMENTARY
Although neurolymphomatosis conventionally is thought to present as multiple mononeuropathy, as opposed to the more symmetrical presentation of inflammatory or drug-induced neuropathy, demyelinating or mixed axonal and demyelinating neuropathy also may be seen in neurolymphomatosis. Four main patterns of peripheral nervous system involvement have been described: painful polyradiculopathy or neuropathy, painless neuropathy, cranial neuropathy, and mononeuropathy.
When evaluating peripheral neuropathy, a high degree of suspicion for neurolymphomatosis is necessary, since the presenting symptoms vary, conventional radiology has only modest sensitivity, and a pathological diagnosis often is difficult. FDG-PET helps in the early diagnosis and treatment of this condition.
