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.

Computerized tomography and adrenoleukomyeloneuropathy.

Five cases of adrenoleukomyeloneuropathy illustrate the differential computerized tomographic (CT) appearance of the disease subtypes adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN). In ALD, the CT is distinctive, reflecting predominant involvement of cerebral white matter. The CT in AMN may be nonspecifically abnormal since the spinal and peripheral white matter are mainly affected. Recognition of an obscure neurologic disease as a leukodystrophy may aid the clinician in designing appropriate biochemical testing and in categorizing the disease process.

Neurologic complications of hairy cell leukemia.

Involvement of the nervous system in some forms of leukemia is a common, well-recognized problem. To our knowledge, no study has investigated hairy cell leukemia (HCL) with this question in mind, so we reviewed the records of 108 patients with HCL seen during a seven-year period. Neurologic complications developed in roughly 5% of these patients. Direct infiltration of the nervous system in cases of HCL has rarely been reported in the literature, and the clinico-pathologic appearance is insufficiently documented. We found no cases of direct invasion of the nervous system and only one case of vertebral-body invasion and radicular compression, indicating that epidural spread is also rare. Infection was the most frequent cause of neurologic problems in this series of patients with HCL.

Use of adrenal biopsy in diagnosing adrenoleukomyeloneuropathy.

A 22-year-old man was seen with Addison's disease, psychosis, and neurologic abnormalities. A tentative diagnosis of adrenoleukomyeloneuropathy was made. Because of his age, negative family history, and the potentially serious prognosis of this disorder, the diagnosis was verified with an adrenal biopsy. We believe this procedure is the method of choice in confirming the sporadic, atypical case of adrenoleukomyeloneuropathy.

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.

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.

Intramedullary spinal cord metastases: clinical features and treatment outcome.

Our objective was to delineate clinical features and treatment outcome of patients with intramedullary spinal cord metastasis (ISCM). There are no reports of a large experience with this rare cancer complication. We reviewed records retrospectively from 1980 to 1993 to identify patients with histologically confirmed systemic cancer, clinical features of myelopathy, and either tissue-proven ISCM or abnormal neuroimaging findings consistent with ISCM. We identified 40 patients who fulfilled these criteria. In nine, ISCM was the initial presentation of cancer. Nineteen patients had lung primaries (small cell in 12). Twenty-one patients had pain, 35 had demonstrable sensory loss, 37 had weakness, and 25 had urinary incontinence at presentation. Nine patients had true Brown-Séquard syndrome and nine others had pseudo-Brown-Séquard syndrome. Median duration of symptoms at diagnosis was 28 days (range 3 days to 18 months). Thirteen patients had prior brain metastasis, nine had brain metastasis simultaneous with ISCM, and one had brain metastasis after ISCM; 11 had concomitant leptomeningeal metastases. Spinal magnetic resonance findings were abnormal in 30/30 patients, myelographic results were abnormal in 16/20, and eight had pathologic confirmation of ISCM. Thirty-five patients had radiotherapy and five had surgery; four were untreated or treated elsewhere. Median survival was 4 months for patients receiving radiotherapy and 2 months for patients not receiving radiotherapy. Eleven patients survived > 6 months. Twenty-three were ambulatory at ISCM diagnosis, and 21 were ambulatory at letest follow-up. We conclude that ISCM as the initial presentation of malignancy is not rare, and hemicord syndromes occur frequently. Although long-term survival is poor, treatment preserves ambulation in most patients still ambulatory at diagnosis. Focal radiotherapy is indicated in most patients.

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.

Adrenoleukodystrophy: elevated C26 fatty acid in cultured skin fibroblasts and correlation with disease expression in three generations of a kindred.

Varying combination of central and peripheral nervous system disease and Addison disease were previously described in 14 members of a family. The diagnosis of adrenoleukodystrophy (ALD) was documented in affected individuals by increased content of C26:0 C26/C22 fatty acid ratios were not proportional to the neurologic syndrome, severity of disease, or duration.

Familial X-linked Addison disease as an expression of adrenoleukodystrophy (ALD): elevated C26 fatty acid in cultured skin fibroblasts.

Adrenoleukodystrophy (ALD) is a fatal X-linked disorder of very long chain fatty acid (VLCFA) metabolism manifested by disease of the central and peripheral nervous systems and the adrenals. X-linked Addison disease alone, as an expression of ALD, has not been previously reported. We present the results of our study of a unique family among whom clinically apparent Addison disease without neurologic involvement has occurred in affected males, and spastic paraparesis has occurred in female carriers. The presence of ALD was confirmed by VLCFA determination in cultured skin fibroblasts. A comparison group of patients with Addison disease on a putative immunopathogenic basis was normal.

The adrenoleukomyeloneuropathy complex: expression in four generations.

Varying combinations of leukodystrophy, myeloneuropathy, peripheral neuropathy, and primary Addison disease were identified in 14 members of four generations of a kindred of 49 persons. Of these, 26 persons from three generations were evaluated clinically. We propose that adrenoleukomyeloneuropathy (ALMN) is a rare, progressive, presumably biochemical disorder of uncertain inheritance. ALMN is expressed clinically by dysfunction of the central nervous system, peripheral nervous system, and endocrine system. We stress that suspicion of this disorder be high in evaluating uncertain neurologic disorders, and that identification of one manifestation of this complex should alert the clinician to the possibility of a different expression of the same complex in other family members.

Autoimmune paraneoplastic cerebellar degeneration: ultrastructural localization of antibody-binding sites in Purkinje cells.

Sera from three of four patients with paraneoplastic cerebellar degeneration (PCD) associated with gynecologic cancer had antibodies that stained the cytoplasm of Purkinje cells in a characteristic discrete and coarsely granular pattern. No such antibodies were found in PCD patients with small cell cancer of the lung, in patients with cerebellar degeneration without cancer, in nonneurologic patients with small cell carcinoma or gynecologic cancer, or in normal subjects. Immunoelectron microscopy revealed that the antibodies of PCD bound to clusters of ribosomes, granular endoplasmic reticulum, and the trans-face of the vesicles of the Golgi complex in Purkinje cells. Immunostaining was localized in orderly arrays of stacked parallel cisternae of the endoplasmic reticulum in the perikaryon and dendritic processes. This pattern suggested that at least one autoantigen of PCD may be a glycoprotein specific cerebellar tissue that is associated with the endoplasmic reticulum. Some patches of Purkinje plasma membrane also were immunostained.

Computer-assisted stereotaxic biopsy for the diagnosis of primary central nervous system lymphoma.

Primary CNS lymphoma was diagnosed in 13 patients after stereotaxic biopsy of indeterminate intracerebral mass lesions. Two patients also had laser extirpation of CT-visible tumor. The group consisted of 10 men and 3 women, aged 17 to 81 (mean, 55 years; median, 60 years). The lesions on CT were characteristically hyperdense, homogeneously contrast-enhancing, and associated with mild to moderate mass effect. Five patients had more than one lesion visible on CT. Complete staging procedures for occult systemic lymphoma were negative in all 13 patients. The majority (eight) of the tumors were of the diffuse, large-cell type. Five biopsy specimens underwent special immunostaining as a supplemental diagnostic effort. Two patients with small lymphocytic tumors demonstrated features consistent with T cell phenotype. Two patients with diffuse, large-cell tumors were confirmed as B cell phenotype by monotypic immunoglobulin light chain content. Primary CNS lymphomas represent a treatable group of primary brain tumors. Because of their tendency to develop in deep cerebral regions, they are often inaccessible to conventional neurosurgical techniques. We propose that stereotaxic neurosurgery can provide safe and accurate diagnosis, which is a prelude to planning comprehensive management.

Adrenoleukodystrophy (ALD): clinical and CT features of a childhood variant.

A variant of childhood adrenoleukodystrophy (ALD) affected two male cousins. The characteristic features include a progressive frontal lobe syndrome, frontal pole CT hypodensity, abnormal levels of plasma very-long-chain fatty acids, and a family history consistent with X-linked inheritance.

Adrenoleukodystrophy: clinical and biochemical manifestations in carriers.

We studied 21 women from four definite adrenoleukodystrophy (ALD) kinships . Nine women had a spastic paraparesis, including two with peripheral neuropathy. Fifteen women were assigned heterozygote status based on abnormal very-long-chain fatty acid ( VLCFA ) concentrations in plasma, fibroblasts, or both. These 15 included those with abnormal examinations and all women judged to be carriers by clinical criteria. Some ALD heterozygotes have varying degrees of neurologic disease, usually spastic paraparesis. Carrier detection is possible by determination of VLCFA concentrations in plasma and cultured skin fibroblasts. Any woman at risk in an ALD kinship, and who demonstrates a spastic paraparesis, should be assumed to be a carrier until biochemical testing is obtained. To determine whether a woman is an ALD carrier, measurement of plasma VLCFA levels should be done initially. If this gives normal or equivocal results, VLCFA levels should be measured in cultured skin fibroblasts.

Familial spastic paraparesis: an adrenoleukodystrophy phenotype?

Adrenoleukodystrophy (ALD) must be considered in the diagnosis of men with progressive nervous system disease. We found the biochemical defect characteristic of ALD in two brothers with spastic paraparesis of late adult onset. Family study then revealed other affected men and asymptomatic heterozygotes in a pattern that conformed to an X-linked pattern of inheritance.

Primary leptomeningeal lymphoma: report of 9 cases, diagnosis with immunocytochemical analysis, and review of the literature.

We describe 9 patients who presented with a neoplastic meningitis of lymphomatous origin. No evidence of parenchymal central nervous system or systemic tumor was identified either at the time of presentation or throughout the course of their disease. We have chosen to call this entity "primary leptomeningeal lymphoma" (PLML). This unusual form of neurologic lymphoma must be differentiated from the more common clinical situations of primary parenchymal lymphoma with meningeal involvement and systemic lymphoma complicated by lymphomatous meningitis.

Delayed leukoencephalopathy in survivors with small cell lung cancer.

Six patients with small cell lung cancer developed a slowly progressive neurologic syndrome characterized by apathy, abulia, memory loss, gait ataxia, and corticospinal tract signs 26 to 50 months (mean, 35.2 months) after prophylactic cranial irradiation and systemic chemotherapy. In each case this was accompanied by CT and/or MRI evidence of changes in the periventricular white matter. These patients are long-term survivors (41 to 69 months) and do not have CNS metastases.

Adrenoleukodystrophy: increased plasma content of saturated very long chain fatty acids.

With a new method we measured the saturated very long chain fatty acids in the plasma of adrenoleukodystrophy (ALD) hemizygotes, ALD heterozygotes, and controls. ALD hemizygotes showed increased levels of hexacosanoate (C26 fatty acid) which represented 0.081 +/- 0.0066% (SEM) of total fatty acids, compared to 0.015 +/- 0.0032% in the controls. C25, C24, and C23 fatty acids were also increased, but the C22 and C20 fatty acids were normal. C26 levels were also increased in most ALD heterozygotes, with a mean level 0.057 +/- 0.0063% of total fatty acids. The technique can be used for diagnosis and carrier identification, and in the evaluation of therapy.