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The frequency of the involvement of non-Hodgkin's lymphoma in the CNS has been reported to be less than 10%.1-3Moreover, as those patients have often been resistant to both chemotherapy and radiation therapy, their prognosis has been very poor.1-3 We report herein a rare case of malignant lymphoma showing bilateral homogenous and symmetric enhancement of multiple cranial nerves, with the patient's postmortem examination providing controversial pathological findings. A 50 year old woman developed supraclavicular lymph node swelling about 1 year ago, and was diagnosed as having malignant lymphoma (non-Hodgkin's lymphoma, diffuse large B cell type) after pathological examination of the lymph node. She then received systemic chemotherapy and peripheral blood stem cell transplantation. After six courses of CHOP therapy, she achieved complete remission and was discharged. A few weeks later, she gradually lost her appetite and her temperature remained consistently raised above 38°C for several days. One day before readmission, she noticed double vision, dysphagia, and hoarseness. Neurological examination demonstrated bilateral ptosis, dilatation of bilateral pupils being sluggishly reactive to light, paralysis of extraocular movement, paralysis of soft palate movement, and bilateral hearing disturbances. Except for the involvement of cranial nerves, no other neurological deficits were evident. Intriguingly, her cranial MRIs demonstrated marked bilateral swelling of oculomotor nerves and trigeminal nerves, both with homogenous gadolinium (Gd) enhancement (fig 1A and B). The facial and acoustic nerves showed Gd enhancement partly in the their canals. The accessory nerves also demonstrated homogenous enhancement without definite swelling. Within the spinal cord, some of the cauda equina showed partial Gd enhancement (figure E). Cerebrospinal fluid examination disclosed pleocytosis (64/mm3) and raised protein content (586 mg/dl). Cytological examinations demonstrated class V, which were compatible with malignant lymphoma cells. On the basis of these findings, we suspected the recurrence of malignant lymphoma in the CNS system, and performed whole brain irradiation and intrathecal administration of both methotrexate (MTX) and cytosine arabinoside (Ara-c). Even after a total of 20 Gy irradiation and four courses of intrathecal chemotherapy, her clinical symptoms did not improve, and lymphoma cells still remained in the CSF. The number of cells (8/mm3) and protein content (84 mg/dl) in the CSF, however, had very much improved, repeated MRI studies could not detect any Gd enhancement in the cranial nerves, and previously recognised swelling in the oculomotor nerves and trigeminal nerves had been fully resolved. During the course of her treatments, she developed multiple organ failure, disseminated intravascular coagulation, and finally she died. Postmortem examination disclosed massive infiltration of lymphoma cells into the liver, kidney, bone marrow, and visceral lymph nodes. Lymphoma cells were recognised histologically in the dura and cauda equina, which had previously exhibited Gd enhancement in the spinal cord (fig1E and F). Immunohistochemical examinations of that specimen indicated that these infiltrating cells were positive with L26, and were subsequently determined to be B cell lymphoma. However, despite our further extensive investigations of other parts of her CNS, no lymphoma cells could be detected, even in the cranial nerves that had shown previous Gd enhancement. Additionally, we could not detect even the smallest traces of the previous tumour infiltration including their necrosis affected by the irradiation or intrathechal chemotherapy (fig1C). Without any infiltration of lymphoma cells, the oculomotor nerves and trigeminal nerves had markedly lost Luxol fast blue (LFB) staining and indicated a wide range of myelin damage (fig 1D). Until now, the enhancement of cranial nerves or spinal nerve roots on MRI has often been reported in inflammatory neuropathies, such as chronic inflammatory demyelinating neuropathy (CIDP). In these circumstances, abnormal enhancement may be secondary to myelin breakdown and the low degree of inflammation seen in nerve biopsies. In the present patient, no inflammatory changes, including cellular infiltrates, vasculitis, or microangiopathy, were recognised in the examined tissues and therefore the simple inflammatory processes could not explain the pathological alterations of the cranial nerves. To our knowledge, there have been no previous reports describing MRI enhancement of multiple bilateral cranial nerves in patients with lymphoma, or detailed pathological findings regarding those damaged cranial nerves. Most of the reported cases have demonstrated direct tumour invasion (classically known as Garcin syndrome, skull base tumour invasion) and accordingly, have allowed the diagnosis of leptomeningeal carcinomatosis.4 5 Initially, we also considered that she had leptomeningeal carcinomatosis because positive results of cytological examinations of the CSF may well suggest the infiltration of the lymphoma cells into the cranial nerves. However, retrospectively, the enhancement pattern of the cauda equina that contained lymphoma cells was quite different from that of cranial nerves without lymphoma cells. The former showed spotty or partial enhancement, but the latter demonstrated a homogenous enhancement pattern accompanied by nerve swelling. These homogenous enhancement patterns looked more like neuropathies mediated by the immunological disturbances rather than neuropathies influenced by direct tumour infiltration, and might be characteristic features. Although we could not necessarily exclude the possibility of direct infiltration of lymphoma cells into the cranial nerves, our results, as confirmed by pathological investigations, could indicate the existence of another mechanism associated with lymphoma inducing cranial neuropathy, especially related to the loss of myelin.
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