Incidence, Clinical Features, Treatment and Outcome ofPrimary Central Nervous System Lymphoma in Norway

A Ten-year National Survey

Ingfrid Salvesen Haldorsen, Jan Harald Aarseth, Aase Hollender, John Ludvig Larsen,Ansgar Espeland and Olav Mella

From the Department of Radiology (I.S. Haldorsen, J.L. Larsen, A. Espeland), the Department of Neurology (J.H.Aarseth), the Department of Oncology and Medical Physics (O. Mella), Haukeland University Hospital, Bergen,Norway, and the Department of Oncology, the Norwegian Radium Hospital, Oslo, Norway (A. Hollender)

Correspondence to: Ingfrid Salvesen Haldorsen, Department of Radiology, Haukeland University Hospital, 5021Bergen, Norway. Tel: 47-55972327. Fax: 47-55975140. E-mail: ingfrid.haldorsen@helse-bergen.no

Acta Oncologica Vol. 43, No. 6, pp. 520�/529, 2004

The incidence of primary central nervous system lymphoma (PCNSL) has been reported to increase in some parts of the world, while beingstable in other regions. In an attempt to characterize the incidence rate, clinical features, treatment, outcome, and prognostic factors ofPCNSL in Norway, we report our experience in a large unselected series of patients. Clinical features, histological diagnosis, radiologicalfindings, treatment, and outcome of all patients diagnosed with PCNSL in Norway in the years 1989�/1998 were registered. During the10-year period 58 new cases of histologically verified PCNSL were registered in Norway. The annual incidence rate of PCNSL was on average1.34 cases per million people with a non-significant increasing trend (p�/0.069). For patients diagnosed before death (n�/45) the estimatedsurvival following histological diagnosis was 55%, 47%, and 23% at 1, 2, and 5 years, respectively. In Cox-regression analysis age, WHOperformance status and treatment had independent prognostic impact on survival. In the studied decade, there was a non-significant trendtowards increased incidence of PCNSL, perhaps due to increased availability of diagnostic imaging, especially magnetic resonance imaging.

Received 29 December 2003Accepted 10 May 2004

Primary central nervous system lymphomas (PCNSL)

are extranodal malignant lymphomas arising in the

brain, the spinal cord, the leptomeninges or the eyes,

with the absence of lymphoma outside the nervous system

at the time of diagnosis. In the last two decades an

increase in incidence of PCNSL in immunologically

normal as well as in immuno-compromised individuals

has been reported in the US (1, 2), Southeast England (3)

and Southeast Netherlands (4). In the same period, a

stable incidence of PCNSL has been found in studies

from the province of Alberta (Canada) (5), western

Denmark (6), Southeast Scotland (7), Hong Kong (8)

and northern India (9). These divergent findings suggest

regional differences in PCNSL incidence during the last

decades.

PCNSL may affect all age groups with a peak incidence

in the fifth to seventh decade and a median age in the

sixth decade in non-AIDS patients (10). The most

common clinical symptoms at time of diagnosis are

personality change, focal neurological deficit and symp-

toms of raised intracranial pressure (6, 10�/12).

Prognosis of PCNSL in patients receiving only sympto-

matic therapy is extremely poor with a median survival

of 2�/3 months (13). After short-term steroid treatment

15�/25% of the tumours show dramatic volume shrinkage

but this lasts only a few weeks in the majority of patients

(14). Radiotherapy was earlier considered the mainstay of

therapy, and it will normally induce complete or partial

tumour regression. Few patients, however, are cured with

radiation alone and the survival time is often reported to be

12�/16 months, with only 3�/4% long-term survivors (15). A

combination of radiotherapy and chemotherapy has sub-

stantially improved survival in the last decade with a

reported median survival of up to 42 months and a 5-year

survival of 22�/40% (16, 17). The disadvantage of this

combination is the well-documented long-term treatment-

induced neurotoxicity, especially affecting the age group of

over 60 (16, 18). Chemotherapy alone has a well-documen-

ted effect on PCNSL and seems to cause less neurotoxic

sequelae than the combination of radio- and chemotherapy,

perhaps at the cost of a little decreased median survival

(19, 20).

�ORIGINAL ARTICLE �

# Taylor & Francis 2004. ISSN 0284-186X Acta Oncologica

DOI: 10.1080/02841860410015640

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The aims of this retrospective study were to investigate

the incidence rate, clinical features and therapeutic outcome

of a population of patients with PCNSL comprising all

patients with histologically verified diagnosis in Norway

during a 10-year period. Our material represents an

unselected patient population from a well-defined and

circumscribed geographical region, comprising an entire

country with a population of 4.4 million (1998). The

registration of cancer in Norway is very reliable because

all new cases of cancer are required by law to be reported to

the Norwegian Cancer Registry by involved physicians and

pathology laboratories. The unselected nature of the

material in this study makes it suitable for investigating

trends such as alterations of incidence.

MATERIAL AND METHODS

A complete list of all patients recorded as PCNSL in

Norway from 1 January 1989 to 31 December 1998 (n�/

101) was obtained from the Norwegian Cancer Registry.

The majority of the patients (n�/95) were diagnosed and

treated at one of the 5 major university hospitals in Norway.

During a period of 4 months the first author visited all the

university hospitals in order to go through the complete

medical records of these patients. The medical records of

the remaining 6 patients diagnosed at other hospitals were

sent to the authors by mail. Clinical features, morphologic

diagnosis, radiological findings, medical treatment, and

outcome were registered.

A total of 58 patients with histologically or cytologically

verified PCNSL were diagnosed and treated in Norway in

the studied decade. We excluded 27 of the 101 patients

recorded as PCNSL because we found they had lymphoma

in other locations at the time of diagnosis (n�/10),

intraspinal extradural tumour involving vertebral corpora

(n�/6), plasmocytoma (n�/3), Langerhans cell histiocytosis

X (n�/3), or only clinical and radiological signs of PCNSL

without histologic verification (n�/5). A further 16 HIV-

infected patients diagnosed with AIDS-related PCNSL were

also excluded from the following evaluation.

For the present study, we analysed data from the

remaining 58 patients with histologically or cytologically

verified PCNSL diagnosed in 1989 to 1998. The histo-

pathological material has been re-examined and the

findings will be presented in a separate publication. In

none of the patients has this review led to a change in

diagnosis.

Statistical analysis

Calculation of the incidence rates was based on the number

of new cases with primary central nervous system lym-

phoma each year and the population in Norway as at 1

January in the same year. The trend test and 95%

confidence intervals for incidence were calculated according

to the Poisson distribution.

Duration of survival was calculated as time between date

of procedure (operation/biopsy/cytology) that led to con-

clusive histologic diagnosis and date of death or 1 May 2002

if still alive. Survival curves were calculated and plotted

using the method of Kaplan and Meier (21). For univariate

comparison of survival curves the log-rank test was used.

The Cox Proportional Hazard Model was used to study the

effect on survival of several factors simultaneously and to

estimate hazard ratios (22). The assessment of the propor-

tional hazard assumption was done by comparing the Cox

model with a time dependent model (23). All p-values in the

analyses are two-sided. The analyses were performed with

StatXact, SPSS, and S-plus.

RESULTS

Incidence of PCNSL

During the 10-year period from 1 January 1989 to 31

December 1998 58 patients were identified with morpholo-

gically verified non-AIDS related PCNSL. The average

annual incidence rate of PCNSL in the population of

Norway during the period was 1.34 cases per million (95%

confidence interval: 1.02�/1.74). Fig. 1 shows the number of

patients diagnosed with PCNSL each year. There was a

trend towards but not significant increase in annual

incidence (p�/0.069).

Clinical and histological assessment

The diagnosis of PCNSL in our material was established

pathologically by either open biopsy (n�/29), stereotactic

biopsy (n�/14), or cytology of cerebrospinal fluid (n�/2). In

13 patients the diagnosis was first established by autopsy.

The diagnosis was based on both routine light microscopic

and in most cases (n�/44) also immunohistochemical

examinations performed at the time of initial presentation.

Fifty-three out of 58 specimens were analysed at university

hospital pathology laboratories.

Three of the patients had received immuno-suppressive

medication prior to diagnosis. One patient used sulfasalazin

for ulcerative colitis and one patient azathioprin after a

renal transplant. One patient used systemic steroids and

azathioprin for uveitis for one year prior to diagnosis.

In addition to a thorough physical examination, most

patients went through a list of supplementary radiological

and medical examinations at the initial diagnostic work-up

(Table I). In none of the patients was systemic lymphoma

found.

In addition to the 13 patients whose diagnosis was

established by autopsy, 5 of the patients had their diagnoses

confirmed by autopsy. In all of the cases the autopsies

confirmed that lymphoma was restricted to the central

nervous system. Of the remaining 40 patients without

autopsies confirming that lymphoma was restricted to the

central nervous system, 38 patients (95%) had a negative

Acta Oncologica 43 (2004) Primary nervous system lymphoma in Norway 521

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ultrasound and/or computerized tomography (CT) of the

abdomen/pelvis and 32 patients (80%) had a negative bone

marrow biopsy.

Clinical features

The characteristics of the patient population are given in

Table II.

The overall male/female ratio was 29/29. The median

age was 68 years (range 11�/83), with only 10 patients (17%)

aged less than 50 years at the time of histological diagnosis.

At time of initial presentation the most common symptoms

were personality changes (53%) and focal neurological

symptoms (53%), usually hemiparesis.

The WHO performance status at time of histological

diagnosis was specified in the medical records of 17 patients.

For the rest of the patients diagnosed while alive (28

patients), the performance status was estimated retrospec-

tively according to clinical information from the medical

records. Twenty-seven patients had a good or relatively

good performance status (WHO 0�/2) and 18 patients

had poor performance status (WHO 3�/4) at time of

diagnosis.

The findings on computerized tomography (CT) or

magnetic resonance imaging (MRI) are based on the

ordinary radiological reports. Forty patients (69%) had a

single detectable lesion on CT/MRI at the time of diagnosis.

Multiple lesions were present in 13 (22%) patients. For the 5

(9%) patients not having visible expansive lesions on CT or

MRI, two patients had signs of an old infarction, and one

had extensive cerebral atrophy. One patient had signs of

increasing subdural haematoma and another signs of

encephalitis. Ten (43%) of the 23 patients diagnosed in

1989 to 1993 had MRI in the course of the initial diag-

nostic work-up and 27 (77%) out of 35 diagnosed in 1994 to

1998.

The median duration of symptoms before histological

diagnosis was 13 weeks (range 0�/183) for all patients, 9

weeks (range 0�/183) for those diagnosed before death,

and 13 weeks (range 0�/119) for those diagnosed post

mortem.

Fig. 1. Number of cases diagnosed with PCNSL each year in Norway.

Table I

Examinations undertaken at the initial diagnostic work-up (n�/58)

Examinations undertaken Patients diagnosed while alive (n�/45;

20 men, 25 women)

Patients diagnosed after death (n�/13;

9 men, 4 women)

n % n %

X-ray of the chest 45 100 12 92

CT of the chest 17 38 1 15

Abdominal ultrasound and/or CT of

the abdomen and pelvis

40 89 5 39

Bone marrow biopsy 33 73 2 15

522 I. Salvesen Haldorsen et al. Acta Oncologica 43 (2004)

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Primary treatment

There was no consensus on primary treatment concerning

PCNSL in Norway in the period studied, although some

patients were treated in accordance with joint Nordic

protocols in the later part of the interval. Twelve of the

13 patients diagnosed after death had received no chemo-

or radiotherapy and one patient had received chemo-

therapy.

The 45 patients whose diagnosis was verified histologi-

cally before death had received a wide spectrum of

treatment (Table III). Nine (20%) of the 45 patients did

not receive any chemo- or radiotherapy. These patients had

a mean age of 72.6 years (compared with 62.9 in the

material as a whole). Two of them died suddenly in the

postoperative period; the other 7 had a poor general

condition, which excluded them from active therapy.

Six (13%) of the 45 patients received chemotherapy alone

with various regimens. Three patients had received a

combination of intravenous (i.v.) chemotherapy and in-

trathecal (i.t.) chemotherapy, while three patients had only

i.v. chemotherapy.

Seven (16%) of the 45 patients received only radiotherapy

consisting of total brain irradiation with an average dose of

43 Gy (range 30�/54 GY) given in 10�/28 fractions. In two of

the patients the therapy included booster fractions towards

the tumour.

Twenty-three (51%) of the 45 patients had received both

chemo- and radiotherapy. In 21 patients the treatment with

various chemotherapy regimens preceded the radiotherapy.

In two cases the chemotherapy was preceded by radiation.

Twelve of the patients had intrathecal (i.t.) methotrexate

and/or cytarabin in addition to intravenous (i.v.) regimens.

One patient had only i.t. methotrexate and 10 patients only

i.v. chemotherapy. Of the 22 patients who received i.v.

chemotherapy, 13 received high-dose methotrexate with

folic acid rescue either alone or in combination with other

chemotherapy. Six of the regimens included the CHOP

(cyclophosphamide, adriamycin, vincristine, and predni-

sone) and four included cytarabin. One patient had addi-

tional chemotherapy with i.v. etoposid and carboplatin at

the time of recurrence 6 months after initial therapy. The

radiotherapy consisted initially of total brain irradiation

with an average dose of 45 Gy (range 20 Gy�/50 Gy) given

in 5�/28 fractions. In 17 of the patients the dosage was

partly given as a booster towards the macroscopic tumour.

One patient received an additional radiation of the spine (30

Gy) and one patient received fractions towards the eyes (30

Gy and 40 Gy) months after the initial brain irradiation.

Of the 30 patients who received chemotherapy, the

treatments had been initially well tolerated in 20 patients.

Four patients had elevation of blood creatinine after i.v.

high-dose methotrexate, and one patient developed a rash

secondary to methotrexate therapy. Two patients had

septicaemia and another patient meningitis. One patient

had a deep venous thrombosis and another patient

pulmonary oedema with resulting death after a few days.

Data on late neurotoxicity have not been available for

evaluation.

Outcome

For the 45 patients diagnosed before death the overall

estimated survival following histological diagnosis was 55%,

47%, and 23% at 1, 2, and 5 years, respectively (Fig. 2) and

the median survival was 22 months. For the 13 patients

diagnosed post mortem the median survival from initial

symptoms was 3 months and only 15% were alive 1 year

after initial symptoms.

In the group of patients diagnosed while alive the survival

curve seemed greatly influenced by the treatment (Fig. 3).

The 23 patients receiving both chemo- and radiotherapy

had a median survival of 49.2 months, compared with 0.9

months in the untreated group (9 patients). The correspond-

ing median survival times for the patients receiving only

Table II

Clinical features of patients with primary central nervous system

lymphoma

Categorical variables n %

Sex, n�/58

Female 29 (50)

Male 29 (50)

Symptoms on admission, n�/58

Focal neurological 31 (53)

Personality change 31 (53)

Cerebellar symptoms/vertigo 24 (41)

Increased intracranial pressure 23 (40)

Visual disturbance 9 (16)

Epilepsy 7 (12)

Performance status at histological

diagnosis, n�/45

WHO 0�/2 27 (60)

WHO 3�/4 18 (40)

Cerebrospinal fluid examination

with regard to

Malignant cells, n�/24 3 (13)

Elevation of cell count, n�/18 12 (67)

Elevation of total protein, n�/14 8 (57)

Decrease of glucose, n�/3 1 (33)

Lesions on CT/MR, n�/58

No detectable expansive lesion 5 (9)

Single 40 (69)

Multiple 13 (22)

Opthalmologic examination, n�/12

Normal or irrelevant pathology 8 (67)

Uveitis 4 (33)

Continuous variables Mean Median Range

Age at diagnosis (years), n�/58 62.9 68.3 11�/83

Time until diagnosis (weeks), n�/58 21.7 12.8 0�/183

Acta Oncologica 43 (2004) Primary nervous system lymphoma in Norway 523

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radiotherapy (7 patients) or only chemotherapy (6 patients)

were 16.7 months and 2.7 months, respectively.

Table IV summarizes the univariate survival analysis

of possible prognostic factors for survival for the patients

diagnosed while alive. Factors found to be significant

were treatment (pB/0.001), WHO performance status

(pB/0.001), age (p�/0.001) and malignant cells in cere-

brospinal fluid (p�/0.044). A multivariate Cox Proportional

Table III

Age, sex, performance status, primary treatment regimens, and survival after histopathological diagnosis in the 45 patients diagnosed while alive

Age Sex Perf. status Chemotherapy Radiotherapy Survival (months)

No chemo- or radiotherapy (n�/9)

55 F 4 No No 0.9

67 M 4 No No 0.4

70 F 1 No No 1.0

72 M 4 No No 0.3

73 F 4 No No 0.7

77 M 4 No No 0.6

78 F 4 No No 0.9

80 M 3 No No 5.4

81 F 4 No No 2.2

Only chemotherapy (n�/6)

11 M 1 Vincristine, Mesna Ara C:i.v., MTX, Ara C:i.t. No Alive 73.4

13 M 1 MTX, Ara C, vincristine i.v., MTX i.t. No Alive 62.7

53 F 4 MTX i.v. No 3.7

57 M 4 MTX, vincristine i.v. No 2.7

69 F 2 CHOP i.v., MTX i.t. No 1.6

75 M 1 Ara C i.v. No 0.4

Only radiotherapy (n�/7)

54 M 3 No 54 GY 11.0

59 F 2 No 44 GY 16.7

72 M 1 No 50 GY 56.1

76 F 3 No 30 GY 39.6

78 F 1 No 54 GY 31.9

79 F 1 No 34 GY 2.3

81 F 3 No 40 GY 1.8

Radio- and chemotherapy (n�/23)

Pre-irradiation chemotherapy (n�/21)

30 F 1 MTX i.v., MTX i.t. 48 GY Alive 70.0

46 M 1 MTX i.v. 50 GY Alive 77.6

48 M 1 CHOP, MTX i.v. 50 GY Alive 102.7

49 F 1 CHOP i.v., MTX i.t. 50 GY Alive 81.1

49 M 1 MTX, etoposid, carboplatin i.v., MTX i.t. 50 GY 19.7

56 M 2 MTX i.v., MTX i.t. 50 GY 43.5

56 M 3 MTX i.t. 30 GY 2.5

56 M 1 MTX i.v., MTX i.t. 50 GY 63.6

56 M 1 MTX, BCNU, Ara C, vincristine i.v., MTX, Ara C i.t. 41 GY Alive 44.6

56 F 1 BCNU, vincristine, MTX i.v., MTX, Ara C i.t. 50 GY Alive 42.1

58 M 1 MTX i.v. 50 GY 38.6

60 F 3 CHOP i.v. 50 GY 21.6

66 F 1 Ara C i.v. MTX i.t. 46 GY Alive 91.3

67 F 4 MTX i.v., MTX i.t. 50 GY 5.4

68 M 1 CHOP i.v. 38 GY 52.7

71 M 1 MTX i.v. 50 GY 49.2

71 F 2 Ara C i.v., MTX i.t. 24 GY 7.1

72 F 1 CHOP i.v. 50 GY 6.4

72 F 2 Ara C i.v., MTX i.t. 20 GY 56.8

74 F 3 MTX i.v. 46 GY 29.7

75 F 1 MTX i.v., MTX i.t. 50 GY 23.8

Post-irradiation chemotherapy (n�/2)

44 F 4 MTX i.v. 9 GY�/30 GY Alive 105.7

60 F 2 CHOP i.v. 50 GY 27.5

524 I. Salvesen Haldorsen et al. Acta Oncologica 43 (2004)

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Hazard Model including the variables age, WHO perfor-

mance status and treatment (no treatment/only chemother-

apy/only radiotherapy versus radio-chemotherapy) showed

that all three variables had a statistically significant effect

on survival. The hazard ratio for age was 1.05 (95%

confidence interval: 1.02�/1.08, p�/0.002). WHO status

had a hazard ratio of 2.39 (95% confidence interval:

1.13�/5.09, p�/0.023) and the treatment a hazard ratio of

2.35 (95% confidence interval: 1.07�/5.18, p�/0.034). Since

cerebrospinal fluid (CSF) samples were available in only 19

cases, the variable with malignant cells in CSF was omitted

in this multivariate model.

Fig. 2. Kaplan�/Meier survival curve with 95% confidence interval from date of histological diagnosis for 45 patients diagnosed pre mortem

(10 censored). Median survival: 22 months. Vertical axis represents proportion of patients still alive.

Fig. 3. Kaplan�/Meier survival curve from date of histological diagnosis for patients with different treatment regimens, diagnosed pre

mortem. Patients receiving no treatment (9 patients, 0 censored), only chemotherapy (6 patients, 2 censored), only radiotherapy (7 patients, 0

censored) and a combination of chemo- and radiotherapy (23 patients, 8 censored). Vertical axis represents proportion of patients still alive.

Acta Oncologica 43 (2004) Primary nervous system lymphoma in Norway 525

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DISCUSSION

In the 10-year period studied we have registered 58

new cases of non-AIDS related and morphologi-

cally verified PCNSL in Norway. Our study is one of few

population-based materials published, and as far as we

know the only material covering the entire population of a

country.

The average annual incidence rate of non-AIDS related

PCNSL in the population of Norway during the 10-year

period studied was 1.34 new cases per million inhabitants.

These findings are relatively similar to those of Krogh-

Jensen et al. (24) who estimated the average annual

incidence rate in the population of a region of Denmark

to be 1.56 per million in the 10-year period 1983�/1992.

Relatively similar incidence rates have been reported from

Hong Kong (1.03 per million, 1982�/1997) (8), Alberta,

Canada (age-standardized incidence rates 0.178�/1.631 per

million, 1975�/1996) (5) and Southeast Netherlands (World

Standardized Rate of 2.3 and 1.7 cases per million males

and females respectively, 1989�/1994) (4). These incidence

rates contrast with those of Olson et al. (1), who, having

excluded never-married patients and patients of unknown

marital status (to exclude possible HIV infection), reported

an annual incidence rate of 4.8 per million in the period

1985�/1997, based on epidemiological data covering about

10% of the US population. However, Olson et al. based

their findings on data from the nine Surveillance, Epide-

miology and End Results (SEER) registries without a

review of the medical records. The review of the medical

records performed in the present study has led to exclusion

of 27 out of 85 patients with incorrect registration of

PCNSL, such as patients with systemic lymphomas. Similar

experiences have been reported in the Danish (24) and

Canadian study (5).

Table IV

Prognostic factors for survival in PCNSL: univariate analyses

n Median survival in

months (95% CI)

Log-rank test

(p value)

Treatment, n�/45 B/0.001

No treatment 9 0.9 (0.5, 1.3)

Only chemotherapy 6 2.7 (0.2, 5.3)

Only radiotherapy 7 16.7 (2.1, 31.2)

Chemo- & radiotherapy 23 49.2 (29.7, 68.8)

Age at diagnosis, n�/45 0.001

0�/60 20 43.5 (0.0, 87.5)

Above 60 25 5.4 (0.0, 12.2)

Sex, n�/45 0.46

Female 25 16.7 (0.0, 41.4)

Male 20 38.6 (0.0, 90.6)

Performance status, n�/45 B/0.001

WHO 0�/2 27 49.2 (27.7, 70.7)

WHO 3�/4 18 2.5 (1.4, 3.6)

Time to diagnosis (weeks), n�/45 0.99

0�/5.6 15 19.7 (0.6, 38.9)

5.7�/14.3 15 38.6 (0.0, 90.3)

above 14.3 15 16.7 (0.0, 39.9)

Year of diagnosis, n�/45 0.23

1989�/1993 15 11.0 (0.0, 25.2)

1994�/1998 30 31.9 (5.3, 58.5)

Lesions on CT/MR, n�/43 0.32

Single 33 23.8 (9.1, 38.5)

Multiple 10 5.4 (0.0, 78.6)

Malignant cells in CSF, n�/19 0.044

No 16 23.8 (0.0, 63.9)

Yes 3 2.5 (0.0, 5.9)

Raised protein level in CSF, n�/11 0.18

No 5 56.1 (0.0, 117.5)

Yes 6 3.7 (0.0, 26.3)

Operation prior to diagnosis, n�/43 0.28

Tumor resection 29 19.7 (1.2, 38.3)

Stereotactic biopsy 14 27.5 (12.7, 42.3)

526 I. Salvesen Haldorsen et al. Acta Oncologica 43 (2004)

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Despite mandatory cancer reporting to the Norwegian

Cancer Registry, some cases may not have been reported,

resulting in an underestimation of incidence. In addition, we

are aware of 5 patients in the Norwegian Cancer Registry

and 1 additional patient treated at a university hospital with

clinical and radiological signs of PCNSL that were never

histologically verified and are therefore not included in our

material. On the other hand, some of the patients in our

material could possibly have occult systemic lymphoma

since adequate staging regimens were not performed in all

of the patients. However, an autopsy that excluded systemic

lymphoma was performed in 18 of the patients. Of the

remaining 40 patients, 38 had a negative abdominal CT or

ultrasound and 32 a negative bone marrow biopsy, demon-

strating that the vast majority underwent relevant staging.

Furthermore, experiences from others indicate that systemic

lymphoma masquerading as PCNSL is a relatively rare

occurrence (in the order of 4%) (25, 26). All taken

together, we consider our estimate of incidence to be fairly

reliable.

The rarity of PCNSL makes statistical assessment of

incidence alterations difficult. In our 10-year study period

there was a trend towards but not significant increase in

annual incidence of PCNSL (p�/0.069). During this period

(1989�/1998) diagnostic imaging with MRI has been

increasingly available in addition to CT at the hospitals in

Norway. Four hospitals had MRI in 1988, 6 in 1991, 8 in

1993, and 17 in 1998. The observed slight increase in

PCNSL could therefore be due to more sensitive and

accurate diagnostic evaluation. Patients receiving immuno-

suppressive therapy, such as transplant patients, carry an

increased risk of developing PCNSL (27). As only 3 of the

patients in our study had received immuno-suppressive

treatment, it would seem that this factor has little influence

on the findings. There was no reliable registration of the

entity PCNSL at the Norwegian Cancer Registry in the

decades prior to 1989, so that comparable data before 1989

are not available. Future studies, however, will, it is hoped,

be able to establish whether there is a real increase in non-

AIDS related PCNSL in Norway.

The 58 cases of morphologically verified PCNSL ac-

counted for 1.7% of all primary brain tumours (tumours in

meninges, corpus pineale, hypophysis, and cranial nerves

excluded) recorded at the Norwegian Cancer Registry in the

studied 10-year period. Similar percentages have been

reported from Denmark (6) and India (9), while studies

from The Netherlands (4) and the US (28) have reported a

percentage of 4�/6%. Morphologically verified PCNSL

accounted for 0.9% of newly diagnosed non-Hodgkin’s

lymphomas recorded at the Norwegian Cancer Registry in

the studied period.

The median age at time of diagnosis in our study was 68

years, which is 5�/15 years above the findings reported in

most other studies (6, 10, 11, 18, 19, 27). Compared with

those studies a relatively high percentage (22%) of our

patients were diagnosed after death. Varying autopsy

frequencies and different indications for autopsy in the

specific countries could possibly influence the age at which

the patients have their diagnosis established. In our study,

however, the median age of the patients diagnosed while

alive did not differ significantly from those diagnosed post

mortem (67 and 70 years respectively). Another explanation

of the differences in median age could be that older patients

in some countries go through less aggressive diagnostic

evaluation resulting in under-registration of PCNSL in

older age groups. The increased availability and geographi-

cal distribution of MRI during the time period must also be

taken into account. Finally, it is possible that our findings

reflect a real difference in age at diagnosis for Norwe-

gian PCNSL patients compared with those in other

countries.

We found a male/female ratio of 1.0, which is similar to

other findings (6, 11), although a male predominance also

has been reported (19, 29). In our study the median time

span between first symptom and diagnosis was found to be

13 weeks, which is consistent with reports from other

groups (11, 30). The lag time before diagnosis has been

found by others to have prognostic value (31), but this was

not apparent in the present study.

The clinical features in our patients corresponded well

with the literature (6, 10, 11). Personality change and focal

neurological symptoms, usually hemiparesis, were the most

frequent symptoms prior to diagnosis. The CSF was

examined less often than expected in our material. Eleva-

tion of cell count was found in 67% of the samples and

elevation of total protein in 57% of the samples. This

corresponds to the findings of other groups, reporting

elevated cell count in 35�/75% and increased total protein

in 54�/85% of samples (10, 29). Likewise, our finding of

malignant cells in CSF in 13% of the samples corresponds

with findings by the same groups and demonstrates that

CSF cytology is unreliable for the exclusion of PCNSL.

The prognosis of primary central nervous system lym-

phoma is considerably worse than for most other lympho-

mas in spite of advanced therapy. The comparison of the

mortality rates in different studies is hampered by selection

bias and the fact that only a few studies are population

based. In the present population-based study the median

survival of the patients diagnosed before death was 22

months. This compares favourably with other population-

based studies (4, 5, 24). Although treated patients are

positively selected, survival in our study seemed greatly

influenced by the treatment. In accordance with other

studies, patients receiving radiotherapy or both chemo-

and radiotherapy had a significantly better survival than

patients receiving no therapy at all (11, 12, 15�/17, 29). It

was not possible to demonstrate a significantly better

survival among patients receiving only chemotherapy than

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among non-treated patients. However, this could be due to

the limited size of the series. The heterogeneity of the

chemotherapy and the radiation regimens applied and

the limited sample size makes it difficult to compare

the survival among patients receiving the different regim-

ens.

By univariate analysis we have demonstrated that young

age, good performance status, radiotherapy either alone or

in combination with chemotherapy, and lack of malignant

cells in CSF are associated with longer survival. Multi-

variate analysis confirmed the independent prognostic value

of age, therapy, and performance status. These findings

correspond with reports by other groups (11, 13, 15, 19, 29,

32).

In summary, the results of this national 10-year survey of

PCNSL are in agreement with data from single institutions

and regional surveys concerning clinical features and

response to therapy. The age at diagnosis is higher than in

most reports. There was a non-significant trend towards

increased incidence, perhaps related to increased availability

of diagnostic imaging, especially MRI.

ACKNOWLEDGEMENTS

This study was supported in part by grants from Amersham Health

AS and grants from Haakon and Sigrun Ødegaard’s Foundation.

Thanks are offered to the following institutions that have made

possible the review of the medical records of the patients treated at

their hospitals: Akershus University Hospital, Baerum Hospital,

Haukeland University Hospital, Hedmark Central Hospital, Laer-

dal Hospital, Rikshospitalet, Rogaland Central Hospital, St Olav

Hospital, the Norwegian Radiumhospital, Ullevaal University

Hospital, the University of Northern Norway Hospital and West-

Agder Central Hospital.

REFERENCES

1. Olson JE, Janney CA, Rao RD, et al. The continuing increase

in the incidence of primary central nervous system non-

Hodgkin lymphoma: a surveillance, epidemiology, and end

results analysis. Cancer 2002; 95: 1504�/10.

2. Corn BW, Marcus SM, Topham A, et al. Will primary central

nervous system lymphoma be the most frequent brain tumor

diagnosed in the year 2000? Cancer 1997; 79: 2409�/13.

3. Lutz JM, Coleman MP. Trends in primary cerebral lymphoma.

Br J Cancer 1994; 70: 716�/8.

4. Van der Sanden GA, Schouten LJ, van Dijck JA, et al. Primary

central nervous system lymphomas: incidence and survival in

the Southern and Eastern Netherlands. Cancer 2002; 94: 1548�/

56.

5. Hao D, DiFrancesco LM, Brasher PM, et al. Is primary CNS

lymphoma really becoming more common? A population-

based study of incidence, clinicopathological features and

outcomes in Alberta from 1975 to 1996. Ann Oncol 1999; 10:

65�/70.

6. Krogh-Jensen M, D’Amore F, Jensen MK, et al. Clinicopatho-

logical features, survival and prognostic factors of primary

central nervous system lymphomas: trends in incidence of

primary central nervous system lymphomas and primary

malignant brain tumors in a well-defined geographical area.

Population-based data from the Danish Lymphoma Registry,

LYFO, and the Danish Cancer Registry. Leuk Lymphoma

1995; 19: 223�/33.

7. Yau YH, O’Sullivan MG, Signorini D, Ironside JW, Whittle

IR. Primary lymphoma of central nervous system in immuno-

competent patients in south-east Scotland. Lancet 1996; 348:

890.

8. Au WY, Chan AC, Srivastava G, et al. Incidence and pathology

of primary brain lymphoma in Hong Kong Chinese patients.

Leuk Lymphoma 2000; 37: 175�/9.

9. Powari M, Radotra B, Das A, et al. A study of primary central

nervous system lymphoma in northern India. Surg Neurol

2002; 57: 113�/6.

10. Herrlinger U, Schabet M, Bitzer M, et al. Primary central

nervous system lymphoma: from clinical presentation to

diagnosis. J Neurooncol 1999; 43: 219�/26.

11. Bataille B, Delwail V, Menet E, et al. Primary intracerebral

malignant lymphoma: report of 248 cases. J Neurosurg 2000;

92: 261�/6.

12. Schlegel U, Schmidt-Wolf IG, Deckert M. Primary CNS

lymphoma�/Clinical presentation, pathological classification,

molecular pathogenesis and treatment. J Neurol Sci 2000; 181:

1�/12.

13. Henry JM, Heffner RR, Jr., Dillard SH, et al. Primary

malignant lymphomas of the central nervous system. Cancer

1974; 34: 1293�/302.

14. Weller M. Glucocorticoid treatment of primary CNS lym-

phoma. J Neurooncol 1999; 43: 237�/9.

15. Nelson DF. Radiotherapy in the treatment of primary central

nervous system lymphoma (PCNSL). J Neurooncol 1999; 43:

241�/7.

16. Abrey LE, DeAngelis LM, Yahalom J. Long-term survival in

primary CNS lymphoma. J Clin Oncol 1998; 16: 859�/63.

17. Ferreri AJ, Reni M, Villa E. Therapeutic management of

primary central nervous system lymphoma: lessons from

prospective trials. Ann Oncol 2000; 11: 927�/37.

18. Herrlinger U, Schabet M, Brugger W, et al. Primary central

nervous system lymphoma 1991�/1997 �/ Outcome and late

adverse effects after combined modality treatment. Cancer

2001; 91: 130�/5.

19. Ferreri AJ, Blay JY, Reni M, et al. Prognostic scoring system

for primary CNS lymphomas: the International Extranodal

Lymphoma Study Group experience. J Clin Oncol 2003; 21:

266�/72.

20. Ferreri AJ, Abrey LE, Blay JY, et al. Summary statement on

primary central nervous system lymphomas from the Eighth

International Conference on Malignant Lymphoma, Lugano,

Switzerland, 12 to 15 June 2002. J Clin Oncol 2003; 21: 2407�/

14.

21. Kaplan EL, Meier P. Nonparametric estimation from incom-

plete observations. J Am Stat Assoc 1958; 53: 457�/81.

22. Cox DR. Regression models and life tables. J Roy Statist Soc

1972; 34: 187�/220.

23. Grambsch P, Therneau TM. Proportional hazards tests and

diagnostics based on weighted residuals. Biometrika 1994; 81:

515�/26.

24. Krogh-Jensen M, D’Amore F, Jensen MK, et al. Incidence,

clinicopathological features and outcome of primary central

nervous system lymphomas. Population-based data from a

Danish lymphoma registry. Danish Lymphoma Study Group,

LYFO. Ann Oncol 1994; 5: 349�/54.

25. O’Neill BP, Dinapoli RP, Kurtin PJ, et al. Occult systemic

non-Hodgkin’s lymphoma (NHL) in patients initially

diagnosed as primary central nervous system lymphoma

528 I. Salvesen Haldorsen et al. Acta Oncologica 43 (2004)

Act

a O

ncol

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

190.

201.

225.

93 o

n 05

/20/

14Fo

r pe

rson

al u

se o

nly.

(PCNSL): how much staging is enough?. J Neurooncol 1995;

25: 67�/71.

26. Herrlinger U. Primary CNS lymphoma: findings outside the

brain. J Neurooncol 1999; 43: 227�/30.

27. Schabet M. Epidemiology of primary CNS lymphoma. J

Neurooncol 1999; 43: 199�/201.

28. Miller DC, Hochberg FH, Harris NL, Gruber ML, Louis DN,

Cohen H. Pathology with clinical correlations of primary

central nervous system non-Hodgkin’s lymphoma. The Mas-

sachusetts General Hospital experience 1958�/1989. Cancer

1994; 74: 1383�/97.

29. Hayakawa T, Takakura K, Abe H, et al. Primary central

nervous system lymphoma in Japan*/A retrospective, co-

operative study by CNS-Lymphoma Study Group in Japan. J

Neurooncol 1994; 19: 197�/215.

30. Hochberg FH, Miller DC. Primary central nervous system

lymphoma. J Neurosurg 1988; 68: 835�/53.

31. Kim DG, Nam DH, Jung HW, et al. Primary central nervous

system lymphoma: variety of clinical manifestations and

survival. Acta Neurochir (Wien) 1996; 138: 280�/9.

32. Watne K, Scott H, Hager B, et al. Primary malignant

lymphoma of the brain. A report of 24 cases from

the Norwegian Radium Hospital. Acta Oncol 1992; 31:

545�/50.

Acta Oncologica 43 (2004) Primary nervous system lymphoma in Norway 529

Act

a O

ncol

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

190.

201.

225.

93 o

n 05

/20/

14Fo

r pe

rson

al u

se o

nly.