Non-Hodgkin's lymphomas (NHLs) are a group of more-or-less malignant diseases that are characterized by transformation and proliferation of B- or T-lymphocytes. Abnormalities of the peripheral nervous system occur in 5% of patients with lymphoma;1 the evident clinical heterogeneity has been ascribed to various pathogenic processes that have been linked to the different lymphoma subtypes.2 There have been isolated reports of patients with B-cell NHL subtypes with multifocal motor neuropathy or subacute sensory/sensorimotor demyelinating polyneuropathy associated with serum autoantibodies against peripheral-nerve glycolipid or glycoprotein antigens.

I report herein on two patients with low-grade B-cell NHL with progressive sensory polyneuropathy linked to serum autoantibodies directed against peripheral-nerve antigens. Maintenance intravenous immunoglobulin G (IgG; IVIG) infusions halted the neuropathy symptom progression, and a "watchful waiting" approach was chosen to manage the lymphoma.

This report draws attention to the concept of presumed autoantibody-mediated sensory polyneuropathy associated with indolent lymphomas of mature B-cells. Sophisticated technological analyses were applied to accurately diagnose mantle-cell and marginal-zone lymphomas in our two patients. These two lymphomas constitute about 6% and 8% of B-cell NHLs, respectively;3 a progressive axonal sensory polyneuropathy has not previously been reported against a background of these typically indolent lymphoma subtypes.

Based on all available evidence, we presumed that the pathogenesis of neuropathy in our patients was autoimmune; therefore, nerve biopsy sampling was deemed unnecessary and was not performed. Clinical or serological evidence of autoimmunity in patients with NHL commonly (70%) precedes the diagnosis of lymphoma.45 However, based on the presumed slow-growing behavior of the NHL subtypes of our patients, we presumed that the lymphoma probably existed prior to the onset of the neuropathy symptoms. The mechanism underlying neuropathy in patients with lymphoma varies,2 which makes it important to identify the cause of this neuropathy in these patients in order to help determine the optimum therapeutic approach.

This is the first report on sensory neuropathies associated with elevated serum autoantibodies directed against peripheral-nerve antigens in patients specifically with mantle-cell and marginal-zone B-cell lymphomas. In patient 1, we hypothesized that anti-GD1a antibodies played a pathogenic role in the unusual presentation of sensory (rather than motor) axonal neuropathy,67 while in patient 2 the concept of an association between anti-MAG/SGPG antibodies and sensory-nerve damage was deemed better established.8 The development of clinical or biological signs of autoimmunity at initial diagnosis/during the disease course of lymphoma implicates an interrelationship between lymphoproliferative malignancies and autoimmune diseases.9

It appears that the frequency of biological and/or clinical autoimmunity is higher in patients with indolent (e.g., marginal-zone or follicular) lymphoma than in those with more aggressive lymphomas.10 In our patients, the detection of multiple serum autoantibodies directed against various distinct antigens suggested that these immunoglobulins were not secreted by a specific tumoral clone, but were probably the consequence of a lymphoma-induced generalized more-or-less disordered immune regulation. It is conceivable that the regulatory T-cells (T_reg-cells; which are frequently overrepresented in biopsy specimens of B-cell NHL11) that modulate the immune response against lymphoma cells may also be involved in the development of autoimmune manifestations.9 T_reg-cells have been shown to prevent autoimmune diseases by suppressing self-reactive T-cells as well as the immune response against cancer. Other hypotheses on lymphoma-induced immune dysregulation include 1) autoantibody production after malignant transformation (e.g., due to continuous challenge by autoantigens) of autoreactive CD5+ B-cells12 (but also B-cells that lose CD5 expression during lymphomatous transformation13); 2) an alteration of the cell-surface receptor Fas-Fas-ligand pathway involved in cell-death signaling (acquired somatic mutations of Fas may be acquired during normal germinal center reaction, and are prevalent in NHL with autoimmune manifestations14); and/or 3) lymphocyte chronic antigenic (e.g., infectious agents) stimulation that leads to an emergence of autoreactive lymphoma cells.15

A bone marrow evaluation was deemed reasonable in patient #2 based on progression of polyneuropathy in this patient with a serum M-band with elevated anti-MAG/SGPG antibodies; other established independent clinical-laboratory predictors of a possible hematological malignancy did not apply (e.g., serum M-protein level >1 g/L or constitutional symptoms such as weight loss, unexplained fever, or night sweats).16 It is conceivable that adhering to a combination of these predictors too strictly may lead to underinvestigation of the marrow and underestimation of the true frequency, particularly of indolent malignancy.

We managed the immune-mediated neuropathy with monthly maintenance-dose IVIG infusions. Since the neuropathy symptoms stabilized during the observation period in both patients, this approach to care appears to have been appropriate. Based on a risk-benefit analysis, the oncologists elected for a "watchful waiting" approach to management of these indolent lymphomas in our elderly patients. Thus, the principle of treating the source of the illness underlying neuropathy does not always seem warranted or necessary-the diagnosis of low-grade B-cell lymphoma in our patients had no immediate treatment implications. It is generally believed that treatment of lymphoma rarely leads to recovery of the associated neuropathy.1 Moreover, it has not been established with certainty that the presence of neuropathy warrants a more aggressive treatment of quiescent hematologic malignancies.17 Since the pathogenesis of lymphoma-associated neuropathy varies, a case-by-case approach to patient care seems most appropriate and sensible.

Based on this case series, we cannot advocate routine bone-marrow examination in elderly patients with autoantibody-mediated neuropathies, in part because the diagnosis of low-grade B-cell lymphoma appears to have no immediate treatment implications. Conversely, it seems reasonable to test for the presence of serum autoantibodies in patients with established indolent B-cell NHL who develop neuropathy, since detection of antibodies directed against specific nerve antigens has therapeutic implications, in terms of providing an evidence-based decision to offer immune modulation therapy to patients.