J Neurooncol (2014) 117:311–320 DOI 10.1007/s11060-014-1390-9
CLINICAL STUDY
Natural history of cavernous malformations in children with brain tumors treated with radiotherapy and chemotherapy Angela Di Giannatale • Giovanni Morana • Andrea Rossi • Armando Cama Luisella Bertoluzzo • Salvina Barra • Paolo Nozza • Claudia Milanaccio • Alessandro Consales • Maria Luisa Garre`
•
Received: 28 October 2013 / Accepted: 27 January 2014 / Published online: 11 February 2014 Ó Springer Science+Business Media New York 2014
Abstract Cavernous malformations (CM) are cerebral irradiation-related late complications. Little is known about their natural history and the pathogenetic role of concomitant chemotherapy. We present a retrospective, singleinstitution study of 108 children affected with medulloblastoma, ependymoma, or germinoma treated with radioand chemotherapy. The frequency, clinical and radiological presentations, and outcomes were analyzed to investigate the relationship among radiation dose, associated chemotherapy, age, latency and localization of radiation-induced CM. 100 out of 108 children were treated with radiotherapy for primary brain tumor; 34 (27 with medulloblastoma and 7 with other histologies) out of 100 patients developed CM. No significant relationship was found between CM and gender (p = 0.70), age (p = 0.90), use of specific chemotherapy (standard versus high-dose, p = 0.38), A. Di Giannatale (&) C. Milanaccio M. L. Garre` Neuro-Oncology, Istituto Giannina Gaslini, Genova, Italy e-mail:
[email protected] G. Morana A. Rossi Neuroradiology Operative Unit, Istituto Giannina Gaslini, Genova, Italy A. Cama A. Consales Neurosurgery, Istituto Giannina Gaslini, Genova, Italy L. Bertoluzzo Epidemiology and Biostatistics, Istituto Giannina Gaslini, Genova, Italy S. Barra Radio-Oncology Department, IRCCS AOU San Martino, IST, National Institute for Cancer Research, Genova, Italy P. Nozza Anatomo-pathology Department, Istituto Giannina Gaslini, Genova, Italy
methotrexate (p = 0.49), and radiation dose (p = 0.45). However, CM developed more frequently and earlier when radiotherapy was associated with methotrexate (70 % of cases). Radiation-induced CM prevailingly occurred in the cerebral hemispheres (p = 0.0001). Only 3 patients (9 %) were symptomatic with headache. Three patients underwent surgery for intra- or extra-lesional hemorrhage. CM was confirmed by histopathology for all 3 patients. The vast majority of radiation-induced CM is asymptomatic, and macro-hemorrhagic events occur rarely. Concomitant therapy with methotrexate seems to favor their development. We recommend observation for asymptomatic lesions, while surgery should be reserved to symptomatic growth or hemorrhage. Keywords Cavernous malformation Brain tumors Radiation therapy Methotrexate
Introduction Irradiation plays a central role in the management of childhood brain tumors. Late delayed brain injury includes vascular abnormalities, such as cavernous malformations (CM), demyelination, white matter necrosis, brain atrophy, and dystrophic mineralization [1]. In 1994, Ciricillo et al. [2] first suggested that CM could be induced by irradiation. Since then, several additional cases have been reported [3– 28]. However, the cumulative incidence of radiationinduced CM is not exactly documented, and the mechanism underlying the induction of CM by cerebral irradiation (CI) remains largely unknown, as well as the relationship with radiation dose, age, associated chemotherapy, and the prevalence of hemorrhage. Furthermore CM can occur as an autosomal dominant inherited condition; to date familial
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forms have been attributed to mutations in three genes CCM1, CCM2, and CCM3 [29]. We retrospectively investigated the natural history of CM in a cohort of 108 children affected with medulloblastoma, ependymoma or germinoma treated with radiotherapy and chemotherapy at a single institution. The frequency, pattern of clinical and radiological presentations, and outcome were analyzed with the aim of identifying a possible relationship with radiation dose, concomitant chemotherapy, age and latency of radiationinduced CM.
Materials and methods Institutional board approval is not required in our country for retrospective studies that do not involve disclosure of patients’ sensitive data to the public. Patients were retrospectively identified using our institutional brain tumor database. All patients were diagnosed before 17 years of age, and had long-term MR imaging surveillance. Those followed up for less than 1 year after radiotherapy, who died during treatment, or who did not have complete radiological documentation were excluded. Patients’ clinical data (including age, gender, primitive tumor characteristics, and presence of associated syndromes), treatment (chemotherapy and/or radiotherapy), CM features, and follow-up information were collected. All patients were followed clinically and radiologically at different intervals depending on the natural history of their disease. Available radiological records of all patients were retrieved, and all neuro-imaging studies were consensually reviewed by two experienced pediatric neuro-radiologists for the presence, number, size, and anatomic location of CM. MR imaging studies were obtained on a 1.5 T magnet, and included axial T1-, T2-, and gradient echo (GE) T2*-weighted images, and triplanar post-contrast T1-weighted images. Surveillance imaging was performed at 3–6 months postoperatively, and was repeated every 3–6 months for the first year, and then yearly for at least 5 years. CM were defined as focal rounded areas of very low signal intensity on GE T2*-weighted images (due to magnetic susceptibility artifacts of iron related to the presence of hemosiderin or deoxyhemoglobin) and/or lesions characterized by a peripheral T2-hypointense rim (hemosiderin halo) surrounding a central core of heterogeneous signal on T1 and T2-weighted images (popcorn-like appearance due to mixed-age blood products). Hemorrhage was defined as the presence of new methemoglobin or deoxyhemoglobin signals on MRI, either confined within the hemosiderin halo (micro-hemorrhage) or beyond it (macro-hemorrhage). Within this definition we
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did not include a mere increase in CM diameter without evidence of recent hemorrhage. The size, location, signal characteristics, presence of perilesional edema, and time to evolution of the CM were noted. The lesions were classified by size into three groups: small (\5 mm in diameter), medium (5–15 mm in diameter), and large ([15 mm in diameter). CM were grouped into these three size based categories on the basis of the average measurements of CM in prior studies focusing on their natural history and considering also that size was a factor significantly associated with symptomatic presentation [30–32]. In each case, we recorded the first MR imaging appearance of each lesion. The patients were divided into three groups according to histology (medulloblastoma, ependymoma, and germinoma). Due to the greater sample size and higher percentage of CM in the medulloblastoma group, we elected to perform a statistical analysis only in this subgroup; a descriptive analysis was performed in the other two groups. Kaplan–Meier curves by Log-rank test were used to evaluate the relationship between CM and age, radiation treatment, and associated chemotherapy (methotrexate [MTX] and high-dose chemotherapy). Statistical significance was defined as a p value \0.05.
Results General characteristics Between 1987 and 2009, a total of 187 patients were identified. One hundred eight out of 187 patients met the inclusion criteria: 59 had medulloblastoma, 28 ependymoma, and 21 germinoma. Patient characteristics are summarized in Table 1. None had a family history of cavernomatosis. Genetic screening for CCM1-3 mutations was not performed. The treatment of these patients variably included surgery, radiation, and chemotherapy (standard and high dose) according to tumor characteristics. Sixty out of 100 children irradiated received a craniospinal irradiation (46 medulloblastomas, 5 metastatic ependymomas and 9 germinomas), 40 patients received only involved field irradiation. Patients with CM One hundred out of 108 patients received irradiation for primary tumor, and 34 (31.5 %) of them developed CM, 46 % of whom in the medulloblastoma cohort (a summary of characteristics of these patients is presented in Tables 2 and 3). There was a male predominance (sex ratio 1.8). Age at irradiation ranged from 1 to 16 years (median 7 years) and from 3 to 16 years in those who developed CM (median 6.5 years).
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Table 1 Patient characteristics Patients’ characteristics
All patients
Medulloblastoma
Ependymoma
Germinoma
Number of patients
108
59
28
21
Gender
64/44
32/27
17/11
15/6
(1.4)
(1.2)
(1.5)
(2.5)
Median
6 (25th–75th p: 4–9)
5.9 (25th–75th p: 2.9–8.7)
5 (25th–75th p: 3–8)
11 (25th–75th p: 10–14)
Mean
6.6 ± sd 3.9
5.9 ± sd 3
5.8 ± sd 3.7
11.4 ± sd 3
7 (25th–75th p: 4.25–10)
7 (25th–75th p: 4–9)
5 (25th–75th p: 3–10)
11.4 (25th–75th p: 10–14.3)
7.6 ± sd 3.6
6.7 ± sd 2
6.2 ± sd 3.8
11.5 ± sd 3
Ma/Fe (sex ratio) Age at diagnosis (y)
Age at RT (y) Median Mean CT type HD/Standard
25/72
25/33*
0/21
0/18
MTX
20
18
2
0
3D-CRT
73
45
24
4
IMRT
10
7
3
/
ND
17
0
0
17
Whole-brain irradiation [2,340** Whole-brain irradiation B2,340**
47 13
35 11
3 2
9 0
Involved field irradiation e/o boost (range dose 4,000–5,940)
100
52 (PF)
27 (21 PF, 6 H)
21
Whole-brain
60
46
5
9
Only Local-boost irradiation
40
6 (PF)
22 (16 PF/6 H)
12
Median
6.9 (25th–75th p: 3.6–10.8)
8.7 (25th–75th p: 6.6–14)
5 (25th–75th p: 3–8)
6.2 (25th–75th p: 3.4–8.6)
Mean
7.6 ± sd 4.8
10.1 ± sd 5.4
5.8 aa ± sd 3.9
6.2 ± ds 3.4
Median
6.3 (25th–75th p: 3.6–10.2)
7.7 (25th–75th p: 5.3–11.3)
4.7 (25th–75th p: 3–6.5)
5.6 (25th–75th p: 3.2–8.6)
Mean
7.2 ± sd 4.5
8.6 ± sd 4.8
5.7 ± sd 3.9
6.2 ± sd 3.3
RT type
RT dosage (cGy)
Radiation field
Follow-up period (y) from diagnosis
Follow-up period (y) from RT (y)
Ma masculine, Fe feminine, y years, 25th–75th p: 25th–75th percentile, sd standard deviation, * 1 patient didn’t receive chemotherapy, ND not done, CT chemotherapy, RT radiotherapy, F frontal, G basal ganglia, T temporal, P parietal, O occipital, L limbic lobe, PF posterior fossa, H hemisphere, 3DCRT three-dimensional conformal radiation therapy, IMRT intensity-modulated radiation therapy ** Whole brain in craniospinal irradiation
Among patients with CM, 29 out of 34 patients (25 with medulloblastoma, 2 with ependymoma and 2 with germinoma) received craniospinal irradiation, while the remainder received involved field irradiation. Among those who received whole-brain radiation (WBRT), 24 had high dose ([2,340 cGy) and 11 had low dose (B2,340 cGy) treatment. All patients (except one with ependymoma) received chemotherapy; commonly used medication included carboplatin, etoposide, thiotepa, and melphalan. Nineteen patients with medulloblastoma received conventional chemotherapy with MTX.
Imaging Neuro-imaging at initial tumor presentation did not reveal CM in any case. One hundred patients were followed up clinically and radiologically for a median period of 6.3 years (25th–75th percentile: 3.6–10.2 years) and a mean of 7.2 ± sd 4.5 (range 1–22.6 years) from initial radiation therapy. The surveillance neuro-imaging studies included MRI in all patients. We found GE T2*-weighted images to be superior to conventional T2-weighted images in detecting the number and distribution of CM. In our
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Table 2 Summary of characteristics of patients with post-irradiation CM Patients characteristics
All patients with CV
Medulloblastoma
Ependymoma
Germinoma
No. of patients with CV (%)
34 (31.5 %)
27 (46 %)
4 (14 %)
3 (14 %)
Gender: Ma/Fe (sex ratio)
22/12 (1.8)
15/12 (1.25)
4/0
3/0
Median age at RT (y)
6.5 (25th–75th p: 4–9)
6 (25th–75th p: 4–9)
Ages: 3–4–5–10
Ages: 7–7–16
Mean age at RT (y)
6.8 ± sd 3
6.6 ± sd 2.7
Ages: 3–4–5–10
Ages: 7–7–16
CT type Standard/HD
22/11
16/11
4/0
3/0
19
19
0
0
34
27
4
3
29 5 (4 PF)
25 2 (PF)
2 2 (PF)
2 1
Whole-brain irradiation [2,340
24
20
2
2
Whole-brain irradiation B2,340
11
11
/
/
Range
0.4–15
1.7–15
1.5–7
0.4–8
Median Mean
3.8 (25th–75th p: 2.6–6.5) 4.8 ± sd 2.9
3.8 (25th–75th p: 3–6) 4.6 ± sd 2.3
/ /
/ /
1
16 (47 %)
11 (41 %)
3
2
2-3
11 (32 %)
10 (37 %)
1
0
4-5
4 (12 %)
4 (15 %)
0
0
6-7
3 (9 %)
2 (7 %)
0
1
Supratentorial no. (%)*
68: 16 F, 16 T, 16 G, 11 P, 5 L, 4 O (90.5 %)
56: 15 F, 4 L, 13 G, 11 T,10 P, 3O
6: 1 F, 1 G, 2 T, 1 O, 1P
6: 3 T, 2 G, 1 L
Infratentorial no. (%)*
7 (9.5 %)
6
0
1
56 16
47 8
6 3
3 5
4
4
0
0
6
5
1
0
0
MTX Radiation type 3D-CRT Radiation field Whole-brain Only local-boost RT Radiation dosage (Gy)
Latency post RT (y)
Number of CV (%)
Site of CV
CV Size Small (\5 mm) Medium (5–15 mm) Large ([15 mm) Hemorrhage Microhemorrhage Macrohemorrhage
1
0
Clinical presentation
Headache (3 pts)
1
Headache (2 pts)
Headache (1 pt)
0
CV treatment
3 Excision
2 Excision
1 Excision
Observation
Ma masculine, Fe feminine, y years, 25th–75th p 25th–75th percentile, sd standard deviation, CV cavernoma, CT chemotherapy, RT radiotherapy, F frontal, G basal ganglia, T temporal, P parietal, O occipital, L limbic lobe, PF posterior fossa * Some patients presented with multiple cavernomas
analysis, small lesions were identified only on T2*weighted imaging, while they were not seen on other MR imaging sequences. Fifty-six CM were small, sixteen medium, and 4 large; the largest lesion was 25 mm in diameter.
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CM evolution CM were diagnosed incidentally in all patients during routine surveillance imaging. The latency interval between radiation therapy and the development of the CM was
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Table 3 Cases of radiation-induced CM Case n°
Age (y)/ gender
Primary tumor
CT type
RT suprat. dose/field
Age at RT (years)
Latency post RT (y)
Site of CV
No. CV
Hem
Clinical presentation
CV therapy
1
7/M
MB
HDCT
[2,340/CS
8
3 years
T-P-G
4
2
8/M
MB
STCT
B2,340/CS
8
2 years 8 months
F
1
No
Headache
Obs
No
Incidental
3
9/F
MB
HDCT
[2,340/CS
10
3 years7 months
PF
1
No
Obs
Incidental
Obs
4
5/M
MB
HDCT
[2,340/CS
5
1 years 9 months
F-T-PF
3
No
Incidental
Obs
5
4/M
MB
STCT
[2,340/CS
5
4 years
F-T-P-O-G
7
No
Incidental
Obs
6
7/M
MB
STCT
[2,340/CS
6
9 years 6 months
P
1
No
Incidental
Obs
7
2/M
MB
HDCT
-/PF
3
3 years 10 months
T
1
No
Incidental
Obs
8
11/F
MB
STCT
B2,340/CS
11
2 years 3 months
F-T-G
3
Micro
Incidental
Excision
9
3/M
MB
STCT
[2,340/CS
4
4 years 2 months
T-P-G
4
Micro
Incidental
Obs
10
8/F
MB
HDCT
[2,340/CS
9
8 years
F
1
No
Incidental
Obs
11
5/F
MB
HDCT
[2,340/CS
5
7 years 9 months
G
1
No
Incidental
Obs
12
4/M
MB
HDCT
B2,340/CS
5
3 years 5 months
F-P
2
Micro
Headache
Excision
13
4/F
MB
STCT
[2,340/CS
5
8 years 10 months
F-T
2
No
Incidental
Obs
14
6/F
MB
STCT
[2,340/CS
7
6 years
F-T-O
2
Micro
Incidental
Obs
15
9/M
MB
STCT
[2,340/CS
10
15 years
T
1
No
Incidental
Obs
16
8/F
MB
STCT
[2,340/CS
9
3 years 9 months
F-P-G-PF
6
No
Incidental
Obs
17
10/F
MB
HDCT
[2,340/CS
10
1 years 7 months
G
1
No
Incidental
Obs
18
6/F
MB
STCT
[2,340/CS
7
6 years 1 months
PF
1
No
Incidental
Obs
19
4/M
MB
STCT
[2,340/CS
5
6 years
F
1
No
Incidental
Obs
20
6/M
MB
STCT
[2,340/CS
7
3 years 1 months
F-T-PF
4
No
Incidental
Obs
21
1/M
MB
HDCT
-/PF
3
2 years 5 months
O-G
2
No
Incidental
Obs
22
2/M
MB
HDCT
B2,340/CS
4
3 years 10 months
P-PF
2
No
Incidental
Obs
23
5/M
MB
HDCT
B2,340/CS
6
3 years 1 months
F-G
2
No
Incidental
Obs
24
4/M
MB
STCT
[2,340/CS
5
4 years
T-O
2
No
Incidental
Obs
25
1/F
MB
STCT
[2,340/CS
4
6 years 4 months
O
1
No
Incidental
Obs
26
12/F
MB
STCT
[2,340/CS
13
8 years 3 months
F-G
2
No
Incidental
Obs
27
9/F
MB
STCT
[2,340/CS
10
2 years 2 months
F-T-P-G
5
No
Incidental
Obs
28
6/M
GERM
STCT
[2,340/ventricular ? pineal
7
6 years 5 months
G
1
No
Incidental
Obs
29
7/M
GERM
STCT
[2,340/CS
7
8 years
P-T-G
6
No
Incidental
Obs
30
16/M
GERM
STCT
[2,340/CS
16
4 months
T
1
No
Incidental
Obs
31
7/M
EPEND
STCT
[2,340/CS
10
3 years 10 months
F
1
Macro
Headache
Excision
32
4/M
EPEND
STCT
-/PF
4
7 years
O
1
No
Incidental
Obs
33
3/M
EPEND
STCT
-/PF
3
2 years
T-G
2
Micro
Incidental
Obs
34
5/M
EPEND
No
[2,340/CS
5
1 years 5 months
T
1
No
Incidental
Obs
MB medulloblastoma, GERM germinoma, EPEND ependimoma, M masculine, F feminine, STCT standard chemotherapy, HDCT high dose chemotherapy, y years, CV cavernoma, CT chemotherapy, RT radiotherapy, F frontal, G basal ganglia, T temporal, P parietal, O occipital, L limbic lobe, PF posterior fossa, obs observation, micro microhemorrhage, macro macrohemorrhage
0.4–15 years (mean 4.8). The median latency period was 4 years for the 28 patients irradiated in the 1st decade of life (mean latency, 5 years), and 3 years for the 6 patients irradiated in the 2nd decade of life (mean latency, 3.3 years). Seven patients had more than three lesions. CM location included the cerebral hemisphere (69.5 %), basal ganglia (21 %), and cerebellum (9.5 %). In 4 patients (2 with medulloblastoma and 2 with ependymoma) who received local radiation in posterior fossa, CM developed outside the irradiated field (occipital lobe, caudate nucleus, thalamus and temporal lobe).
Out of the 76 CM that were followed over time, thirteen increased in size, 62 remained stable, and 1 decreased in size. In 5 patients, micro-hemorrhage (intralesional hemorrhage) was documented, being symptomatic in 1 (mild headache). Only one patient presented with macro-hemorrhage (extra-lesional hemorrhage); this patient complained with headaches. All remaining patients with CM had no neurologic deficits or other symptoms. Overall, three out of 34 patients (patients # 8, 12, and 31) underwent surgery (9 %). Patients #8 and 12 presented with progressive hemorrhage and enlarging
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Fig. 1 Patient 31. Histologically confirmed CM. a, b, c Baseline MRI reveals absence of focal lesions. d, e, f A routine MRI follow up performed 3 years and 10 months later demonstrates a focal small lesion in the left subcortical frontal white matter in keeping with a micro hemorrhagic CM (thin arrows). g, h, i Subsequent MRI followup performed 1 year later shows increased extension of the CM undergoing a macro hemorrhagic event (thin arrows) with surrounding edema (open arrows, g, i). The lesion was surgically removed and histology confirmed a CM
subcortical frontal CM on follow-up MRI; patient #8 was asymptomatic, whereas patient #12 had a history of headaches lasting several months. Patient #31 had a subcortical frontal CM associated with macrohemorrhage and mild headache (Fig. 1). Because these lesions were surgically accessible, resection was performed due to the progressive hemorrhaging and to reduce the risk of further severe bleeding. Histopathology confirmed the diagnosis of CM in all three cases, and the recovery after surgery was complete. Statistical analysis (medulloblastoma) Numerous variables were analyzed in the medulloblastoma subgroup. No significant differences were identified
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concerning gender (p = 0.70), age (p = 0.90), use of specific chemotherapy (standard versus high-dose p = 0.38, MTX p = 0.49) and radiation dose (p = 0.45). Age at radiotherapy and radiotherapy dose Thirteen out of 59 patients with medulloblastoma were excluded from this analysis (7 without radiotherapy and 6 with localized PF irradiation);among the 6 patients with exclusive PF irradiation ([2,340 cGy), two had supratentorial CM and no one had CM in the PF. All 6 other patients with CM in the PF had undergone WBRT and PF boost. To evaluate the relationship between age and the risk of developing CM, we divided the patients into three age groups at the time of radiotherapy (C 1 \ 5:
Chemotherapy Patients receiving HD and STD chemotherapy developed CM in similar percentage (44 and 48 %, respectively). Regarding MTX chemotherapy, there was no significant difference in the frequency of CM between those who received it and those who did not (p = 0.49). However, nineteen out of 27 CM (70 %) developed in patients undergoing MTX followed by radiotherapy, while the remainder arose in patients with RT only. Fifty percent of CM developed during the first 6 years after treatment onset in patients treated with MTX followed by RT, and during 11 years in patients treated with RT only. The cumulative incidence of CM development at 3, 5, and 10 years was 17, 37, and 46 %, respectively, in the RT group, and 19, 39, and 67 %, respectively, in the MTX and RT group. CM location and HD RT Owing to the high frequency of CM in supratentorial regions, we evaluated their distribution in this location after HD radiation exposure. The patients were divided into four groups: (1) CM located in the basal ganglia and in the hemispheres; (2) CM in the hemispheres only; (3) CM in the basal ganglia only; and (4) patients without CM after RT. We found that CM occurred more frequently in the hemispheres (p = 0.0001), and that the interval to diagnosis was longer in the hemispheres (50 % of development at 6 years) than in other locations (basal ganglia plus hemispheres: 50 % at 3.8 years; basal ganglia: 50 % at 1.5 years) (Fig. 2).
Discussion Although radiation-induced CM are relatively rare in the pediatric population, a number of clinically important implications warrant their close follow-up and, possibly,
0.75
E NO
0.25
0.50
C G
0.00
11 patients, C 5 \ 10: 24 patients, C10: 11 patients). The CM developed in 41 % of those C 1 \ 5 years, in 53 % of those C 5 \ 10 years, and in 54 % of those C10 years. We categorized 46 patients into low-dose (LD, B 2,340 cGy: 11 patients) and high-dose (HD, [2,340 cGy: 35 patients) groups on the basis of the administered whole-brain radiation dose. HD irradiation was not a significant risk factor (p = 0.45). Twenty (57 %) out of the 35 patients in the HD group (mean age at irradiation 7 years), and 5 (45 %) out of the 11 patients in the LD group (mean age at irradiation 8 years) developed CM. Fifty percent of CM developed after 6.5 years of radiotherapy in the HD group and after 3.4 years in the LD group.
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0
5
10
15
20
analysis time Fig. 2 Frequency estimates by supratentorial CM location correlated to high dose radiotherapy (Kaplan–Meier) C basal ganglia ? hemispheres, G basal ganglia, E hemispheres, NO patients without cavernomas or infratentorial cavernomas
surgical intervention in some cases. In two reviews on radiation-induced CM [33, 34] presenting the largest series of cases reported in the literature to date (76 and 89 patients, respectively), medulloblastoma was the most common primary tumor, which was confirmed in our series. CCM1-3 mutations can be detected in patients with familial CM [29]. Although genetic studies for these mutations were not performed in our patients none reported a family history of cavernomatosis. Previous studies described a correlation between radiation-induced CM and younger age [1, 5, 19, 33], especially less than 10 years old [14]. Our study did not confirm this observation, and the percentage was actually slightly greater in children C10 years (54 %) than in those \5 years (41 %). Koike et al. [35] similarly found that CM developed at a slightly higher frequency in children aged [15 years at the time of radiation therapy, owing to the higher total cranial radiation dose received by this group. In another study, the median age at radiotherapy was 7 years and the median latency between radiotherapy and CM development was 3 years [25], which was similar to our group (3.8 years). It has also been suggested that patients irradiated at younger ages develop CM after shorter intervals [14, 21], and that there is an inverse relationship between radiation dose and latency. Our study did not confirm these assumptions, and we actually demonstrated that age at irradiation and radiation dose bear no direct relationship to the latency to diagnosis. Most CM grow in the radiation field [21, 36], but several authors reported that they usually arise at the margins of the main radiation field suggesting that low radiation doses would be more efficient than high doses at inducing them. This also supports the contention that the radiation delivered at the center of the field may result in extensive cellular apoptosis, thus preventing CM formation, while the
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periphery of the field is subject to radiation doses that alter genetic stability without substantial cell apoptosis [34]. In particular, treatment with whole brain irradiation may predispose patients to development of CM within the cerebrum rather than in the cerebellum [24]. Previous reports have shown that the most common localization of CM is supratentorial, particularly in the subcortical (frontal, temporal) and deep white matter [24, 35]. In the present study, 64 % of CM were located in the frontal and temporal lobes and in the deep white matter, whereas only 9.5 % were located in the cerebellum. Furthermore, four patients irradiated exclusively in posterior fossa (two with ependymoma and two with medulloblastoma) presented CM at the margins of the main radiation field (temporal and occipital lobes, thalamus, and caudate head). This evidence supports the hypothesis that low doses of radiation could induce CM more effectively. We also found that CM occurred more frequently in the cerebral hemispheres of children irradiated with high doses (p = 0.0001), and that the onset is earlier when CM develop both in the hemispheres and basal ganglia; this could be influenced by an individual susceptibility. CM have a wide spectrum of clinical presentations, ranging from asymptomatic lesions discovered on routine follow-up investigations to rare reported cases of fatal hemorrhage [37]. Radiation-induced CM seem to have a lower incidence of seizures compared with isolated CM. In two literature reviews of 85 and 72 cases [33, 34], 58 % of patients were asymptomatic at the time of diagnosis; sixteen percent and 24 % of these patients, respectively, presented with seizures. Another study [38] described two cases with medically refractory epilepsy related to CM following radiotherapy treatment for acute lymphoblastic leukemia. In our study, no patients experienced seizures, and only 3 (9 %) complained with headaches. Two of the latter had evidence of hemorrhage and underwent surgery. Hemorrhage is a common clinical presentation of CM [39, 40]. The annual incidence of bleeding in CM is estimated at 0.2–3 % [40–44]. The definition of ‘‘hemorrhage’’ varies considerably in several studies; some authors have suggested radiological definitions [34], while others proposed neurological deterioration as a marker of hemorrhage [43]. To standardize definitions and reporting, a recent consensus statement defined CM hemorrhage as requiring acute or subacute onset symptoms (any of headache, epileptic seizure, impaired consciousness, or new/worsened focal neurological deficit referable to the anatomic location of the CM) accompanied by radiological, pathological, surgical, or rarely only cerebrospinal fluid evidence of recent extra- or intra-lesional hemorrhage [45]. In two pediatric surgical series, hemorrhagic events occurred in 21 (65.6 %) [27] and in 17 (77 %) of patients [46], respectively. Keezer [34] and Nimjee [33] found
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spontaneous hemorrhage in radiation-induced CM in 40 and 76 % of patients included in their reviews. In another series, only 1 out of 18 patients with medulloblastoma [24] presented CM bleeding. In our series, one patient showed macro-hemorrhage and 6 micro-hemorrhage, of which five in medulloblastoma patients. Three cases, one with macroand two micro-hemorrhages, required surgery. Hemorrhages are usually intra-parenchymal, and clinical findings depend mainly on location. It has been reported that CM in deep anatomic locations have a higher rate of hemorrhage than superficial lesions (4.1 % per patient-year vs. 0 % per patient-year) [43]. All 3 patients underwent surgery in our series had a frontal location at the subcortical level. We did not find significant relationships between the development of multiple CM and radiation dose, in particular HD RT (p = 0.16). Keezer [34] demonstrated that multiple CM occur independently of radiation dose and age, whereas Baumgartner et al. [16] suggested that patients irradiated at younger ages are more likely to develop multiple CM. In our series, intravenous MTX administration was not significantly associated with an increased incidence of CM (p = 0.49). However, CM developed mainly in patients who received MTX followed by radiotherapy than RT-only receivers (70 versus 30 %), and the latency was shorter in the same patient group (50 % in the first 6 years for MTX followed by RT versus 11 years for RT only). MTX is thought to induce microangiopathy, probably related to excess of homocysteine, a byproduct of folate deficiency [47]. Small-vessel disease presumably accounts for cortical perfusion defects documented in children with acute lymphoblastic leukemia (ALL) previously treated with intravenous and intrathecal MTX [48]. In our series, three patients underwent surgery: one asymptomatic patient who presented micro-hemorrhage associated to perilesional edema (patient 8) and two symptomatic patients with micro-hemorrhage (patient 12) and macro-hemorrhage (patient 31). The indications for surgery of cerebral and cerebellar CM remain unclear. In agreement with the majority of the authors [27, 38, 49, 50], we believe that surgical resection should be considered in case of recurrent hemorrhage, progressive neurological deterioration, or refractory epilepsy in presence of a sufficiently low risk-to-benefit ratio. The relatively high incidence of CM found in our study, in line with more recent researches focusing on radiation induced CM, could be in part due to better imaging techniques and in particular to the routine use of GE T2*weighted images. Indeed, MRI sequences sensitive to the magnetic susceptibility artifact of iron (such as GE images) are much more sensitive than conventional spin echo sequences for the detection of CM. In addition the increased awareness of radiation induced CM has lead
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neuroradiologist to pay much more attention to the identification of these lesions, possibly contributing to their increased incidence. In conclusion, increase of radiation-induced CM occurs over time in children who receive cranial radiotherapy, and medulloblastoma is the most common primary tumor. The vast majority of radiation-induced CM are not associated with neurological symptoms and seem to have lower incidence of seizures than sporadic CM. Macro-hemorrhagic events occur rarely and are mostly symptomatic. CM develop more frequently and earlier in patients who received to MTX followed by radiotherapy, suggesting that MTX favors CM development possibly through small-vessel vasculopathy; these lesions do not behave differently from other radiation-induced CM. T2*-weighted MR imaging strongly increases the sensitivity to small lesions; however, given their benign course, little evidence supports a routine use of these sequences in brain tumor surveillance. Furthermore, the psychological stress resulting from a neuroradiological diagnosis of CM and the possible consequent negative effects on the quality of life of these patients should be taken into account. We recommend observation for asymptomatic lesions, and consideration for surgery in the event of symptomatic growth or hemorrhage. Acknowledgement We thank The ‘‘Associazione per la ricerca sui Tumori Cerebrali del Bambino’’ and The ‘‘Fondazione Berlucchi’’ for supporting our research.
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