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Cerebral involvement is an uncommon complication of multiple myeloma. We report on a 64-year-old man hospitalized for a partial seizure. MRI showed two intra-cerebral lesions, which proved to be plasmacytomas. After complete staging, we retained the diagnosis of immunoglobulin G lambda-type multiple myeloma with CNS involvement. Cytogenetic analysis of plasma cells detected a deletion in the p53 gene at 17p13.1. Despite cranial radiotherapy and systemic chemotherapy, the patient’s disease progressed rapidly and he died five months after diagnosis. What makes this case unusual is that overt multiple myeloma had been absent before cerebral involvement was discovered. It confirms the extremely poor prognosis of patients with CNS myeloma even in the presence of aggressive treatment. Cytogenetic abnormalities could be a marker of chromosomal and genetic instability, conferring to multiple myeloma a more aggressive profile.
Involvement of the CNS in multiple myeloma is very rare. Diagnosis of multiple myeloma subsequent to initial cerebral involvement is confined to exceptional cases. In this communication, we report on a 64-year-old man who presented with epileptic seizures caused by cerebral plasmacytomas and without significant events in his medical history. We discuss the extremely poor prognosis of patients who have multiple myeloma with extramedullary spread and the cytogenetic abnormalities frequently observed. The deletion of the p53 tumor-suppressor gene in our patient could help explain the dismal prognosis of patients with this form of the disease and its propensity to spread into the CNS.
A 64-year-old man was hospitalized because of partial motor seizures affecting his right side. His medical history had been uneventful except for type 2 diabetes mellitus, which had been treated with oral medication. He had experienced no symptoms of fatigue, weakness, bone pain, or recurrent infection during the preceding months. There had been no evidence of mental or neurological impairment prior to the seizures.
The physical examination showed no abnormalities other than mild right hemiparesis. Abnormalities found on routine blood analysis were confined to mild anemia (hemoglobin, 118 g/liter). MRI revealed two intracranial lesions: a left-sided frontal mass adjacent to the falx cerebri and a nearby mass located in the diploë (Fig. 1). Because of the patient’s deteriorating neurological status, the two lesions were resected through a craniotomy.
Histological examination of the left frontal mass revealed diffuse sheets of large, slightly pleomorphic cells displaying a high nuclear-cytoplasmic ratio with poor basophilic cytoplasm and large nuclei characterized by relatively loose chromatin and central nucleolus. Few tumor cells revealed eccentric nuclei. Immunohistochemical analysis showed that the tumor cells expressed CD45 and CD138 but were negative for CD20, CD79a, Pax-5, and bcl-6 (Fig. 2). They also revealed monotypic expression of the immunoglobulin G (IgG) heavy and lambda light chains. The MIB-1 proliferation index greatly exceeded 50%. These findings indicated the presence of a plasma-cell immunophenotype and established the diagnosis of an IgG lambda plasmacytoma made up of immature plasma cells and plasmablasts.
After diagnosis, further laboratory studies revealed an elevated erythrocyte sedimentation rate at 110 mm/h, mild hypercalcemia at 2.63 mmol/liter, a slight increase in serum proteins (90 g/liter), and a reduced albumin level (30 g/liter). The level of β2-microglobulin was increased (3.75 mg/dl compared to the normal range of 0.7–1.8). Serum creatinine was normal, and so was the viscosity of serum. Serum protein electrophoresis demonstrated a spike in the gamma fraction, with immunofixation showing a monoclonal IgG lambda gammopathy with a paraprotein level of 38.9 g/liter. No light chains were found in the urine.
Bone marrow aspiration revealed massive infiltration by plasma cells, confirming the diagnosis of multiple myeloma. Interphase fluorescence in situ hybridization was performed on CD138+ cells isolated with magnetic beads. A deletion in 17p13.1 was detected in 38% of cells when using a probe specific for the p53 gene (BAC RP11-199F11) (Fig. 3). Cytological analysis of cerebrospinal fluid revealed that cells similar to those found in the resected lesions were neither widespread nor accompanied by pleocytosis. Skeletal surveying demonstrated several lytic lesions involving the spine and left humerus.
Soon after admission, the patient’s condition became complicated by pulmonary embolism and pneumonia, which precluded any type of chemotherapy. Cranial radiotherapy was delivered to the tumor bed in the form of 30 Gy over 10 fractions. A cycle with dexamethasone as single agent was administered. Subsequently the patient’s condition improved, with paraprotein levels decreasing to 30 g/liter. Then a chemotherapeutic regimen combining vincristine, doxorubicin, and dexamethasone was initiated. Soon thereafter, the patient fell and developed a subdural hematoma requiring drainage. His neurological status deteriorated two weeks after surgery, with paraprotein levels increasing up to 40 g/liter. Treatment was then discontinued. The patient died five months after diagnosis.
CNS involvement in multiple myeloma is extremely rare. Few cases are documented in the literature. The largest single-center experience has been published by Fassas et al.,1 who reported on 18 cases diagnosed at the University of Arkansas over 10 years. The overall incidence of CNS involvement was only about 1%. Even more unusual is CNS involvement as the initial presentation of multiple myeloma. In fact, the median interval from diagnosis to detection of CNS involvement tends to be around 13–14 months.1,2 The two largest series on record have included a total of 27 patients; CNS involvement was diagnosed concurrently with multiple myeloma in only one of those cases.1,2 Presenting symptoms of CNS involvement most commonly include headaches, limb weakness, mental changes, and cranial nerve palsies. We are unaware of any documented cases in which seizures were the first sign of multiple myeloma.
Despite aggressive systemic treatments, including autologous stem cell transplantation and local treatments such as cerebral radiotherapy, the prognosis for patients with CNS myeloma is extremely poor.3 The median survival has been estimated at approximately 4–5 months.1,2 This pattern is confirmed by the present case report.
Today it is well known that multiple myeloma really includes a number of distinct clinical entities that are defined by specific cytogenetic abnormalities underlying the disease and influencing its prognosis.4 For instance, abnormalities of chromosome 13 or deletions of 17p13.1 (which affect the p53 tumor-suppressor gene) are associated with poor survival.4,5 Chang et al.2 investigated nine cases of multiple myeloma with CNS involvement and found that the majority (89%) harbored a p53 deletion. By comparison, this percentage was only 10%–15% in reports on multiple myeloma patients without CNS disease. It is therefore conceivable that p53 deletions constitute a marker of chromosomal and genetic instability, conferring to multiple myeloma a more aggressive profile and a greater propensity to spread into extramedullary sites, including the CNS.
Our case report seems consistent with this hypothesis, given the significant proportion of clonal plasma cells harboring p53 deletions. We therefore suggest that cytogenetic analysis should be applied more frequently in monitoring multiple myeloma because this could increase the accuracy of prognosis and alert clinicians to imminent aggressive developments or unusual CNS involvement.