Acta Neurochir (Wien) (2006) 148: 831–838

DOI 10.1007/s00701-006-0790-9

Primary CNS lymphoma in immunocompetent patients

from 1989 to 2001: a retrospective analysis of 164 cases uniformly
diagnosed by stereotactic biopsy

F. Feuerhake1 , C. Baumer1, D. Cyron2 , G. Illerhaus3 , M. Olschewski4 , J. Tilgner2,

C. B. Ostertag2 , and B. Volk1

1
Department of Neuropathology, University of Freiburg, Neurozentrum, Freiburg, Germany
2
Department of Stereotactic Neurosurgery, University of Freiburg, Neurozentrum, Freiburg, Germany
3
Department of Internal Medicine I, University of Freiburg, Freiburg, Germany
4
Department of Medical Biometry, University of Freiburg, Freiburg, Germany

Received October 13, 2005; accepted March 29, 2006; published online June 21, 2006
# Springer-Verlag 2006

Summary arises in the CNS in the absence of any obvious mani-

Background. We present outcome data of a cohort of 164 immuno-
competent PCNSL patients uniformly diagnosed at a single center for
stereotactic neurosurgery, and evaluate the acceptance and impact of
combination radiotherapy (RT) and chemotherapy (CHT) with high-dose
methotrexate (HD-MTX) over time.
Method. We assessed choice of treatment and patient survival in a
series of 164 PCNSL cases diagnosed from 1989 to 2001, and performed
a re-evaluation of histopathology and pre-operative clinical data.
Findings. From 1989 to 1993, RT was the predominant therapy, and
additional CHT did not improve survival. After 1994, the use of combi-
nation CHT=RT increased continuously, consistently contained MTX, and
was associated with longer survival than RT only: median survival was 14
months after CHT=RT (2-year survival 35.7%) and 10 months (2-year
survival 26.2%) after RT only (not significant). Overall median survival
remained poor, increasing from six (1989–1993) to nine months (1994–
2001) ( p ¼ 0.008). Survival was variable, with a few patients surviving
>4 years after diagnosis in the CHT=RT as well as in the RT only group.
Conclusions. Despite considerable improvement of PCNSL therapy,
the overall benefit of combined CHT=RT versus RT only was lower than
that expected from previous phase II clinical trials. The striking vari-
ability of survival in either treatment group may suggest a yet undefined
biological heterogeneity of PCNSL, which may also include a more
aggressive PCNSL subtype in the group of patients with rapidly progres-
sive disease and not eligible for standard therapy.
Keywords: Primary CNS lymphoma; combined therapy; clinical
outcome; diagnosis; stereotactic brain biopsy.
Introduction
Primary central nervous system lymphoma (PCNSL)
is defined as an extranodal malignant lymphoma that
festation of lymphoma outside the nervous system. The
large majority of tumours express surface molecules
characteristic of B-lymphocyte lineage and resemble dif-
fuse large B-cell lymphoma (DLBCL) both histologi-
cally and with regard to molecular characteristics [25].
PCNSLs have been shown to have clonal rearrange-
ment and somatic hypermutation of the immunoglobulin
heavy chain (IgH) gene [22] and aberrant somatic hyper-
mutation [23], consistent with B-cell lymphoma origi-
nating at a germinal center developmental stage.
The incidence of PCNSL in immunocompetent patients
has been increasing over the past decades [21]. However,
it is a subject of controversy whether this trend continued
during the period covered by the present study. The con-
flicting results reported in the literature include studies
claiming a continued increase [3, 20, 24, 34], and those
indicating that PCNSL incidence may be stabilizing
[1, 18, 35] or even be decreasing [16]. Two large popula-
tion-based studies, one from Canada covering 1975–1996
[12] and one from the Netherlands covering 1989–1994
[32], did not find a substantial change in PCNSL inci-
dence. Currently, PCNSLs account for 3.3% of all brain
tumours the United States according to the most recent
available data from the Central Brain Tumour Registry [2].
Whole-brain radiotherapy (RT), the standard therapy
for PCNSL for many years, was largely replaced by
832
combination chemotherapy (CHT) with high-dose meth-
otrexate (HD-MTX) and radiotherapy (RT) during the
time covered by this study. The protocol was first pub-
lished in 1992 [5], proving to be superior to RT alone
in several smaller phase II clinical trials, and eventually
became widely accepted as clinical standard. The en-
couraging results of the initial clinical studies were con-
firmed by a larger multicenter trial showing superior
outcome of combination therapy, when compared to pre-
viously published results on RT alone [6]. Even without
a larger randomized study available, these results led
to a widely accepted consensus to include HD-MTX in
PCNSL therapy [9]. However, the benefit of the new
therapy modality for a general population of PCNSL
patients was less striking in large retrospective multi-
center studies [4, 7, 13, 30] than that expected based
on the smaller Phase II trials. Subgroups of PCNSL
patients clearly had prolonged survival after an aggres-
sive therapy regimen [14], but for a majority of cases the
prognosis remained poor [14, 17, 29].
In contrast to other PCNSL series in the past that
were based on clinical records, the present work relies
on the neuropathological archives, reflecting the ex-
perience of a single referral center for stereotactic
neurosurgery. The PCNSL patients referred to our in-
stitution include a group of patients with histologically
proven CNS lymphoma in relatively poor clinical con-
dition who received only supportive treatment. Our
approach to identifying PCNSL patients based on the
pathology archive rather than on clinical records of
large specialized haemato-oncological centres enabled
us to reflect this aspect of PCNSL management during
the 1990s that may have been missed by other retro-
spective studies. Encompassing a time of significant
changes in PCNSL treatment, it also aimed at investi-
gating the general acceptance of such an important new
treatment modality as combined RT=CHT, and its ac-
tual impact on clinical outcome.
Materials and methods
Search methods and case definition
Patient identification was based on the neuropathological archive,
encompassing the years from 1989 to 2001. The series was restricted
to cases diagnosed by stereotactic biopsy, an approach that represents
the state-of-the art diagnostic procedure in PCNSL and allowed us to
relate the annual patient numbers to the overall frequency of brain
tumours diagnosed by the same method. 210 cases of cerebral lympho-
ma were identified. 34 were secondary lymphoma and=or had evidence
of immunosuppression (history of HIV-related disease or tested positive
for HIV, long-term immunosuppressive medication due to organ trans-
plantation or auto-immune disease, pre-existing immune defects or pre-
vious chemotherapy for solid tumours). 12 cases were excluded because
F. Feuerhake et al.
the clinical material was not sufficient to exclude immunosuppression, or
to determine survival. 164 PCNSL cases met the following inclusion
criteria: (1) high-grade lymphoma diagnosed by routine histology and
immunohistochemistry, (2) clinical records sufficient to exclude immu-
nosuppression and=or systemic lymphoma at the time of diagnosis (3)
survival data available until July, 2002.
Stereotactic biopsy technique and processing of specimens
Stereotactic serial biopsy was performed under computer guidance,
with a neuropathologist attending the surgical procedure and evaluating
intra-operative tissue preparations. Consecutive specimens were either
fixed in formaline, or used for touch=smear preparations stained with
methylene blue in an alternating manner. The clinical records from
the Department of Stereotactic Neurosurgery were retrieved to obtain a
description of the pre-operative cranial computed tomography (cCT), a
summary of the presenting complaints, the pre-operative clinical course,
and the approximate date of onset of the symptoms. The neuropatholo-
gical work-up of older cases, particularly the immunohistochemical de-
tection of leucocyte antigens, was completed with current methods of
immunohistochemical signal detection and antigen retrieval if necessary.
In addition to the available routinely performed immunohistochemical
stainings, new 5 mm thick paraffin sections were cut from selected cases
and stained following routine protocols using the following antibodies:
polyclonal anti-CD3, monoclonal anti-CD45 (clone LCA), monoclonal
anti-CD20, clone L26, and monoclonal mouse anti-CD79a, clone JCB
(DAKO, Glostrup, Denmark). Antibody binding was detected using the
Histostain Plus Kit (Zymed, distributed by Zytomed, Berlin, Germany)
following the manufacturer’s instructions. All histopathological reports
available from the neuropathological archive were reviewed for clinical
data provided by the referring physician, radiographic findings, intra-
operative, and histopathological diagnoses. Histologically, all but two
cases were consistent with diffuse large B-cell lymphoma according to
the current WHO classification including the expression of the B-cell
lineage markers CD20 and CD79a; the two exceptions showed surface
immunoreactivity for the T-lineage marker CD3.
Corticosteroid therapy and intra-operative diagnosis
Patients were considered to have received corticosteroid therapy if
they either were receiving treatment at the time of the surgical procedure
or had discontinued treatment less than 5 days prior to the stereotactic
biopsy. The intra-operative diagnosis was based on methylene blue-
stained smear or touch preparations, which were evaluated by the attend-
ing neuropathologist during each biopsy procedure in the operating
theater. The diagnostic categories considered for statistical analysis were
‘‘high-grade lymphoma,’’ ‘‘probable high-grade lymphoma, other differ-
ential diagnoses not excluded,’’ or ‘‘other diagnosis’’ such as glioma or
metastasis. The accuracy of the intra-operative diagnosis was graded as
‘‘complete correlation’’ if intra-operative diagnosis of lymphoma was
confirmed by histological diagnosis based on paraffin-embedded speci-
mens, ‘‘partial correlation’’ if lymphoma had been considered during the
surgical procedure but other diagnoses could not be ruled out, and ‘‘no
correlation’’ if intra-operative diagnosis did not include lymphoma and
the diagnosis of PCNSL was based solely on the paraffin-embedded
material) [31].
Clinical follow-up
Clinical follow-up was recorded until July, 2002. All clinical records
available from the archive of the Department of Stereotactic Neuro-
surgery were reviewed. In the majority of cases, the patients had been
referred from other medical institutions, which limited the available
information on the preclinical patient history to data provided by the
Primary CNS lymphoma in immunocompetent patients from 1989 to 2001 833

referring physicians. Usually, the patients were also treated in the exter- Table 1. Characteristics of 164 patients at diagnosis and therapy
nal hospitals they came from, or community-based hospitals close to modality
their home towns. These institutions, and=or general practitioners re-
sponsible for the patient’s care, were contacted by phone, fax, or mail Number of
and asked to complete a questionnaire. Information on the therapy patients (%)
modality, the clinical response, the relapse-free interval and the overall
Sex male 89 (54.3)
survival was requested. Generally, patients were placed into one of four
female 75 (45.7)
treatment categories: 1) those treated with RT only who received the full
dose as planned after diagnosis (at least 40 Gy whole brain irradiation); Age (y) <65 98 (59.8)
2) those treated by combined RT and CHT; 3) those who received
65 66 (40.2)
supportive therapy only because of severe neurological deficits and poor Localization single 90 (54.9)
clinical performance status or who had such rapidly progressive disease multiple 71 (43.3)
that the planned therapy could not be completed (either the full dose of unknown 3 (1.8)
radiation was not reached, or the chemotherapy cycles were interrupted);
Infratentorial supratentorial only 135 (83.3)
and 4) those who received novel therapeutic modalities such as high-
involvement supra- and infratentorial 12 (7.3)
dose chemotherapy with stem cell rescue. Any documented change in
infratentorial only 14 (8.5)
response to therapy including neuroradiological evidence of tumour
unknown 3 (1.8)
regression, restitution of neurological deficits, and disruption of a pre-
viously progressive clinical course of the disease was considered as im- Bilateral unilateral 109 (66.5)
provement of the clinical condition. involvement bilateral 52 (31.7)
unknown 3 (1.8)
Preoperative yes 38 (23.2)
Statistical considerations corticoid no 99 (60.4)
treatment unknown 27 (16.5)
Data are presented as means and, if appropriate, as medians for
quantitative variables and as frequencies=percentage for qualitative Therapy radiation only 47 (28.7)
variables. Comparisons between treatment groups, age groups, and combined CHT=RT 65 (39.6)
groups as defined by year of diagnosis were performed with the other (high dose chemotherapy) 8 (4.9)
Mann-Whitney rank sum test and Fisher’s exact test (for binary data). not completed=supportive only 40 (24.4)
The difference in frequency of diagnosis was evaluated with a chi- unknown 4 (2.4)
square test, grouping cases by year of diagnosis. The probability of
survival was estimated by the Kaplan-Meier method. Differences
between subgroups were analyzed with the log-rank test. Only vari- Histology
ables reaching a significance level of p < 0.1 in the univariate test
were included in the multivariate analysis. Cox stepwise regression The final histological diagnosis of high-grade lym-
was used for multivariate analysis of possible prognostic variables.
The accepted significance level was 0.05. Software used for statis-
phoma was documented in 157 cases. In seven cases,
tical analysis and generation of graphics was the Statistical Package the intra-operative diagnosis of lymphoma, which was
for Social Sciences (SPSS, Chicago, Illinois), and the language and based on methyleneblue-stained smear=touch prepara-
environment for statistical analysis ‘‘R’’ [27].
tions, could not sufficiently be confirmed in the paraffin-
embedded material at the time of the surgical procedure
Results due to extensive necrosis. In all these seven cases, patients
had been treated with corticosteroids prior to the biopsy.
Patients’ characteristics and frequency of newly Additional immunohistochemical studies using advanced
diagnosed cases of PCNSL antigen retrieval and current staining procedures con-
firmed the diagnosis of lymphoma in five out of these
Among the 210 cases of cerebral lymphoma diag- seven cases. In two cases, the available paraffin material
nosed between 1989 and 2001 we identified 164 cases was too small for additional studies, and the diagnosis
of PCNSL in immunocompetent patients, excluding 34 was based on the report on intra-operative cytological
patients with immunosuppression and 12 cases due to findings. There was no statistically significant association
lack of sufficient clinical data. The mean age of the between pre-operative corticosteroid treatment and accu-
patients was 61.7 years (range, 28–84 years); 54.3% were racy of the intra-operative diagnosis. Based on immuno-
male and 45.7% were female. Their clinical characteris- histochemical studies, 162 were classified as diffuse large
tics, tumour localization, and therapy are summarized in B-cell lymphoma (DLBCL), and two cases were classi-
Table 1. The absolute number of PCNSL cases per year fied as T-cell lymphoma.
did not show any statistically significant trend. Also, the
percentage of PCNSL in relation to all brain tumours did
Clinical symptoms and tumour localization
not significantly change over time. PCNSL represented
on average 3.9% of all intracranial tumours diagnosed The initial presenting sign, defined as the first symp-
by stereotactic brain biopsy from 1989 to 2001. tom noticed by the patients or relatives, was documented
834 F. Feuerhake et al.

Table 2. Clinical symptoms and signs and time to diagnosis in cases correlating clinical features such as localization, multi-
with available pre-operative clinical history (n ¼ 160)
plicity, or presenting symptoms with survival, none of
Symptoms Total (%) Median time Median the parameters reached a significance level of p< 0.01.
to diagnosis survival
(months) (months)

Focal neurological deficit 70 (43.8) 2.0 6.0

Changing treatment modalities over time
Psychological symptoms 42 (26.3) 2.0 7.5
In 160=164 cases, clinical information on whether
Ataxia=co-ordination deficit 15 (9.4) 2.0 5.0
Headache 14 (8.8) 2.0 13.0 combined CHT=RT or RT only had been used was avail-
Generalized seizures 9 (5.6) 2.0 53.0 able. From 1989 to 1993, RT alone was the predominant
Raised ICP 6 (3.8) 1.0 8.0 treatment mode. The minority of patients treated with
Visual symptoms and signs 4 (2.5) 1.0 27.5
CHT in addition to RT usually received variable pro-
tocols without HD-MTX. Starting in 1994, the use of
in 160 of 164 cases. The most common initial signs were combined treatments increased markedly and the proto-
focal motor or sensory neurological deficits (43.8%), cols more consistently included HD-MTX. After 1998,
followed by psychological symptoms (26.3%) such as RT alone was only used if patients were not eligible for
decline in the level of alertness or changes in mood chemotherapy as part of supportive therapy (Fig. 1).
and=or personality (Table 2). Ataxia and disturbance More recently, an increasing number of patients was
of co-ordination without focal deficits were reported in treated with high-dose chemotherapy and stem cell res-
9.4% of cases. Of interest, these cases were character- cue, as part of a clinical pilot study [15].
ized by a relatively unfavorable prognosis. Generalized
seizures were relatively rare as an initial presenting symp-
tom (in only 5.5% of cases as presenting symptom);
however, there was a striking association of this symp-
tom with a favorable prognosis. Information on the
tumour localization was available in 161 of 164 cases.
Multiple intracerebral lesions were described in 71
(44.1%) of 161 cases, in 52 (32.3%) of 161 cases as a
bilateral tumour manifestation and in 12 (7.5%) of 161
as supra-and infratentorial localization. Isolated infra-
tentorial lymphoma localization was reported in only
two cases (1.2%). The majority of cases (135 of 161;
83.9%) showed only supratentorial involvement. Infra-
tentorial localization was not significantly associated with
the initial presenting symptoms of ataxia=disturbance of
co-ordination, and no statistically significant correlation
was found between infratentorial localization and any of Fig. 1. Change of treatment modalities over time. (RT radiation ther-
the clinical outcome parameters. In the univariate analysis apy; CHT chemotherapy)

Table 3. Patients’ characteristics and clinical outcome in relation to therapy modality

Supportive Radiation Combined High-dose Total

therapy therapy only chemotherapy= chemotherapy (n ¼ 160)
(n ¼ 40) (n ¼ 47) radiation (n ¼ 65) (n ¼ 8)

Age (y) 65.3 65.2 58.2 55.2 61.9

Sex (m:f) 19:21 23:24 37:28 7:1 86:74
Multiple localization 14=38 (36.8%) 22=47 (46.8%) 31=64 (48.4%) 1=8 (12.5%) 68=157 (43.5%)
Bilateral involvement 12=38 (31.6%) 15=47 (31.9%) 21=64 (32.8%) 1=8 (12.5%) 49=157 (31.2%)
Infratentorial involvement 6=38 (15.8%) 9=47 (18.5%) 8=64 (12.5%) 2=8 (25%) 25=157 (15.9%)
Mean survival (months) 1.8 17.9 25.4 29 17.5
Median survival (months) 1 10 14 28 7.5
Improvement of clinical condition 0% 51.1% 71.4% 100% 48.7%
Primary CNS lymphoma in immunocompetent patients from 1989 to 2001
Overall clinical outcome in PCNSL from 1989–2001
The median follow-up time for all 164 patients was
7.5 months (mean, 17.5 months; range, 1–122 months).
A clinical response was reported for 48.7% of the
cases. Table 3 summarizes the patient characteristics
in each of the therapy groups, across the entire series
(n ¼ 160; in 4 cases the therapy modality was not avail-
able for analysis). Patients who received combined
therapy were generally younger (58.2 years) than pa-
tients who received RT only (65.2 years) or supportive
therapy (65.3 years). Among those who received only
supportive therapy, the median survival was 1 month
(mean, 1.8 months). None of these patients showed
substantial improvement of their clinical condition for
more than a couple of weeks in the postoperative
period. The small group of patients (n ¼ 8) who received
high-dose chemotherapy had a median survival of 28
months (mean, 29 months), and in all these patients a
persistent improvement of the clinical symptoms was
recorded. To address the question of whether the avail-
ability of combined CHT=RT with HD-MTX improved
clinical outcome in PCNSL patients in general, we com-
pared the survival of patients diagnosed 1989–1993 with
patients diagnosed since 1994, the time when in our
series the use of the novel treatment modality became
more widely accepted. Overall, the median survival of
patients diagnosed 1994–2001 was longer (9 months)
than in those diagnosed 1989–1993 (6 months)
(p ¼ 0.008, Fig. 2).
Fig. 2. Median survival of patients diagnosed from 1994 to 2001 was
longer than that of patients diagnosed from 1989–1993. The
statistical significance of this difference in the univariate analysis
was not held up in the multivariate analysis when age was included as
variable (see text)
835
Comparison of combined CHT=RT versus RT only
We performed the statistical comparison between pa-
tients treated with RT versus combined CHT=RT in the
subset of 112 patients who received a complete course
of planned therapy. As a first assessment of treatment
effect, we generally asked if patients treated with com-
bined CHT=RT had a better outcome than those treated
with RT only. The difference was significant in the uni-
variate analysis (p ¼ 0.029). However, when age was
included in the multivariate analysis, the difference
was not longer significant. Given that the CHT protocols
used from 1989–1993 largely did not contain HD-MTX
and thus were likely to be ineffective in PCNSL, a se-
parate analysis was necessary to distinguish between
patients diagnosed 1989–1993, and those diagnosed
since 1994 when the more effective treatment was more
Fig. 3. Survival analysis before and after introduction of combined
therapy modalities a) From 1989–1993, patients treated with additional
chemotherapy (CHT=RT) did not show longer survival than after RT
only. b) From 1994 to 2001, there was a trend towards longer survival
after combined therapy (not significant, see text)
836
commonly used. From 1989–1993, 29 patients received
RT only (mean age, 64 years), and 13 patients were
treated with additional CHT (mean age, 52 years). The
survival was not different between those groups (Fig. 3a).
From 1994–2001, 18 patients were treated with RT only
(mean age, 68 years), and 52 received combined treat-
ment (mean age, 60 years). Median survival was longer
after combined CHT=RT (median survival, 14 months;
2-year survival, 35.7%) than after RT only (10 months,
2-year survival 26.2 years, p ¼ 0.108) (Fig. 3b). Since
age is reportedly associated with prognosis in PCNSL,
and patients were clearly younger in the combined
CHT=RT group, we included age in our analysis. Expect-
edly, younger age was associated with favorable surviv-
al (median survival was 17 months in patients younger
than 65 years, and 7 months in patients 65 years and
older; p ¼ 0.0085). The multivariate analysis in the sub-
group of patients who received a complete course of
treatment from 1994 to 2001 confirmed that age, but
not choice of therapy was significantly correlated with
survival (Age, p ¼ 0.016; Therapy, p ¼ 0.164).
Discussion
The present series covers a time of significant change
of the standard therapy recommendations for PCNSL.
Combined CHT=RT containing HD-MTX gradually
replaced the former widely accepted stand-alone whole-
brain RT as standard treatment. Asking what the impact
of the novel treatment modalities on clinical outcome
was over time, we found a longer overall median survi-
val in PCNSL from 1994–2001 than before 1994, and a
survival advantage for patients treated with combina-
tion CHT=RT 1994–2001 over patients treated with RT
only during the same period of time. The overall survival
in our series was a little longer than in a previously
published series of PCNSL patients that was based on
a tumour registry [32]. However, survival was shorter
than that reported in several previous retrospective stud-
ies performed at haemato-oncological centres [7, 13,
29, 30]. This observation most likely reflects that our
patient population includes patients in poor clinical con-
dition, who received only supportive treatment and=or
did not complete the planned course of therapy. Also,
patients who were referred to our clinic for histopatho-
logical confirmation of presumed PCNSL were often
treated in community-based hospitals without extensive
experience with this disease, which was recently found
to be associated with poorer outcome than treatment in
specialized centres [17].
F. Feuerhake et al.
Patients receiving chemotherapy and RT had a longer
median survival, a twofold higher two-year survival rate,
and a higher response rate than patients who received
RT only; however the survival advantage as detected in
the univariate analysis was not upheld in the multivar-
iate analysis. In contrast, the correlation between the
patients’ age and clinical outcome was statistically sig-
nificant in the multivariate analysis, which supported
previous reports claiming that the patients’ age is one
of the most important prognostic factors [4, 8, 13].
Clearly, the survival analysis should be interpreted with
some caution, given that the retrospective approach
requesting more than 10 year-old patient data from dif-
ferent medical institutions did not allow for a detailed
analysis of single treatment components and exact ra-
diation doses. However, our findings are consistent with
recent data from a large single-center study [29] and
confirm that the potential benefit of novel therapy ap-
proaches, in general clinical practice, is less significant
than that documented in smaller Phase II studies.
In both patient groups, those treated with combined
CHT=RT and those who received RT only, the outcome
was variable with single patients surviving up to 4 years.
This clinical heterogeneity was not well explained by
patient characteristics such as age and tumour locali-
zation, or choice of therapy, and suggests that a small
subset of PCNSL patients is more likely to respond to
therapy and to achieve a permanent remission than the
majority of cases. Currently available prognostic sys-
tems [8], aiming at predicting prognosis under current
standard treatment, provide important information; how-
ever, they do not address the underlying causes for clin-
ical heterogeneity of the disease. Further basic research
is needed to understand the molecular mechanisms that
determine different clinical behavior of PCNSL, and to
develop risk-adjusted therapy approaches.
In our institution, the annual number of newly diag-
nosed PCNSL cases did not show a significant increase
between 1989 and 2001; instead, a slightly decreasing
trend was observed. Changes in the annual patient
numbers in a single center can only represent an esti-
mate of epidemiological trends, particularly in a rare
disease in which even the population-based epidemio-
logical studies produced conflicting results on trends
in PCNSL incidence in the past. However, a continuing
steep increase of PCNSL incidence as predicted by
some authors [3] seems unlikely based our experience
from 1989 to 2001.
Previous reports claiming that the diagnosis of
PCNSL is frequently obscured by pre-operative cortico-
Primary CNS lymphoma in immunocompetent patients from 1989 to 2001
steroid treatment [10, 28] were recently questioned in a
larger study [11], raising the question of whether it is
still justified to postpone corticosteroid treatment until
the diagnosis is histologically confirmed. In the present
series, we did not observe a statistically significant cor-
relation between an accurate intra-operative diagnosis
and pre-treatment, but we found that all patients in
whom the final diagnosis based on paraffin-embedded
material was complicated by extensive necrosis had
been treated with corticosteroids. Our results show that
corticosteroids may complicate the final diagnosis in
single cases, indicating that this treatment should be
postponed if possible from a clinical point of view.
In conclusion, the presented results confirm that the
overall survival of a majority of PCNSL patients re-
mained low despite the availability of novel therapies
and remarkable improvements for certain subgroups of
patients. The present study underlines the need to un-
derstand the molecular basis for the variable response
to therapy, and to further reduce the number of patients
who are not eligible for aggressive treatment at time of
diagnosis. Improving PCNSL management in general
practice will require an interdisciplinary effort involving
neurosurgeons, neurologists, haemato-oncologists, neu-
roradiologists, and neuropathologists. Ongoing clinical
trials [15, 26] that aim at improving the treatment pro-
tocols themselves are one central element in this pro-
cess. Further important factors are early histological
confirmation of diagnosis, a straight-forward subsequent
diagnostic process, and development of therapeutic op-
tions for patients in poor clinical condition. Our results
also support recent recommendations to treat PCNSL
preferably in neuro-oncological centres that provide
the specific expertise in the haemato-oncological, neu-
rological, neurosurgical, as well as the physiological as-
pects [33] of the disease.
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Comment
A well written paper containing data that will be useful for assessing
the development of treatment for PCNSL. Specifically, the pathology
seems to have been well performed and the survey has been controlled
by ensuring that a histological diagnosis was made in the 164 cases. The
authors have made some distinction between treatment early in the test
period and later in the test period.
R. O. Weller
Southampton
Correspondence: Friedrich Feuerhake, Department of Neuropathol-
ogy, University Clinic of Freiburg, Neurozentrum Breisacher Strasse
64, 79106 Freiburg, Germany. e-mail: friedrich_feuerhake@uniklinik-
freiburg.de