http://neurology.thelancet.com Vol 6 January 2007 75 Review Peripheral nervous system involvement in patients with cancer Jean-Christophe Antoine, Jean-Philippe Camdessanché Involvement of the peripheral nervous system (PNS) is common in patients with cancer and any part, including motor neurons, sensory ganglia, nerve roots, plexuses, cranial and peripheral nerves, and neuromuscular junctions, can be affected. Different mechanisms can initiate damage associated with cancer-related PNS disorders. These include tumour infiltration, toxicity of treatments, metabolic and nutritional perturbations, cachexia, virus infections, and paraneoplastic neurological syndromes. The type of cancer, lymphoma, or solid tumour is a further determinant of a PNS disorder. In this Review we discuss the different causes and mechanisms of disorders of the PNS in patients with cancer and we will focus on their assessment and diagnosis. Introduction Clinically overt peripheral nervous system (PNS) involvement is common in patients with cancer, occurring in 1·7–16% of cases. 1,2 The association between cancer and the PNS is multifaceted and involves at least four tightly intricate levels of complexity (table 1). The first level concerns the different mechanisms by which cancer affects the PNS. These mechanisms can include compression or infiltration by the tumour, deleterious effects of treatments—sometimes months or years after their application—metabolic and nutritional factors, and virus infections as a result of the immunodepression, which can accompany cancer treatment. Paraneoplastic neurological syndromes are restricted to disorders that are not explained by any of the mechanisms mentioned above. The second level of complexity is topographic because any part of the PNS can be affected including motor neurons in the ventral horn of the spinal cord, sensory ganglia, nerve roots, plexuses, cranial and peripheral nerves, and the neuromuscular junction. The third level corresponds to the cellular structures that are damaged, such as the neuron cell body, axon, or myelin sheath. The nature of cancer is responsible for the fourth and last level of complexity because lymphomas and carcinomas have different mechanisms that induce PNS lesions. Thus, nerve infiltration occurs more frequently with non-Hodgkin’s lymphomas than with solid tumours. All of these levels have practical consequences for the diagnosis and management of patients. In this Review we discuss the different causes and mechanisms of disorders of the PNS in patients with cancer and we focus on their assessment and diagnosis. Malignant tumours and metastases Malignant tumours that develop from the peripheral nerve sheath are rare and most malignancies of the PNS result from metastases, which occur with both carcinomas and lymphomas. 3,4 PNS infiltration usually results from a locoregional extension of the tumour or metastatic lymph nodes to adjacent neural structures. Spreading to the leptomeninges mainly occurs through blood vessels, but other mechanisms are possible including seeding via retrograde venous pathways along valveless venous plexus and progression along nerve plexus, cranial nerves, and satellite lymphatic vessels and veins. In contrast to Hodgkin’s disease, non-Hodgkin’s lymphomas commonly invade the PNS. The ability of malignant lymphocytes to adhere to neural-cell-adhesion molecules may be a determinant of neural infiltration. 5,6 Typically, patients with PNS metastases have a poor prognosis. However, it is important to obtain an accurate diagnosis as soon as possible because therapeutic strategies can substantially improve pain and stabalise, or sometimes improve, neurological deficits. Malignant nerve sheath tumours Malignant nerve sheath tumours arise from plexiform neurofibromas or normal peripheral nerves. 7,8 Almost 50% of these tumours occur in the setting of neurofibromatosis type 1. Radiation therapy may be a causal factor with or without neurofibromatosis. 9 Malignant transformation from plexiform neurofibromas to malignant nerve sheath tumours have been associated with mutations in the p53 and INK4a genes and with aberrant signalling of the Notch pathway. 10 The clinical presentation depends on the peripheral nerve that is involved but severe pain and rapidly growing tumours are common and suggestive of malignant transformation. As a whole, the prognosis is poor. Leptomeningeal metastases Leptomeningeal infiltration occurs in 5–15% of patients with solid tumours, mostly in those with cancer of the breast, lung, head, or melanoma, or those with gastric cancer. 11,12 About 5–10% of lymphomas spread to the leptomeninges, especially acute lymphoblastic leukaemia, and lymphoblastic and Burkitt’s lymphoma for which a prophylactic treatment is warranted. 13 With other lymphomas, old age, high initial tumour grade or localisation of the tumour in the testicle, sinuses, bone marrow, blood, or digestive tract are associated with an increased risk of meningeal infiltration. 14 Whatever the tumour type, involvement of the cranial nerve and lower spinal roots is typical. 15,16 The most commonly affected cranial nerves are the oculomotor nerves followed by the facial, optic, and auditory nerves. Lancet Neurol 2007; 6: 75–86 Service de Neurologie, Hôpital Bellevue, CHU de Saint-Etienne (J-C Antoine MD, J-P Camdessanché MD) Correspondence to: Dr Jean-Christophe Antoine, Service de Neurologie, Hôpital Bellevue, 42055 Saint-Etienne, Cedex 02, France j.christophe.antoine@chu-st- etienne.fr