Neuroradiology (1994) 36:652-655

Neuro--

radiology 9 Springer-Verlag 1994

Late cranial M R I after cranial irradiation in survivors of childhood cancer E. P~i~ikk61, K. Talvensaari 2, J. Pyhtinen 1, M. Lanning 2 1 Department of Diagnostic Radiology, University of Oulu, Finland 2 Department of Pediatrics, University of Oulu, Finland Received: 25 September 1993/Accepted: 3 December 1993

Abstrac t. We carried out M R I on 43 survivors of childh o o d cancer after different treatment protocols with or without Cranial radiotherapy. They were free of disease, therapy having been discontinued 2 - 2 0 y e a r s earlier. Treatment had been for various malignancies, excluding brain tumours; 27 had received cranial irradiation for acute lymphoblastic leukaemia ( A L L ) or lymphoma. Two asymptomatic young w o m e n treated for A L L had falx'meningiomas. White matter changes, low intensity foci [representing calcification or old haemorrhage) and heterogeneous intensity focic old haemorrhages) were seen only in patients who had undergone radiotherapy. B e c a u s e of the possibility of benign, potentially curable brain tumours occurring after cranial irradiation, it may be wise to carry out occasional cranial imaging in th:e follow-up of these patients. No routine imaging follow-up is n e e d e d after c h e m o t h e r a p y alone.

Key words: Brain

- Magnetic resonance imaging Acute lymphoblastic leukaemia - Radiotherapy - Meningioma

I m p r o v e d survival rates following childhood neoplasia have l e d t o a growing n u m b e r of young adults who are considered cured of their malignancy. The more effective treatment protocols have nevertheless led to many late effeclts which may severely compromise the quality of life or e v e n threaten it. Neuropsychological defects may not be associated with structural cerebral changes, but white m a t t e r lesions, atrophy and calcification are well documented, especially: in children who have had acute lymphoblastic leukaemia ( A L L ) [1-4]. The risk of the most serious late sequelae of treatment, malignant and benign neoplasms, is higher in patients who have received radiotherapy [5, 6], and the combination of cranial radiotherapy with c h e m o t h e r a p y has most potential delayed perCorrespondence to: E. Pg~ikk5, Department of Diagnostic Radiology, University of Oulu, Kajaanintie 50, SF-90220 Oulu, Finland

m a n e n t central nervous system (CNS) damage [7], although c h e m o t h e r a p y alone, especially methotrexate, may also produce cerebral white matter abnormalities

[8, 91. The role of cranial M R I in the follow-up of survivors of childhood cancer after different treatment protocols with or without cranial irradiation was studied by examining 43 who were free of disease and had no neurological complaints.

Patients and methods Cranial MRI was performed on 19 males and 24 females, aged 10.5-31.2 years (median 18.3 years) who had childhood cancer diagnosed in 1973-1982. This series represents part of a larger survey of the late deleterious effects of therapy for childhood cancer. Patients with brain tumours were excluded. The diagnoses and ages at diagnosis and follow-up are shown in Table 1. All patients were free of disease at the time of this study, therapy having been discontinued 2-20 years (median 10.9 years) earlier. Twenty-seven patients had received cranial irr~adiation, 21 20-25 Gy, two 1015 Gy and four 35-46 Gy (Table 2). All except two received multidrug cytostatic therapy, according to various protocols, for 13 years. Two children with ALL were in their second remission at the time of follow-up, and allogenic bone marrow transplantation had been performed on two patients. The patients' records were reviewed for major neurological events, especially convulsions and intracranial haemorrhage during the therapy.

Table 1. Clinical data on 43 survivors of childhood cancer Diagnosis

Acutelymphoblastic leukaemia Nephroblastoma Neuroblastoma Lymphoma Sarcoma Other Total

Number (male/ female) 27 (11/16)

Age at diagnosismedian (range) years 3.6 (0.3-14.0)

Age at follow-up median (range) years 17.5(10,8-25.7)

7 (2/5) 2 (0/2) 3 (3/0) 2(2/0) 2(1/1) 43 (19/24)

2.1 (0.1-5.9) 1.0 (0.9-1.2) 14.4 (12.7-14.9) 10.2(9.4-11.1) 10.5 (9.1-11.9) 3.6 (0.1-14.9)

16.9 (10.5-24.6) 14.3 (11.3-17.2) 25.9 (25.%27.7) 24.8(18.3-31.2) 23.8(21.0-26.7) 18.3(10.5-31.2)

653

Fig.la-c. Meningioma in a 19-year-old woman treated for A L L with cranial irradiation and chemotherapy at the age of 5 years. a T2-weighted, b Tl-weighted images; c after contrast-enhancement trast enhancement. The pituitary gland findings from this series form the basis of another report [10]. The research was approved by the Ethical Committee of the Medical Faculty, and informed consent was obtained from the patients and their parents. Fisher's exact probability test was used for statistical analysis.

Results

Fig.2. Mild white matter changes i n a 20-year-old woman after cranial irradiation and chemotherapy for ALL. An axial T2weighted image shows areas of high signal intensity in the periventricular white matter

Fig.3. A small low-signal focus is seen in the right middle cerebellar peduncle on a T2-weighted image of a 25-year-old man treated for lymphoma with cranial irradiation and chemotherapy (no Lasparginase). The focus represents a small old haemorrhage or calcification

The M R I examinations were performed with a 1.0 T superconducting unit. Tl-weighted, 500-630/15/2 (TR/TE/excitations), 3 mm sagittal and 5 mm coronal images were obtained, the latter before and after intravenous contrast medium; 4 patients did not have contrast-enhanced imaging. Axial T2-weighted 5 mm images (2200-2300/15, 80-90/1) were obtained in all cases. The protocol also included a coronal Tl-weighted series with 3 mm thick slices through the sellar region. The images were analysed by two radiologists, paying special attention to parenchymal signal abnormalities, especially increased signal in white matter on the T2-weighted images, the size of the ventricles and sulci and pathological con-

The MRI findings in these 43 neurologically intact patients are shown in Table 2. Two falx meningiomas were seen in young women who had received 21 and 25 Gy of cranial irradiation for ALL at the age of 2 and 5 years, 18 and 14 years ago, respectively (Fig. 1). The larger, parietal meningioma, 3 cm in diameter was operated on and proved to be meningothelial. It was bright on T2-weighted images and gave intermediate signal on Tl-weighted images, enhancing with contrast medium. The smaller (< 1 cm) meningioma, visible only after contrast enhancement, was followed clinically and by MRI and showed no evidence of growth one year later. Mild periventricular white matter changes were seen in three patients (Fig. 2), and another had numerous, small, high-signal foci throughout the cerebral hemispheres on the T2-weighted images; all had received radiotherapy for ALL. Small low-signal foci were seen in the cerebral parenchyma on the T2-weighted images in six patients, all of whom had received cranial irradiation and chemotherapy (Fig. 3). They probably represent haemosiderin following haemorrhages or small zones of calcification, but no cranial CT confirmation

Table 2. Cranial M R I in 43 survivors of childhood cancer treated with and without cranial radiotherapy Diagnosis

Acute lymphoblastic leukaemia

Number radiated/ not radiated

MRI Meningioma

White matter changes

Low intensity foci a

Heterogeneous intensity loci b

Ventricular/sulcal enlargement

25/2

2/0

4/0

5/0

3/0

10/1

Nephroblastoma

0/7

0

0

0

0

0/2

Neuroblastoma

0/2

0

0

0

0

0

Lymphoma

2/1

0

0

1/0

0

2/1

Sarcoma

0/2

0

0

0

0

0

2/0

4/0

6/0

3/0

Total

27/16

a Old haemorrhage or calcification b Old haemorrhage

12/4

654 was available. Small, heterogeneous foci with a high intensity centre and low signal rim, interpreted as old haemorrhages, were seen in three cases. Venous angiomas were observed in three cases; a probable hamartoma in a patient with neurofibromatosis type I and one small hypothalamic lipoma were also seen. Ventricular and/or sulcal enlargement was seen in 16 patients (37 %), 12 of whom (75 %) had received cranial irradiation. The difference between the groups with and without cranial irradiation was not significant. Of the 27 patients with A L L 11 (41%) showed enlargement of the cerebrospinal fluid spaces. Convulsions had been documented during the treatment in seven children, six of whom had been treated for ALL. Five of these had normal MRI studies, one had mild sulcal enlargement and one a small low-signal focus on a T2-weighted image, probably representing old haemorrhage or calcification. The only patient who had documented intracranial haemorrhage during treatment 14 years previously did not show any abnormality on MRI.

Discussion Radiation-induced meningiomas have been reported after low doses used for tinea capitis and higher doses used in the treatment of cranial tumours [6, 11, 12]. There are few reports on single cases of meningioma or meningeal sarcoma following treatment for childhood malignancies other than brain tumours, especially A L L [6, 11, 13-15], most second brain tumours being gliomas [5, 16, 17]. The two meningiomas we saw in young women showed typical MRI features (Fig. 1) and are likely to be sequelae of irradiation earlier for ALL, because there was no evidence of neurofibromatosis or other predisposing factors apart from the previous radiation therapy. The likelihood of meningioma without predisposing factors is very low in this age group, and the mean age for radiation-induced meningiomas is lower than that for other meningiomas [11]. Postradiation meningiomas may also have distinct histological features, indicating rapid growth and aggressive biological behaviour and an increased incidence of histological malignancy [11, 18]. Our operated case was menigothelial, with no evidence of malignancy. In view of the features of radiation-induced meningiomas, occasional imaging follow-up may be advisable. Mild white matter changes were seen in four patients, all of whom received cranial irradiation for ALL. We found a similar prevalence in another series of 27 patients treated for A L L [2]. The present lesions were less extensive, but the time elapsed since CNS therapy was longer (median 14.0 vs. 3.1 years), which may have influenced the extent of the white matter lesions. Examinations during treatment have shown white matter changes to be transient [8, 19], and although late changes are thought to persist [20], this has not yet been confirmed. A higher frequency of white matter lesions, 31% (11 of 35 patients, including 7 definitely and 4 probably abnormal cases) was reported in a recent series with a me-

dian follow-up of 8 years from diagnosis [20]. Defining what is abnormal is not always straightforward when analysing the white matter [20], and in our experience white matter lesions seen following therapy often appear around the trigone or behind the bodies of the lateral ventricles. This is the area in which myelination is known to be delayed, being seen as variable high signal intensity on T2-weighted images for more than ten years [21]. Our patients with mild white matter changes were 19-24 years old at the time of the examination, when peritrigonal delayed myelination should no longer be seen on MRI. The finding of white matter lesions in this area may reflect its vulnerability to exogenous toxic factors. Cranial radiotherapy may cause vascular damage and ischaemia or demyelination and necrosis [7], and thus affect the peritrigonal watershed area where the vascular supply is easily compromised and myelination delayed [21, 22]. The small, low-intensity loci on T2-weighted images of six-patients may represent calcification or haemosiderin deposits; the two cannot always be distinguished without concurrent CT. Calcification following treatment for A L L tends to occur in the basal ganglia [23], whereas in only one of our cases was the low signal close to the lentiform nucleus, which may favor old haemorrhage. If the low intensity foci represent haemorrhage, they must have been clinically silent, as there was no evidence of intracranial bleeding in these cases. All but one of those patients had received L-asparginase, which has been associated with cerebrovascular insults [24, 25]. There was no significant difference in the size of the ventricles and sulci between the radiated and nonradiated patients. Patients who had received cranial radiotherapy had significantly smaller pituitary glands than nonirradiated subjects or controls (mean pituitary gland height on sagittal images 3.5 mm, 5.9 mm and 5.8 mm, respectively) [10]. This may reflect the higher sensitivity of the growing pituitary gland to radiation. The low frequency of abnormal findings in the patients who had not received cranial radiotherapy is remarkable. This implies that cranial MRI is not cost-effective in these subjects. However, our series did not include patients treated with recent, more aggressive chemotherapy protocols with cytarabine [26] and higher doses of methotrexate, i.e., those in whom routine cranial irradiation for A L L has been withdrawn and chemotherapy intensified.

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