First-line treatment and outcome of elderly patients with primary central nervous system lymphoma (PCNSL)--a systematic review and individual patient data meta-analysis.

BACKGROUND: To investigate prognosis and effects of first-line therapy in elderly primary central nervous system lymphoma (PCNSL) patients. PATIENTS AND METHODS: A systematic review of studies about first-line therapy in immunocompetent patients ≥60 years with PCNSL until 2014 and a meta-analysis of individual patient data from eligible studies and international collaborators were carried out. RESULTS: We identified 20 eligible studies; from 13 studies, we obtained individual data of 405 patients, which were pooled with data of 378 additional patients (N = 783). Median age and Karnofsky Performance Score (KPS) was 68 years (range: 60-90 years) and 60% (range: 10%-100%), respectively. Treatments varied greatly, 573 (73%) patients received high-dose methotrexate (HD-MTX)-based therapy. A total of 276 patients received whole-brain radiotherapy (median 36 Gy, range 28.5-70 Gy). KPS ≥ 70% was the strongest prognostic factor for mortality [hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.41-0.62]. After a median follow-up of 40 months, HD-MTX-based therapy was associated with improved survival (HR 0.70, 95% CI 0.53-0.93). There was no difference between HD-MTX plus oral chemotherapy and more aggressive HD-MTX-based therapies (HR 1.39, 95% CI 0.90-2.15). Radiotherapy was associated with an improved survival, but correlated with an increased risk for neurological side-effects (odds ratio 5.23, 95% CI 2.33-11.74). CONCLUSIONS: Elderly PCNSL patients benefit from HD-MTX-based therapy, especially if combined with oral alkylating agents. More aggressive HD-MTX protocols do not seem to improve outcome. WBRT may improve outcome, but is associated with increased risk for neurological side-effects. Prospective trials for elderly PCNSL patients are warranted.

Primary intramedullary spinal cord lymphoma.

OBJECTIVE: Among the rare causes of myelopathies is primary intramedullary spinal cord lymphoma (PISCL). As PISCL is often underrecognized, delaying appropriate treatment, we sought to describe its presentation, imaging characteristics, and outcomes. METHODS: Mayo Clinic medical records, lymphoma database, and autopsies from 1996 to 2009 were searched. Inclusion criteria were clinical myelopathic presentation, intramedullary spinal cord abnormalities, and pathologically confirmed CNS lymphoma. Exclusion criteria were extramedullary lymphoma, secondary intramedullary lymphoma, or other myelopathic etiology. Clinical features, diagnostic methods, neuroimaging, treatment, and outcomes were assessed. RESULTS: The 14 patients' median age at presentation was 62.5 years (range 41-82 years) and 10 were men (71%). Two had lymphoma risk factors (HIV infection 1; chronic immunosuppression postorgan transplant 1). Most had initial presumptive diagnoses of CNS demyelinating disease and definitive diagnosis of lymphoma was delayed a median of 8 months (range 1-22 months). CNS lymphoma was pathologically confirmed by biopsy (brain 6; spinal cord 4), CSF cytology (3), and autopsy (1). Most patients had multifocal, persistently enhancing lesions on spinal MRI and 8 had involvement of conus medullaris, cauda equina, or both. IV methotrexate was the initial treatment in 9 of 12 (75%) but lymphoma recurred in the majority. Half of the patients were wheelchair-dependent at 10 months and 2-year survival was 36%. CONCLUSIONS: PISCL mimics other causes of myelopathy. Spinal MRI demonstrating multifocal lesions, persistent gadolinium enhancement, and conus medullaris or cauda equina involvement is characteristic. Pathologic confirmation often requires CNS biopsy. Despite chemotherapy, morbidity and mortality is high.

Intraocular use of rituximab.

PURPOSE: To evaluate the toxicity of 1 mg of intraocular rituximab and to present a small case-series of patients treated with intravitreal rituximab. METHODS: Rituximab (1 mg/0.1 ml) was injected in the vitreous of one eye of three Dutch-belted rabbits. Two animals were injected with balanced salt solution as controls. At 1 month the rabbits were killed and the eyes examined by light microscopy. Three patients (five eyes) with intraocular lymphoma were also treated with a 1 mg injection of rituximab. RESULTS: The treated rabbit eyes and the control eyes showed no light microscopic evidence of ocular toxicity at 1 month following injection. The five human eyes of three patients have shown no evidence of intraocular toxicity with a median follow-up time of 3.6 months (range 2.0-6.4 months). One patient received a total of four injections in the right eye and three injections in the left eye. CONCLUSION: Intravitreal rituximab at a dose of 1 mg does not appear to cause toxicity in rabbit eyes and in the five eyes of three patients.

Awake craniotomy for aggressive resection of primary gliomas located in eloquent brain.

OBJECTIVE: To determine with intraoperative neurologic and language examinations the maximal tumor resection achievable with acceptable postoperative neurologic dysfunction in patients undergoing awake stereotactic glial tumor resection in eloquent regions of the brain. PATIENTS AND METHODS: Between October 1995 and December 2000, 65 patients underwent frameless stereotactic resection of glial tumors located in functioning tissue. During the resection, continuous examinations by a neurologist and speech pathologist were performed. The goal of surgery was to resect the maximum neurologically permissible tumor volume defined on preoperative T2 imaging. Tumor resection was stopped at the onset of neurologic dysfunction. Novel segmentation software was used to measure tumor cytoreduction based on pre- and postoperative magnetic resonance imaging. All patients underwent 3-month postoperative neurologic examinations to determine functional outcomes. RESULTS: The cortical and subcortical white matter tracts at risk for injury were the left frontal operculum in 15 patients, the central lobule in 38, the insula in 11, and the left angular gyrus in 1. Thirty-four (52%) had a greater than 90% reduction in T2 signal postoperatively. In 26 patients thought to have low-grade tumors based on preoperative imaging, 12 proved to have grade 3 gliomas. Forty-eight patients (74%) developed intraoperative deficits; 34 (71%) recovered to a modified Rankin grade of 0 or 1 at 3 months postoperatively, 11 (23%) achieved a modified Rankin grade of 2, and 3 patients (6%) achieved a modified Rankin grade of 3 or 4 at 3-month follow-up. There was no operative mortality; 17 patients (26%) died from tumor progression during the follow-up period. CONCLUSIONS: Combining frameless computer-guided stereotaxis with cortical stimulation and repetitive neurologic and language assessments facilitates tumor resection in functioning brain regions. Resecting tumor until the onset of neurologic deficits allows for a good functional recovery. Imaging software can objectively and accurately measure preoperative and postoperative tumor volumes.

Tedisamil and dofetilide-induced torsades de pointes, rate and potassium dependence.

1. Tedisamil is a bradycardiac agent that prolongs the QT interval of the ECG and prevents cardiac arrhythmias. Given this profile, tedisamil might be expected to have proarrhythmic actions similar to Class III antiarrhythmic drugs. To address this question, the actions of dofetilide and tedisamil were examined in rabbit isolated hearts in which bradycardia was induced by AV ablation. 2. The QT interval was prolonged in a reverse rate-dependent fashion by dofetilide (3 and 30 nM) and tedisamil (0.3 and 3 microM). 3. Torsades de pointes was observed in 1/7 hearts treated with 3 nM dofetilide and 0/7 hearts treated with 0.3 microM tedisamil. The incidence of torsades de pointes was increased to 5/7 in hearts treated with 30 nM dofetilide and to 7/7 in hearts treated with 3 microM tedisamil (both P < 0.05 vs control). 4. The actions of 30 nM dofetilide and 3 microM tedisamil were also examined in hearts paced at 50, 100, 200 and 50 beats min(-1) successively. Both drugs caused torsades de pointes in 5/5 hearts paced at 50 beats min(-1); however, the incidence was reduced to 0/5 during pacing at 200 beats min(-1). Thus, drug-induced proarrhythmia was bradycardia-dependent. 5. Drug-induced prolongation of the interval between the peak and end of the T-wave (QTa-e) was reverse rate-dependent and was associated with the occurrence of torsades de pointes (r = 0.91, P < 0.01). 6. The results suggest that tedisamil, like dofetilide, presents a risk for development of torsades de pointes.

Testicular lymphoma is associated with a high incidence of extranodal recurrence.

BACKGROUND: Testicular lymphoma is a rare extranodal presentation of non-Hodgkin lymphoma. The authors report long term follow-up information regarding a group of patients with testicular lymphoma evaluated at the Mayo Clinic and describe the outcome with special attention to patterns of recurrence. METHODS: The medical records of patients with testicular lymphoma seen at the Mayo Clinic between January 1970 and March 1993 were reviewed. Patients were included if they had evidence of testicular involvement at the time of diagnosis of lymphoma. Pathology specimens were reviewed for confirmation of diagnosis. RESULTS: Sixty-two patients with a diagnosis of testicular lymphoma were identified. Their median age was 68 years, and 60 patients underwent orchiectomy as the initial therapeutic and diagnostic procedure. Most of patients (79%) had localized or regional disease at the time of presentation. Other treatment modalities after diagnosis included radiotherapy (37%), combination chemotherapy (37%), and combination chemotherapy and radiotherapy (16%). Although 88% of patients had no residual disease after primary treatment, 80% subsequently experienced disease recurrence. There was no significant difference in the rate of recurrence, including Ann Arbor Stage I disease. Treatment did not appear to affect the recurrence rate. At a median follow-up of 2.7 years, 60% of patients had died of disease. Late recurrences were observed, and there appeared to be no plateau in the disease free survival curve. In half (51%) of the patients with disease recurrence, only extranodal locations were involved. Thirteen patients experienced recurrence in the central nervous system, 11 of whom had parenchymal lesions. In 8 of these 13 patients, the central nervous system was an isolated site of disease recurrence. CONCLUSIONS: Testicular lymphoma is a unique and aggressive extranodal non-Hodgkin lymphoma. Better treatment strategies are needed to prevent recurrences. The risk of extranodal recurrence is high, especially in the central nervous system.

Posttransplant primary CNS lymphoma.

The records and neuro-imaging studies of 8 cases of posttransplant primary CNS lymphoma (PT-PCNSL) diagnosed at Mayo Clinic Rochester between 1970 and 1998 were reviewed retrospectively. All patients received organ transplantation. Patients who had hematologic transplantation were not included in the analysis. The median and mean age of the 4 men and 4 women was 45 years (range, 34 to 50 years). The median duration of symptoms before diagnosis was 36 days (range, 5 to 98 days). At diagnosis, the neurologic examination was focally abnormal in 6 of 8 patients. Compared with the initial computed tomographic study, MRI showed 25 additional brain lesions. Only 43.7% of lesions enhanced with contrast agent; of those that did, all but one were heterogeneous. Ependymal contact occurred in 5 patients. MRI lesion burden increased proportionally to the interval between scans. Diagnostic tissue was obtained by stereotactic biopsy from 6 patients and by open biopsy from 2. Hemorrhage occurred in the biopsy area in 4 patients who had stereotactic biopsy and 2 died (all had normal coagulation studies). Slides available for review (7 patients) showed that the tumors were of CD20-positive lineage and were positive for Epstein-Barr virus, using in situ hybridization. Six patients died. Median survival for the cohort was 13 weeks. PT-PCNSL has clinical and imaging features distinct from typical PCNSL. In our series, (1) PT-PCNSL presented nonspecifically and progressed rapidly, (2) stereotactic brain biopsy had significant morbidity, and (3) despite multimodal therapy, survival was poor.

Prevention of recurrence and prolonged survival in primary central nervous system lymphoma (PCNSL) patients treated with adjuvant high-dose methylprednisolone.

Five patients at risk for primary central nervous system lymphoma (PCNSL) recurrence were treated with high-dose methylprednisolone (HDMP) to prevent 'trafficking' of malignant lymphocytes into the central nervous system (CNS). HDMP was chosen because of its ability to stabilize the 'blood brain barrier (BBB)'. Three men with newly diagnosed PCNSL, ages 62, 76 and 78y, whose survival was projected to be 6.6 months, began treatment after achieving complete response (CR) to initial radiation therapy alone and survived 27, 37 and 59 months after treatment. In none was death from recurrent disease in CNS but one patient did die of systemic non-Hodgkin's lymphoma (NHL) five years after PCNSL diagnosis. A 20 y old man was treated with HDMP after successful combined modality therapy and is alive 75+ months after initial diagnosis without evidence of disease recurrence. A 34 y old man relapsed after combined modality initial treatment and failed to respond to HDMP when treatment was begun after unsuccessful salvage therapy; he died of disease 12 months after initial diagnosis. There were no treatment complications. The promising results in this pilot study from the basis for a North Central Cancer Treatment Group (NCCTG) 96-73-51, a Phase 2 clinical trial of brain radiotherapy and HDMP for PCNSL patients 70y of age and older, a group of patients at high risk for toxicity from intensive combined modality therapy.

Pleomorphic xanthoastrocytoma: what do we really know about it?

BACKGROUND: Pleomorphic xanthoastrocytomas (PXA) may recur and demonstrate aggressive clinical behavior with a mortality rate between 15% and 20%. To the authors' knowledge, no histopathologic features currently are known to reliably predict recurrence or tumor progression. METHODS: The study was based on 71 cases with available information regarding clinical and therapeutic data and follow-up. Diagnostic features included cellular pleomorphism, giant and/or xanthic cells, eosinophilic granular bodies, desmoplasia, and leptomeningeal involvement. The mitotic index (MI), the presence of necrosis, and endothelial proliferation were recorded in all primary resection specimens. RESULTS: The study included 35 females and 36 males, age 26+/-16 years (mean +/- standard deviation). Approximately 98% of tumors were supratentorial, with 49% in the temporal lobe. Seizures were the presenting symptoms in 71% of patients. Extent of tumor removal was macroscopic total resection in 68% of cases and subtotal resection (STR) in 32% of cases. Postoperative radiotherapy, alone or with chemotherapy, was administered in 29% and 12.5% of cases, respectively. The recurrence free survival rates (RFS) were 72% at 5 years and 61% at 10 years, whereas overall survivals rates (OS) were 81% at 5 years and 70% at 10 years. In univariate analysis, the extent of resection was the single factor associated most strongly with RFS (P=0.003), followed by MI (P=0.007) and atypical mitoses (P=0.04). Necrosis was not found to be significant. The extent of resection and MI were confirmed as independent predictors of RFS by multivariate analysis. MI (P=0.001), atypical mitoses (P=0.02), and necrosis (P=0.04) were associated with OS by univariate analysis. In multivariate analysis, only MI was an independent predictor of survival. Information regarding MIB-1 labeling index and the use of adjuvant therapy was too limited to explore their prognostic significance confidently. CONCLUSIONS: The study confirms that PXA is an astrocytic tumor with a relatively favorable prognosis. MI and extent of resection appear to be the main predictors of RFS and OS. Given the slow growth of the tumor, more studied cases and longer periods of follow-up will be essential to confirm our findings regarding prognostic factors affecting this unusual tumor.

Cerebral toxicity in patients treated for small cell carcinoma of the lung.

OBJECTIVE: To present the clinical characteristics of patients enrolled in a trial of treatment of small cell carcinoma (SCC) of the lung and to describe the central nervous system toxicity associated with the chemotherapy and prophylactic cranial irradiation (PCI). MATERIAL AND METHODS: We performed a retrospective analysis of 60 patients with SCC who received chemotherapy and thoracic radiation therapy. PCI was administered to patients who had limited disease or who had extensive disease that was subsequently down-staged to only residual chest disease after initial treatment. The total PCI dose was 3,200 cGy administered in 16 fractions of 200 cGy, given concurrently with systemic chemotherapy. Diagnostic criteria for leukoencephalopathy were based on previously published guidelines. RESULTS: Of the 60 eligible and enrolled patients, 35 received PCI and 25 did not. Leukoencephalopathy developed in 5 of the 35 patients (14%) who received PCI. The median age of the patients in whom leukoencephalopathy developed was 64 years (range, 57 to 69), and the median follow-up time was 59 months. The most common signs and symptoms of leukoencephalopathy were intellectual changes, memory alterations, and motor abnormalities. The mean time to onset of symptoms after termination of irradiation was 357 days (range, 30 to 524). Of all 60 patients, 6 were still alive 4 years after enrollment, and 3 of them (50%) already had leukoencephalopathy. CONCLUSION: Small dosage fractions of PCI may still result in leukoencephalopathy. The routine use of PCI in the management of SCC should be reassessed because of increasing evidence of the toxicity associated with it.

Primary central nervous system non-Hodgkin's lymphoma (PCNSL): survival advantages with combined initial therapy? A final report of the North Central Cancer Treatment Group (NCCTG) Study 86-72-52.

PURPOSE: We herein report updated survival and toxicity data on the entire cohort of 53 eligible patients treated on North Central Cancer Treatment Group (NCCTG) protocol 86-72-52, which is now closed. METHODS AND MATERIALS: An initial report was published in this journal in 1995. No substantive changes in the conclusions of that report were identified in this analysis. Median survival was 9.6 months for the entire cohort; median survival for the 20 patients who completed the prescribed protocol treatment was 20.7 months. The hematologic and non-hematologic toxicity distributions are virtually the same as those reported in the original paper. RESULTS: Results are given for the entire group and for subsets defined by age < or = 60 versus > 60 years, and < 70 versus > or = 70 years of age. CONCLUSIONS: No significant differences were observed in any of the outcome variables by age group. There was, however, a nonsignificant suggestion of poorer outcome in those who were > 60 years of age.

Thrombosis related to the use of L-asparaginase in adults with acute lymphoblastic leukemia: a need to consider coagulation monitoring and clotting factor replacement.

L-asparaginase (L-asp) has become an important component of combination chemotherapy for acute lymphoblastic leukemia (ALL). However, L-asp can produce depletions in many of the clotting factors with an associated risk for thrombosis and hemorrhage. Three consecutive patients seen at the Mayo Clinic with L-asp related thrombosis are described and an in-depth review of the literature is provided. Two of the 3 patients developed central nervous system (CNS) complications with evidence of thrombosis and hemorrhagic infarction. Two of the patients also developed extensive upper extremity thrombosis. The results of comprehensive hemostatic surveys showed marked abnormalities in all 3 patients. Many of the thrombotic complications related to L-asp involve the CNS, as illustrated in 2 of our patients. These patients should be treated aggressively since full recovery is possible. The precise cause of thrombosis is yet to be determined but is likely multifactorial. The optimal treatment and prevention of thrombosis in this group of patients remains poorly defined.

The blood-brain barrier in primary CNS lymphomas: ultrastructural evidence of endothelial cell death.

The vasculature of 24 primary CNS B-cell lymphomas that were not related to acquired immunodeficiency syndrome was systematically studied by electron microscopy. Seven low-grade astrocytic tumors were included for comparison. Classical electron microscopy features of apoptosis were found in lymphoma cells of 21 of 22 subjects. Capillaries of gliomas and lymphomas showed changes reported previously: variability of endothelial cell (EC)-thickness and number, basal lamina thickness and duplication, and fenestrations. Primary CNS B-cell lymphoma ECs showed two distinctive populations of electron-dense and electron-lucent cells. The electron-dense ECs occurred in 38% of all capillaries, with changes consisting of chromatin condensation in bizarre and contracted nuclei, cytoplasmic shrinkage with markedly increased electron density, and dilatation of the endoplasmic reticulum. We interpreted these changes as indicative of apoptosis. Cell death eventually resulted in complete disintegration of the endothelium with frank discontinuities of the EC component of the blood-tumor barrier in capillaries and postcapillary venules. Another population of ECs had increased cell volume, conspicuous cytoplasmic electron lucency, dispersed organelles, scattered vesicles, and apical stress fibers. We interpreted these changes as indicative of cellular regeneration. Individual apoptotic ECs often lay next to normal or regenerating ECs. Neither type of EC change was observed in gliomas, which also lacked perivascular neoplastic lymphocytic cuffing. We believe that these populations of ECs, which have not been described in other disorders affecting the blood-brain barrier, may be induced by cytokines released from necrotic and/or apoptotic tumor lymphocytes and may explain the unusual imaging characteristics of primary CNS B-cell lymphomas treated with corticosteroids.

The consequences of treatment and disease in patients with primary CNS non-Hodgkin's lymphoma: cognitive function and performance status. North Central Cancer Treatment Group.

Per protocol, patients with primary CNS non-Hodgkin's lymphoma in an intergroup phase II trial conducted by the North Central Cancer Treatment Group and the Eastern Cooperative Oncology Group had their cognitive functions measured using the Folstein and Folstein Mini-Mental Status Examination (MMSE) and their physical functions measured using the Eastern Cooperative Oncology Group Performance Score (PS) at study entry, at each treatment evaluation, and at quarterly intervals thereafter until disease progression or death. Of the 53 eligible participants who began therapy, 46 (87%) had baseline MMSE scores recorded, 36 (68%) had at least one follow-up MMSE, and 32 (60%) had both, while 52 (98%) had baseline PS, 49 (92%) had at least one follow-up PS, and 48 (91%) had both. Patterns of MMSE and PS values over time were studied in each individual, in the group as a whole, in the 20 patients who completed the study regimen, in the 23 who survived more than a year, and in patients who were classified as nonprogressors at each key evaluation. For each patient, all recorded values were plotted versus time, with dates of disease progression and death included, to look for signs of decline in cognitive or physical function preceding adverse events. Long-term declines in scores of both cognitive and physical function were observed in many treated patients with primary CNS non-Hodgkin's lymphoma. Nearly all patients who were alive more than 52 weeks after study entry had a demonstrable decline in cognitive and physical functionality. Such declines may occur before disease progression is documented; they may also occur in some patients who have long-term follow-up without evidence of disease progression. Declining MMSE and PS was a poor predictor of disease progression. There was no association of PS and toxicity. The data from this study demonstrated the considerable difficulties we encountered conducting an ancillary study such as this within a multicenter clinical trial. Firstly, the test instruments written into the protocol were unable to tell if the declines seen were due to disease, treatment, co-morbidity, or other factors. Secondly, the missing data created difficulties in interpreting outcome.

Neuroimaging and treatment implications of patients with multiple epidural spinal metastases.

BACKGROUND: Although multiple spinal epidural metastases (MEMs) commonly occur in cancer patients, their clinical significance remains uncertain. The authors attempted to ascertain the incidence of MEMs and their association with the completeness of spinal imaging by magnetic resonance (MR) scanning versus myelography to determine how often they are missed because of incomplete spinal imaging and to assess their prognostic and treatment implications. METHODS: A review of 337 epidural spinal cord compression (ESCC) cases seen at the Mayo Clinic between 1985 and 1993 was conducted. RESULTS: ESCC patients undergoing myelography only were significantly more likely to undergo complete spinal imaging (CSI)than patients undergoing either MR scan only or both imaging modalities (P < 0.0001). MEMs were detected in 32% of patients undergoing CSI and 18% of patients with incomplete spinal imaging (P=0.02). Failure to image the cervical spine in patients with symptomatic thoracic or lumbar epidural lesions would have missed secondary epidural lesions in only 1% of patients; however, this figure increased to 21% for failure to image either the thoracic or lumbosacral spine when symptomatic disease was located elsewhere. Radiation oncologists included secondary epidural deposits in treatment ports in 93% of MEM cases. In a multivariate model, the presence of MEMs was an independent prognostic factor for poorer survival. CONCLUSION: The incidence of MEMs in patients with ESCC is approximately 30%, and their presence frequently alters treatment plans. It appears safe to forgo cervical spine MR scanning in patients with radiographically verified thoracic or lumbar ESCC; however, careful imaging of the thoracic and lumbar spine should be considered in all ESCC patients to detect MEMs.

Risk factors for primary central nervous system lymphoma: a case-control study.

BACKGROUND: The incidence of primary central nervous system lymphoma (PCNSL) has increased over time in both immunocompetent and immunodeficient individuals. The reasons for the increase among immunocompetent patients are unclear. METHODS: The authors conducted a case-control study of PCNSL at the Mayo Clinic based on cases from local community and referral practices. Cases were all PCNSL patients without immunodeficiency diagnosed between 1975 and 1994 (n = 109). Two groups of controls were selected from the same referral practice, namely, patients with other cancer (cancer controls; n = 101), and patients with a different neurologic disease (neurologic controls; n = 109) seen at our institution during the same time period. RESULTS: PCNSL was significantly associated with lower education when cases were compared with cancer controls but only suggestively when cases were compared with neurologic controls. PCNSL cases were less likely to have had a history of tonsillectomy or oral contraceptive use compared with both control groups. The findings regarding autoimmune disorders and cardiovascular diseases were inconsistent for the two control groups. Neither farming nor prior personal or family history of cancer appeared to be risk factors for PCNSL. CONCLUSIONS: The findings of this study warrant further investigation of tonsillectomy and oral contraceptives as possible factors for PCNSL.

Spinal epidural metastasis as the initial manifestation of malignancy: clinical features and diagnostic approach.

The objective of our study was to delineate clinical features and specific diagnostic and therapeutic implications of spinal epidural metastasis (SEM) occurring as the initial manifestation of malignancy (IMM)-a less common event than SEM in the setting of previously established malignancy (PEM). We performed a retrospective review of the clinical histories of 337 patients seen at Mayo Clinic with a radiographically verified diagnosis of SEM between January 1, 1985, and December 31, 1993. Twenty percent of all cases of SEM occurred as SEM-IMM. Carcinoma of the lung, cancer of unknown primary site, multiple myeloma, and non-Hodgkin's lymphoma were disproportionately represented in SEM-IMM, together accounting for 78% of SEM-IMM patients and only 26% of SEM-PEM patients. Inversely, breast and prostate carcinoma contributed only 12% of SEM-IMM patients but 51% of SEM-PEM patients. Only 27% of patients with SEM-IMM had nonspecific symptoms suggesting malignancy, and in only 24% did the history or physical examination suggest the primary site of malignancy. Percutaneous needle biopsy of the vertebral lesion was diagnostic of malignancy in 18 of 19 patients (95%), and no complications ensued. Fifteen patients underwent diagnostic laminectomy with biopsy, and one had a fatal complication. Survival after the diagnosis of SEM did not differ between patients with SEM-IMM and those with SEM-PEM; the median survival was 6.6 months. SEM not uncommonly occurs as the presentation of malignancy, and often it produces the only symptoms or signs of malignancy. The great majority of neoplasms presenting with SEM are carcinomas of the lung, unknown primary lesions, and hematologic malignancies. Computed tomography-guided needle biopsy is a safe, efficacious means of diagnosing malignancy, allowing for rational diagnostic workup and staging. In most patients it obviates a diagnostic spinal surgical procedure.