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Primary CNS Lymphoma of T-Cell Origin: A Descriptive Analysis From the International Primary CNS Lymphoma Collaborative Group

From the Division of Medical Oncology, British Columbia Cancer Agency, Vancouver; Department of Radiation Oncology, Princess Margaret Hospital, Toronto, Canada; Unite Cytokines et Cancers, Hôpital Edouard Herriot, Centre Leon Berard, Lyon, France; Neuro-Oncology Program, Mayo Clinic Cancer Center, Rochester, MN; Dr. Bernard Verbeeten Instituut, Tilburg, the Netherlands; Charite Campus Benjamin Franklin, Berlin, Germany; Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY; Department of Neurology and Neurosurgery, Oregon Health & Science University, Portland, OR; Department of Neurology and Pathology, Harvard Medical School; Massachusetts General Hospital, Boston, MA; Department of Radiochemotherapy and Pathology, San Raffaele H Scientific Institute, Milan, Italy; Department of Radiation Oncology, Newcastle Mater Hospital, Newcastle, Australia; and University of California San Francisco, San Francisco, CA

Address reprint requests to Tamara N. Shenkier, MD, British Columbia Cancer Agency, 600 W 10th Ave, Vancouver, BC, V5Z 4E6, Canada; e-mail: tshenkier{at}bccancer.bc.ca

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix REFERENCES

 
PURPOSE: To describe the demographic and tumor related characteristics and outcomes for patients with primary T-cell CNS lymphoma (TPCNSL).

PATIENTS AND METHODS: A retrospective series of patients with TPCNSL was compiled from twelve cancer centers in seven countries.

RESULTS: We identified 45 patients with a median age of 60 years (range, 3 to 84 years). Twenty (44%) had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Twenty-six (58%) had involvement of a cerebral hemisphere and sixteen (36%) had lesions of deeper sites in the brain. Serum lactate dehydrogenase was elevated in 7 (32%) of 22 patients, and CSF protein was elevated in 19 of 24 patients (79%) with available data. The median disease-specific survival (DSS) was 25 months (95% CI, 11 to 38 months). The 2- and 5-year DSS were 51% (95% CI, 35% to 66%) and 17% (95% CI, 6% to 34%), respectively. Univariate and multivariate analyses were conducted for age ( 60 v > 60 years), PS (0 or 1 v 2, 3, or 4), involvement of deep structures of the CNS (no v yes), and methotrexate (MTX) use in the primary treatment (yes v no). Only PS and MTX use were significantly associated with better outcome with hazard ratios of 0.2 (95% CI, 0.1 to 0.4) and 0.4 (95% CI, 0.2 to 0.8), respectively.

CONCLUSION: This is the largest series ever assembled of TPCNSL. The presentation and outcome appear similar to that of B cell PCNSL. PS 0 or 1 and administration of MTX are associated with better survival.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix REFERENCES

 
Primary CNS lymphoma (PCNSL) in immunocompetent individuals is an uncommon tumor that accounts for approximately 5% of all primary brain tumors and only 1% to 2% of non-Hodgkin’s lymphoma (NHL) in general.^1-3 Although the large majority of PCNSL are of B-cell origin, T-cell lesions are occasionally seen, and case reports have been described in the literature.^4-7 In two previously reported large series of PCNSL from France and Japan, the proportion of patients with T-cell lymphoma was 3.6% and 8.5%, respectively.^8,9 In the largest series of PCNSL cases diagnosed in Western countries, T-cell origin has been reported in 8 (2%) of 370 cases.¹⁰ To date, there has not been a report of a single large series exclusively describing features of patients with primary T-cell CNS lymphoma (TPCNSL).

The International PCNSL Collaborative Group (IPCG) is a multidisciplinary group consisting of neurologists, neurosurgeons, radiation and medical oncologists, hematologists, and pathologists from North America, Europe, and Australia. The group was convened with the support of the International Extranodal Lymphoma Study Group (IELSG) to address clinical and biologic research questions concerning PCNSL. It is also an ideal forum from which to assemble clinical data regarding rare presentations of this disease. Here, we report a retrospective analysis of 45 patients with TPCNSL diagnosed between 1983 and 2003, assembled from 12 institutions in seven countries.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix REFERENCES

 
Study Population
A questionnaire requesting information about patient characteristics, diagnosis, pathology, stage, treatment, site and date of progression, second-line treatment, neurotoxicity, and survival of patients with TPCNSL was sent to participating centers affiliated with the IPCG. Twelve cancer centers with at least one case of TPCNSL each responded. The median number of cases reported per institution was 2.5 (range, 1 to 15 cases). Each center received local ethics committee approval for the release of anonymized data.

The inclusion criteria were histologic or cytologic diagnosis of lymphoma; disease localized exclusively to the brain, meninges, eyes, or spinal cord; no obvious evidence of HIV-1 infection; T-cell phenotype by immunohistochemistry (CD3, CD4, or CD45RO positive); or T-cell–receptor molecular rearrangement.

Retrieval of the original specimens for central pathology review was not feasible due to logistics and regulatory issues, as well as time elapsed from original diagnosis. A vigorous attempt was made to retrieve the original pathology reports. In 25 cases, the original pathology reports were available for central review, and the following information was abstracted: cytologic features, pattern of infiltration, immunophenotyping, and final diagnosis. The other 20 cases were retrieved from lymphoma databases at individual institutions.

Statistical Considerations
Using the Kaplan-Meier method, survival rates were calculated from the date of histologic diagnosis to death (for overall survival [OS]), to death from either lymphoma or toxicity (for disease-specific survival [DSS]), or to progression or death as a result of toxicity (for progression-free survival [PFS]).¹¹ Differences in pairs of survival curves were examined by the log-rank test.¹² Given the descriptive nature of our analysis, we had no a priori power estimates. Thus, working with an overall study population of 45, from which paired sample sizes in each of two prognostic groups are approximately 20, a .05-level two-sided log-rank test for equality of survival only has 15% power to detect a difference of 15% (for example, 45% v 60% and assuming a constant hazard ratio [HR] of 1.6) at 2 years. Multivariate analysis of prognostic factors was carried out using the Cox proportional hazards model. All statistical analyses were carried out using SPSS for Windows, version 11.0 (SPSS Inc, Chicago, IL).

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix REFERENCES

 
Identification of Cases
A total of 45 cases were identified. All patients had disease confined to the brain (n = 42), spinal cord (n = 2), or meninges (n = 1) with no evidence of systemic lymphoma at presentation. Four cases described in previous reports of TPCNSL are included in this cohort.^4-6 One patient had confirmed infection with human T-cell lymphocyte virus-1 (HTLV-1), but serologic testing was not done routinely in all cases.

Pathologic Features
Diagnostic tumor sample was obtained by stereotactic biopsy in 36 patients (80%), surgical resection in seven patients (16%), at autopsy in one patient, and by cytologic examination of the CSF in one other. In 20 cases, the diagnosis of lymphoma of T-cell origin had been previously recorded in a lymphoma database (four from Mayo Clinic Cancer Center [Rochester, MN] and 15 from Federation Nationale des Centres de Lutte Contre le Cancer [Lyon, France]) or clinical records (one from Memorial Sloan-Kettering Cancer Center [New York, NY]) that required central hematopathology review. The original pathology reports were available in the other 25 cases. T-cell origin was ascertained by immunophenotyping of the brain biopsy specimen in 42 patients, immunophenotyping of the brain lesion at autopsy in one patient, and by molecular studies confirming T-cell–receptor rearrangement in one patient. One other patient had the T-cell phenotype confirmed from a skin biopsy at relapse 4 months after the original PCNSL presentation. In the 25 cases in which the pathology reports were reviewed, the tumor was described as "angiocentric" in seven cases (28%). The cell size was described as "small" or "small to medium" in 12 cases (50%). In the other 13 cases, the cells were described as either "pleomorphic" or composed of "medium to large" cells. Among these latter 13 cases, three had features of anaplastic large cell lymphoma and stained positive for CD30 in addition to CD3.

Clinical Features
Staging procedures included slit-lamp examination of the eyes in 26 patients (60%) and CSF cytology examination in 32 patients (71%). In 24 patients (53%), the CSF protein was recorded. Performance status (PS) was defined according to the Eastern Cooperative Oncology Group (ECOG) criteria and was available in 43 cases (96%). Serum lactate dehydrogenase (LDH) was recorded in 22 cases (49%).

The main clinical characteristics are listed in Table 1. To facilitate comparison, these characteristics are shown alongside those of the 378 PCNSL patients assembled by the IELSG and previously reported.¹⁰ That cohort had a median age of 61 years (range, 14 to 85 years). The median age of our 45 patients was 59.5 years (range, 3 to 84 years). Six patients (13%) were older than 70 years at diagnosis, and 21 (47%) of 41 patients had an ECOG PS of 2 or worse. Seven (32%) of 22 patients had an elevated LDH serum level, and 19 (79%) of 24 of patients had an elevated concentration of CSF protein. Involvement of deep brain structures (basal ganglia, corpus callosum, brainstem, and/or cerebellum) was seen in 16 patients (36%). Thirteen patients (29%) had multiple lesions at diagnosis.

Four patients had unusual features of their initial diagnoses. One presented with a 1-year prodrome of progressive neurologic and systemic symptoms. He had multifocal frontal lobe lesions, but no evidence of systemic lymphoma on initial staging. His biopsy was compatible with peripheral T-cell lymphoma. Serology was positive for HTLV-1.

Another patient presented with gait abnormalities and cranial neuropathies and was found to have leptomeningeal disease only. Diagnosis was made on cytologic examination of the CSF. Two patients presented with spinal cord lesions only.

Therapeutic Management
Corticosteroid use before definitive treatment was documented in 21 cases (47%). The dexamethasone dose ranged from 4 to 40 mg/d (median, 16 mg/d). Definitive therapeutic information was available for all patients. In 24 patients (53%), the delivered treatment was chemotherapy followed by irradiation; in seven patients (16%), chemotherapy alone; in two patients (4%), intra-arterial chemotherapy with blood-brain barrier disruption; and in 11 patients (24%), irradiation alone. In the one remaining case, the patient died before treatment was initiated, and the diagnosis was made at autopsy.

Methotrexate (MTX) was the most commonly used drug (n = 29) either alone (n = 11) or in combination with other agents (n = 18).^14-19 The intravenous (or intra-arterial) MTX dose ranged from 2 g/m² to 8 g/m² per month (median, 3.75 g/m²/mo). The number of courses ranged from one to 12 (median, 4.5 courses). Three patients had non–MTX-based regimens. In one patient, no additional information regarding the specific regimen was available. One patient had high-dose chemotherapy and autologous peripheral blood stem-cell transplantation following MTX and irradiation. Information regarding intrathecal (IT) chemotherapy was available in 42 cases (93%). Seventeen patients (40%) received IT MTX either alone (n = 8) or alternating with IT cytarabine (n = 9).

Irradiation was administered to 35 patients (78%). This consisted of whole brain irradiation in 34 patients (76%), with a boost to the tumor bed in twelve patients (27%). In two of these 34 patients, the irradiation field also included portions of the spinal cord (one with cerebellar disease and another with a primary spinal cord lesion). One patient received irradiation to the spinal cord only. The dose ranged from 20 to 55 Gy (median, 35 Gy).

Outcome
The median follow-up time for living patients is 22 months (range, 1 to 246 months) to date. Thirty patients have died: 23 as a result of lymphoma, six as a result of toxicity (four neurologic and two infectious), and one as a result of metastatic carcinoma while in remission for 4 years following treatment for TPCNSL. The median OS and DSS for all patients was 25 months (95% CI, 11 to 38 months). The 2- and 5-year DSS were 51% (95% CI, 35% to 66%) and 17% (95% CI, 6% to 34%), respectively. This data is shown in Figure 1. The median progression-free survival (PFS) was 22 months (95% CI, 14 to 30 months). The 2- and 5-year PFS were 45% and 22%, respectively. There was no difference in OS or DSS between the 25 patients whose pathology report was available for review and the 20 whose pathologic information was obtained from a centralized database.

View larger version (9K): [in this window] [in a new window]   Fig 1. Disease-specific survival for all patients with primary T-cell CNS lymphoma (n = 45).

Salvage treatment was systemic chemotherapy in six patients and localized irradiation in two others (one each to the spinal cord and eyes). Ten patients had no further treatment, and information regarding second-line therapy was unavailable in six others.

The data were analyzed according to several known prognostic factors for PCNSL.^13,20 The results for age 60 years and Eastern Cooperative Oncology Group performance score 2 are shown in Figures 2 and 3. The difference in DSS between patients with good and poor PS was significant, whereas that for younger and older patients showed only a trend towards significance. However, our sample size had a low power to detect a true difference (see Patients and Methods). A primary lesion that involves a deep site of the brain, such as basal ganglia, cerebellum, corpus callosum, or brainstem, has been previously reported to carry an adverse prognosis. In our series, there was a trend to worse outcome for deeper lesions, with the median DSS 23 versus 29 months (log-rank P = .14). Two other previously reported adverse prognostic factors for CNS lymphoma are elevated LDH and elevated protein level in the CSF, but information concerning these variables was available in only half of the cases, and complete information on all five prognostic factors was available for only 14 of the 45 patients. In addition to patient- and tumor-related factors, a treatment-related variable, use of MTX, is also associated with outcome. In our cohort, a significant benefit was seen in favor of those patients who received any MTX. This is shown in Figure 4.

View larger version (11K): [in this window] [in a new window]   Fig 2. Disease-specific survival by age.

View larger version (12K): [in this window] [in a new window]   Fig 3. Disease-specific survival by Eastern Cooperative Oncology Group performance score.

View larger version (13K): [in this window] [in a new window]   Fig 4. Disease-specific survival by treatment with methotrexate.

We conducted a multivariate analysis using four variables: age ( 60 years v > 60 years), ECOG PS ( 1 v 2), site of primary lesion (superficial v deep), and MTX in primary treatment (yes v no). Age was dropped from the model because it failed the proportionality hazard check. The site of the primary lesion did not have sufficient independent predictive value. Therefore, only two factors, ECOG PS and use of MTX, were included in the final model. The hazard ratios for improved DSS for PS 1 and receipt of MTX were 0.2 (95% CI, 0.1 to 0.4) and 0.4 (95% CI, 0.2 to 0.8) respectively. The median DSS according to the number of adverse prognostic factors present at diagnosis (0, 1, or 2) was 43 months (95% CI, 29 to 58 months), 23 months (95% CI, 0 to 46 months) and 3 months (95% CI, 0 to 6 months), respectively (P < .0001; Fig 5).

View larger version (13K): [in this window] [in a new window]   Fig 5. Disease-specific survival by number of adverse factors.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix REFERENCES

The clinical characteristics of this cohort were comparable to those of PCNSL in general.^10,13,20 The median age and ECOG PS were similar to those previously reported. Like patients with B-cell PCNSL, the majority of patients in this series presented with supratentorial lesions. There was a greater male preponderance and higher proportion of patients presenting with "B" symptoms in our series compared to the IELSG data. We also had a lower incidence of ocular involvement than that seen in larger studies of PCNSL. Although our series is large, our methodology cannot guarantee that it is necessarily comprehensive, and any definitive conclusions about how the demographics and clinical characteristics of TPCNSL resemble or differ from those of B-cell PCNSL need to be interpreted in that light. For this reason, a formal statistical comparison was not performed. One patient presenting with a space-occupying solitary cerebral lesion typical of PCNSL had an associated HTLV-1 infection. We also included two cases with exclusive involvement of the spinal cord. These cases show that a range of clinical and radiographic presentations can be seen.

Some authors described two cases and reviewed 20 additional cases from the literature.⁷ Similar to this series, those reports described patients with a wide range of ages, from childhood to the seventh decade, and a slight male predominance. In contrast to our series, in which one third of patients had deep lesions (including cerebellum, brainstem, corpus callosum, and basal ganglia), the posterior fossa was involved in more than one half of cases previously described in the literature.

One study suggested that T-cell phenotype possibly conferred a worse prognosis than B-cell PCNSL, but another hypothesized that since a significant proportion of TPCNSL has "low grade" features (such as small lymphocytic in the Working Formulation), a more favorable outcome could be expected.⁴ In our series, the median survival of patients with TPCNSL appears to be similar to that described for large series of PCNSL in general. Our study population was treated in a manner similar to that described for PCNSL, in that comparable proportions of patients received chemotherapy, irradiation, or combined-modality treatment.¹³ These findings suggest that the outcomes we describe are probably due to intrinsic features of the disease, and not an inherent treatment bias, compared with the more common B-cell PCNSL. In our series cytologic type (small v large) did not affect survival.

We were unable to verify a prognostic scoring system described for PCNSL because information on all five parameters was available in only 14 of the 45 patients.¹³ Furthermore the patients in this series were not prospectively assembled or uniformly treated; therefore, any prognostic analysis is subject to potential bias. Nevertheless, certain patient- and treatment-related factors may be helpful to the clinician managing this rare disease. In our series, ECOG PS was a strong predictor of DSS, but age ( 60 years or > 60 years) was not. Age could not be included in the Cox multivariate regression model because it failed the proportionality hazard check. Since age is a powerful predictor of prognosis for PCNSL and NHL in general, this finding is most likely due to chance and the small number of patients in the subgroup analyses. The site of the lesion (deep v superficial) did not have sufficient predictive power in this series to be included in the Cox model. However, when we used ECOG PS 2 and absence of MTX in a simple two-variable model, we found that patients with no, one, or two factors had a median DSS of 43 months (95% CI, 29 to 58 months), 23 months (95% CI, 0 to 46 months) and 3 months (95% CI, 0 to 6 months), respectively. This information suggests that MTX-based regimens should considered for patients with TPCNSL.

This study has several limitations. Not all members of the IPCG submitted data; some centers had no cases on record, and others did not reply. Institutions from Japan were not included. Therefore, the series may not be representative of all TPCNSL. The cases were not prospectively assembled, and some information was unavailable. We did not verify all of the source information from the original charts, and relied mostly on already abstracted records. We did not have access to the original pathology slides, and were able to review the original pathology reports in only 25 of 45 cases. Despite these limitations, our descriptive and outcome data are similar to those previously reported for TPCNSL.⁷ Given the rarity of this condition, however, such a retrospective review constitutes the best available approach to characterizing TPCNSL. Even assembling 45 cases could be accomplished only with wide international cooperation across many centers.

In summary, TPCNSL is a rare disorder with characteristics at presentation and outcomes similar to that of PCNSL in general. In this series, PS 1 and receipt of MTX were important factors that appeared to influence survival.

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix REFERENCES

 
Members of the IPCG: Abrey, Lauren E.; Armitage, James O.; Baars, Joke W.; Batchelor, Tracy; Bessell, Eric; Betensky, Rebecca; Bierman, Phil; Blay, Jean-Yves; Borisch, Bettina; Cavalli, Franco; Child, Tony; Colombat, Philippe; Connors, Joseph M.; D’Addario, Giannicola; DeAngelis, Lisa M.; Delattre, Jean-Yves; Desablens, Bernard; Doorduijn, Jeannette K; Dorfman, Molly; Ferreri, Andrés; Fine, Howard; Finke, Jürgen; Girinsky, Théo; Glasmacher, Axel; Glass, Jon; Gospodarowicz, Mary; Graus, Frances; Grigg, Andrew; Grossman, Stuart; Guttenberger, Roland; Haaxma-Reiche, Hanny; Hansen, Mads; Harris, Nancy; Herrlinger, Ulrich; Hoang-Xuan, Khé; Hochberg, Fred; Hofer, Silvia; Illerhaus, Gerald; Jacobsen, Elisa; Jahnke, Kristoph; Kluin-Nelemans, Hanneke; Korfel, Agnieszka; Lister, Andrew; Laperriere, Normand; Lugtenburg, Elly; Neuwelt, Edward A.; O’Brien, Peter; O’Neill, Brian P.; Pels, Hendrik; Ponzoni, Maurilio; Poortmans, Philip; Raemaekers, John; Reni, Michele; Rosenthal, Mark; Rosta, András; Rozewicz, Cynthia M.; Rubenstein, James L.; Salles, Gilles; Schiff, David; Schlegel, Uwe; Schmidt-Wolf, Ingo; Sebban, Catherine; Seymour, John; Shenkier, Tamara; Soussain, Carole; Stupp, Roger; Swinnen, Lode; Teodorovic, Ivana; Thiel, Eckhard; Thomas, José; Tsang, Richard; van den Bent, Martin; van Hoof, Achiel; van Imhoff, Gustaaf; van Ossenkoppele, Gert; Weller, Michael; Yahalom, Joachim; and Zucca, Emmanule.

Authors’ Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We thank Franco Cavalli, MD, for spearheading the creation of the IPCG under the IELSG, and James Armitage, MD, for his suggestion to study TPCNSL.

	NOTES

 
Authors’ disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix REFERENCES

 
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Submitted July 19, 2004; accepted December 14, 2004.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shenkier, T. N. Articles by Connors, J. M. Search for Related Content PubMed PubMed Citation Articles by Shenkier, T. N. Articles by Connors, J. M. Social Bookmarking                            What's this?