Paraneoplastic neurological syndromes in Hodgkin and non-Hodgkin lymphomas

Abstract

Paraneoplastic neurological syndromes (PNSs) rarely associate with Hodgkin lymphoma (HL) and non-HLs (NHLs). Except for paraneoplastic cerebellar degeneration (PCD) in HL and dermato/ polymyositis in both HL and NHL, other PNSs are uncommon and have only been reported as isolated case reports or short series. There are several important differences in PNSs when occurring in association with HL and NHL compared with those associated with solid tumors. First, some PNSs such as sensory neuronopathy or Lambert-Eaton myasthenic syndrome rarely occur in lymphomas, whereas others, such as granulomatous angiitis, are only described in HL. Second, onconeural antibodies are absent in most PNSs associated with lymphomas with the exceptions of Tr (δ/notch-like epidermal growth factor-related receptor) in PCD and mGluR5 in limbic encephalitis (LE). The antigens recognized by these antibodies are not expressed in lymphoma cells, suggesting the tumor itself does not trigger the PNS. Third, unlike patients with solid tumors in patients with lymphoma, the PNSs often develops at advanced stages of the disease. Furthermore, the type and frequency of PNSs are different between HL and NHL; whereas LE and PCD occur almost exclusively in patients with HL, sensorimotor neuropathies and dermatomyositis are more frequent in NHL.

Figure 1

Flowchart showing the level of diagnostic evidence for the diagnosis of PNSs. Reprinted with permission from J Neurol Neurosurg Psychiatry 2004;75:1135-1140.

Figure 2

Coronal T2-weighted MRI scan of a patient with LE, mGluR5 antibodies, and HL. There is increased T2 signal of the head of both hippocampi. Study is slightly affected by motion artifact.

Figure 3

Immunoreactivity of mGluR5 antibodies. (A) Sagittal section of rat brain immunostained with the CSF of a patient with mGluR5 antibodies. There is a diffuse staining of the neuropil. (B) Immunoreactivity was particularly robust in the hippocampus that shows the typical staining of antibodies against neuronal cell surface antigens.

Figure 4

Immunoreactivity of Tr(DNER) antibodies. (A) Section of rat cerebellum immunostained with a serum from a patient with Tr antibodies. There is robust staining of the cytoplasm and the main dendrites of the Purkinje cells and a dot-like pattern of staining of the cerebellar molecular layer that is characteristic of Tr immunoreactivity. (B-D) Cell-based assay to confirm that Tr antibodies identify the DNER antigen. HEK293 cells transfected with DNER cDNA plasmid show intense reactivity with the human serum positive for Tr antibodies (green) and that colocalizes (yellow) with the labeling of a commercial monoclonal antibody to DNER (red).

Figure 5

Sural nerve biopsy of a patient with a final diagnosis of neurolymphomatosis. (A) Low power figure of the sural nerve biopsy showing infiltration by lymphomatous cells. (B) The infiltrate involves all layers of the nerve. Arrowheads indicate the perineurium.