Low Grade Non-Hodgkin B-Cell Lymphoma Presenting as Sensory Neuropathy

Abstract

Low-grade non-Hodgkin B-cell lymphoma was found during the evaluation of 3 aged patients with predominantly sensory neuropathy of mild to moderate severity. Presenting manifestations were sensory ataxia and right ulnar mono-neuropathy in a 75-year-old man, and painful dysesthesias of the legs in two 78-year-old women. A neurophysiological study showed mainly axonopathic alterations. M-protein was present in all cases (Ig-K in two, triclonal gammopathy IgG(K)/IgM(K)/IgM-A, in one). The male patient had IgM antisulfatide antibody in high titer, whereas the other 2 patients had cryoglobulinemia (type II and type III, respectively). Our report emphasizes the occurrence of mild polyneuropathy as presenting manifestation of low-grade non-Hodgkin lymphoma, different from the clinicopathological entity of neurolymphomatosis, in which severe nerve damage occurs in association with manifest lymphoma, related to nerve infiltration by lymphomatous cells. Alternative pathogenetic mechanisms, such as antibody-mediated nerve damage, or vasa nervorum changes caused by cryoglobulin, may be implicated in our cases. Non-Hodgkin lymphoma should be considered in the diagnostic evaluation of polyneuropathy of unknown cause, especially in patients with paraproteinemia and/or cryoglobulinemia.

Lymphoma-associated dysimmune polyneuropathies

“…There was no evidence to suggest that autoantibodies were produced in response to peripheral nerve damage of direct lymphoma spread; moreover, any fortuitous association was minimized by adequate search for other causes of polyneuropathy in these patients. In most, but not all [8,48], patients the clinical presentation of neuropathy conformed to the literature descriptions of the specific autoantibodyassociated polyneuropathy subtypes.…”

“…undetected lymphoma) developed fatal EBV+ intracerebral lymphoma after treatment with various courses of immunotherapy [46]; analyses of intrathecal and peripheral M-protein as well as brain immunocytochemical studies suggested a common clonal origin of both immunoblastic cerebral proliferation and the serum paraprotein-secreting cells. Presumably, immune deficiency due to monoclonal B-cell proliferation and/or immunosuppressive therapy resulted in EBV-reactivation and dysregulation of CNS-restricted T-cell control of B-cell proliferation; autopsy did not include search for systemic lymphoma; (c) chronic (up to 3-year duration), slowly progressive [8,56,60] or relapsing-remitting [54] neuropathies preceded diagnoses of either indolent/low grade or diffuse large cell lymphoma, respectively; (d) a patient with a 2-year slowly progressive sensorimotor neuropathy developed B-cell CLL [49]; in this case, HTLV-1 co-infection could have triggered malignant transformation of an antigen-committed B-cell clone [61], or HTLV-1-infected T-cells activated autologous B-cells in a contact-dependent manner [62]. (2) In some patients lymphoma diagnosis preceded onset of neuropathy: (a) in 1 report, relapsing-remitting cranial polyneuropathy occurred in a patient with established cutaneous lymphoma in remission and subsequent recurrence [45]; (b) recurrent, treated [58,59] or indolent, untreated [60] lymphoma preceded the onset of neuropathy symptoms at intervals of 2 years, 10 and 6 months in 3 patients, respectively.…”

“…(2) In some patients lymphoma diagnosis preceded onset of neuropathy: (a) in 1 report, relapsing-remitting cranial polyneuropathy occurred in a patient with established cutaneous lymphoma in remission and subsequent recurrence [45]; (b) recurrent, treated [58,59] or indolent, untreated [60] lymphoma preceded the onset of neuropathy symptoms at intervals of 2 years, 10 and 6 months in 3 patients, respectively. (3) In the remainder of patients, lymphoma was diagnosed during the initial presentation and evaluation of neuropathies of variable duration [8,50,53,55,56].…”

“…Serum mixed cryoglobulins were detected in 3 cases, and possibly played a pathogenic role in neuropathy in 2 patients [8], but were deemed causally unrelated to neuropathy in 1 patient [48].…”

“…Lymphoma can involve any part of the peripheral nervous system. The mechanisms of lymphoma-associated neuropathy (i.e., excluding chemotherapy exposure, viral infections [e.g., HIV/Herpes zoster], and established nutritional disturbances) may entail [3][4][5][6]: (a) local or diffuse peripheral nerve lymphomatous (specifically NHL/T-) cell invasion i.e., neurolymphomatosis; (b) deposition in the endoneurium of circulating monoclonal antibodies (mostly IgM paraprotein) secreted by malignant or non-malignant lymphocytes/ plasma cells; (c) autoantibodies directed against specific peripheral nerve antigens (e.g., myelin-associated glycoprotein or gangliosides) probably produced by non-lymphomatous clonal B-cell expansion due to immune "escape" mechanisms [1]; (d) lymphoma-induced (particularly HL) immune dysregulation that underlies immunemediated inflammatory neuropathy; (e) ischemic neuropathy due to: (1) hematogenous metastases (angiotropic B-cell lymphoma) that occlude vessels by local intravascular proliferation, direct pressure, or tumor emboli; (2) cryoglobulin deposition (types I and II) [7][8][9], or (3) immune/"paraneoplastic" vasculitis; (f) focal amyloid deposition in the vasa nervorum, endoneurium and perineurium in the setting of monoclonal paraprotein (IgM-λ type) [10]; and (g) "other"/unclear explanation, possibly toxic/metabolic/nutritional. This article reviews lymphoma-associated peripheral nerve disorders with presumed immune-mediated pathogeneses.…”