There was no clear suppression of normal immunoglobulins and only mild lymphopenia in 1 patient, suggesting adequate systemic immune competency at time of glioblastoma diagnosis. == Table 2. endothelial growth factor. In cases with anti-myelin-associated glycoprotein (MAG) antibodies, surface MAG on glial cells may act as a target releasing cells from growth inhibition. We suggest that all glioblastoma cases be screened MV1 at diagnosis for serum paraproteins and that such cases be reported to central registries to establish the frequency of the association more accurately. Keywords:IgM paraproteinaemic neuropathy, Waldenstrom’s, Glioblastoma IDH-wildtype, Chemoimmunotherapy == Introduction == Peripheral neuropathy is usually described in the literature as a complication of paraproteinaemia (typically IgM) with a prevalence of 0.0008% in the >50 age group [1,2]. It may also be associated with underlying haematological malignancies such as non-Hodgkins lymphoma, most commonly lymphoplasmacytic lymphoma/Waldenstrom’s subtype, or with IgM monoclonal MV1 gammopathy of clinical significance (MGCS) [3]. M-protein reactivity towards myelin-associated glycoprotein (MAG) has been demonstrated in approximately 5060% of cases [2]. Anti-MAG antibodies have the potential to be neuropathic with a typical progressive illness trajectory [4] with overall limited response to treatment [5]. We present 3 cases of classical IgM paraproteinaemic neuropathy with an associated B-cell clone (1 Waldenstrom’s macroglobulinaemia [WM], 2 MGCS) who developed glioblastoma (summary shown in Table1). Of the 3 cases, two were positive for anti-MAG in their serum. Screening for other causes of neuropathy was unfavorable in all 3 cases. Due to the progressive symptomatic nature of their neuropathy, all 3 patients were treated with a chemoimmunotherapy (CIT) protocol of Rituximab, Cyclophosphamide and Prednisolone (R-CP), similar to that shown to be effective in WM [6]. R-CP CIT has been demonstrated to be an effective treatment in patients with IgM paraproteinaemic neuropathy evidenced by sustained clinical and serological improvement over time [7]. == Table 1. == Summary of demographic, clinical, haematological and neurological data around the cases Glioblastoma is the commonest primary brain tumour, shows astrocytic differentiation, and is a rapidly progressive tumour of high grade (WHO grade IV). However, overall incidence is still only 3 per 100,000 [8]. Most tumours are MV1 seen in Caucasian males with a median age of onset of 64. Acknowledged risk factors seen in some cases include pre-morbid radiation therapy, an immune tumour local environment, as well as single nucleotide polymorphisms [8] and variations inIL-2RA(CD25) genes [9]. Glioblastoma is usually categorized as IDH-wildtype or IDH-mutant. IDH-wildtype glioblastoma typically arises de novo, with no recognizable precursor lesion, and accounts for approximately 90% of glioblastoma [10]. Currently, there are no reports in the literature of glioblastoma related to any form of immunosuppressive therapy. Current understanding of glioblastoma aetiology is limited and whilst both genetic and environmental factors have been observed to be of epidemiological significance, they do not comprehensively explain the overall burden of disease MV1 [8]. We show that this most likely explanation for the occurrence of glioblastoma in our patients is usually a hitherto unrecognized pathogenic link between IgM paraproteinaemia and glioblastoma, which could provide important insight into glioblastoma pathogenesis and ultimately contribute to the development of new treatments. == Case Presentations == == Case 1 == A 56-year-old man initially presented with numbness in the feet ascending to mid-calf over the course of 2 years, as well as gait unsteadiness. Neurophysiology was consistent with a predominantly axonal neuropathy with a borderline increase in the terminal latency in a few nerves. The LRP12 antibody patient was first noted to have an IgM paraprotein a 12 months after presentation, with a normal bone marrow biopsy at this stage. Anti-MAG antibodies were not detected. The patient developed progressive symptoms over a 9-12 months period from diagnosis. He underwent re-staging computed tomography (CT), which showed widespread small volume lymphadenopathy and a normal sized spleen. Bone marrow trephine now showed typical features of WM. Serological studies showed two IgM kappa paraproteins totalling approximately 9 g/L with a moderate immuneparesis. The diagnosis predated the discovery of theMYD88mutation known to be associated with WM and possibly also with paraproteinaemic neuropathy [11]. Repeat anti-MAG titre was MV1 again unfavorable. These findings were diagnostic of WM (lymphoplasmacytic lymphoma) with suspected related sensorimotor neuropathy (shown in Fig.1). == Fig. 1. == Motor nerve conduction studies (Median nerve/APB) from a normal subject (a) and a patient with IgM paraproteinaemic polyneuropathy and anti-MAG antibodies (b). Abnormalities exhibited in B are reduced motor amplitude; severe prolongation of the distal motor latency (from wrist stimulation to the muscle); and moderate slowing of the motor conduction velocity (wrist to elbow), indicating predominantly distal slowing, characteristic of the disorder. In view of progressive severe symptoms, the patient was treated.
