J Neurooncol (2008) 89:169–177 DOI 10.1007/s11060-008-9565-x
CLINICAL-PATIENT STUDY
Radio-induced gliomas: 20-year experience and critical review of the pathology Maurizio Salvati Æ Alessandro D’Elia Æ Graziella Angelina Melone Æ Christian Brogna Æ Alessandro Frati Æ Antonino Raco Æ Roberto Delfini
Received: 9 October 2007 / Accepted: 25 February 2008 / Published online: 20 June 2008 Ó Springer Science+Business Media, LLC. 2008
Abstract The authors report their personal experience with a surgical series of 16 cases of cerebral radiationinduced gliomas, defining diagnostic criteria and surgical and clinical characteristics. There were ten males and six females, with a median age of 45.9 years. Irradiation had initially been given for acute lymphoblastic leukemia (ALL) in six cases, tinea capitis in four cases, scalp hemangioma in three cases, cutaneous hemangioma, cavernous angioma, and medulloblastoma in one case each. There were 14 cases of glioblastoma (grade IV WHO) and 2 cases of astrocytoma (grade II WHO), with a mean latency time of 17 years (range: 6–26 years). For glioblastomas mean survival time was 10.4 months, accounting for 1–3% of all the glioblastomas treated. A thorough revision of the pertinent literature revealed some clinical– biological peculiarities. Keywords High grade Low grade Radiation-induced gliomas Radiosurgery Radiotherapy
M. Salvati Department of Neurosurgery, INM Neuromed IRCCS, Pozzilli, Is, Italy M. Salvati (&) Via Cardinal Agliardi, 15, 00165 Rome, Italy e-mail:
[email protected] A. D’Elia G. A. Melone C. Brogna A. Frati A. Raco R. Delfini Department of Neurological Sciences, Neurosurgery, University of Rome ‘‘Sapienza’’, Policlinico Umberto I, Rome, Italy
Introduction Radiotherapy and, until recently, radiosurgery have represented very important therapeutic instruments for treating various intra- and extracranial pathologies. Although they are not entirely free of immediate and long-term side effects, they have been extensively employed worldwide [41]. Such complications include radionecrosis or the onset of new tumors [41]. Although epidemiological evidence indicates sarcomas and meningiomas as being the most frequent tumors to develop as a side effect of radiation [17, 33], there have also been consistent reports on gliomas, mainly malignant, arising in the previously irradiated region [1–77]. The etiological role of radiation in tumor induction was questioned in early 1902 by Frieben [56]. More evidence was subsequently provided by Lacassagne and coworkers in 1933 from their experiments on guinea pigs [32], while the first cases observed in humans were described in the early 1960s [23, 54]. Since then, a total number of 129 radiation-induced gliomas has been reported, including the patients of our series. In the present study, besides a review of the pertinent literature, 16 cases of radiation-induced glioma treated in our institution from 1970 to 2006, 10 of which were reported in a previous article [57], are described. Two cases of low-grade glioma and one case of c-knife 60Co radiosurgery-induced glioblastoma are particularly interesting, given their rarity. Finally, we attempted to define the frequency of radiation-associated glioblastomas not from the irradiation source registry, as previously performed, but from a neurosurgical point of view. Materials and methods We reviewed all cases of intracranial glioma with a positive anamnesis of previous cranial irradiation. All cases
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satisfied Cahan’s minimal criteria ([9]: see discussion) and were operated on at the Department of Neuroscience —Neurosurgery of the Sapienza University of Rome from 1970 to 2006. Ten of these cases had been described in previous publications [57]. All high-grade cases discovered after 2000 were subjected to further molecular studies, particularly MGMT gene promoter status using PCR gene amplification, according to Hegi et al. [21], and YKL-40 staining with a semi-quantitative scale, according to criteria suggested by Pelloski et al. [45]. The relative frequency of radiation-induced glioblastomas (GBM) among all GBM cases was defined for the period after 2000.
Results Sixteen radiation-induced gliomas were collected, 14 high grade (glioblastoma) and 2 low grade (astrocytoma) (Table 1). Male/female ratio was 5:3, and mean age was 45.9 years (range: 19–79). Mean dosage of first irradiation was 20.5 Gy with a range of 3–30 Gy (except in the case of medulloblastoma, with an adjunctive 45 Gy delivered to the posterior cranial fossa). The mean latency time for development of brain tumor was 17 years (range 6–26 years). Treatment details are shown in Table 2. Mean survival time for GBM cases was 10.4 months: for all five cases in which surgical removal was at least subtotal (namely with a residual disease \10% confirmed at a contrast-enhanced MRI scan performed within 48 h of surgery), overall survival was 20.1 months. There is only one long-surviving patient who is still alive after more than 3 years. Regarding the two lowgrade cases, follow-up is still too short to analyze survival. We observed six cases of radiation-associated GBM after 1 January 2000, with an estimated frequency of 6/450 cases, thus accounting for 1.3% of all glioblastoma cases treated at our institution during the last 7 years: of these cases, two presented methylated MGMT promoter gene (namely MGMT protein not expressed), and three presented nonmethylated MGMT promoter gene (that means MGMT protein expressed). Regarding YKL-40, in three cases it was not expressed (= 0), in one case it was moderately expressed (= 1+), and in one case it was strongly expressed (= 2+). In one case, the patient refused the treatment proposed, and further molecular analyses were not performed. Preoperative Karnofsky Performance Status (KPS) in all these six patients was [80. As far as adjuvant treatment was concerned, six patients were treated by whole brain radiotherapy alone: four patients were treated by 60 Gy conformational radiotherapy, followed by adjuvant PCV (Procarbazine, lomustine CCNU, and Vincristine) chemotherapy (three cycles) in one patient, and integrated with the temozolomide regimen in the other three (Table 2).
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Discussion Among the other long-term complications of radiation therapy, such as radionecrosis, development of a secondary tumor in the cranial region previously irradiated for therapeutic purposes is the most unusual [25, 63]. In a review of the literature we identified 129 cases, including ours, in which a glioma arose after radiotherapy [1–77], (see Table 1). To be considered as radiation-induced, the secondary tumor must satisfy the criteria defined by Cahan [9]: (1) the tumor must originate in the previously irradiated region (but not necessarily in the full-dose region); (2) there must be a sufficient latency time from irradiation to the onset of the postradiation tumor, and this latency period is measured in years, not in months; (3) the histotype of the tumor must be different from the primary one; (4) the patient must not suffer from pathologies favoring the developing of tumors; among these pathologies we could include von Recklinghousen’s disease, Li–Fraumeni’s disease, tuberous sclerosis, xeroderma pigmentosum, or retinoblastoma. Analyzing large series of irradiated patients, some authors also assessed the risk of developing a secondary tumor after radiotherapy [53, 70, 72]. Tsang et al. [70], on the basis of his case series, stated that the cumulative risk of developing glioma after completion of radiotherapy for postoperative treatment of pituitary adenoma is 2.7% at 15 years. In another study, Ron et al. [53], analyzed a serie of 10,834 children irradiated for tinea capitis: they estimated the risk of developing gliomas to be 2.6-fold that of the non-irradiated population. In our study, the first to our knowledge to analyze the frequency of radiation-associated glioblastoma (GBM) among all GBM, we found a 1.3% rate throughout an observation period of 7 years. We only considered clinical cases from 2000 onward because we are not able to guarantee a strictly verified registration of all glioma cases before this date. There does not appear to be a sex-related prevalence [41], and in our series the male/female ratio was 5:3. The average latency time for the development of radiation-induced glioma ranges from 9.1 to 11 years in the literature [25, 41, 72], while in our series it ranged from 6 to 26 years, with a higher median of 17 years: this could have been due to the higher median age of the patients in our series, namely 47 years, with a range of 18–79 years, compared to those reported in the literature, with a high frequency of pediatric series. Moreover, by examining the various case series, it appears that the main reason for first irradiation was treatment of acute lymphoblastic leukemia (ALL) [16, 56, 72], and this fact is confirmed in our study (six ALL-related cases, see Table 2). It has been suggested that contemporary administration of intrathecal chemotherapeutic drugs
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Table 1 Main features of radiation-associated gliomas described in the literature (including our cases) Author (reference)
Age/sex
1st disease
Dose
Latency (years)
Radio-induced glioma
1
Jones
33/M
Meningioma
40
10
Astrocytoma
2
Saenger
11/M
Cervical Adenitis
4
11
Glioblastoma
3
Albert
4/M
Tinea Capitis
5–8
4
Astrocytoma
4
Albert
10/M
Tinea Capitis
5–8
1
Astrocytoma
5
Shore
10/M
Tinea Capitis
3–4
6
Astrocytoma
6
Shore
8/M
Tinea Capitis
3–4
26
Cerebellar astrocytoma
7
Shore
7/M
Tinea Capitis
3–4
5
Astrocytoma
8
Komaki
28/M
Craniopharyngioma
54
6
Glioblastoma
9
Bachman
1/F
Ependymoma
39.6
5
Glioblastoma
10
Sogg
9/F
Craniopharyngioma
60
6
M astrocytoma
11 12
Robinson Robinson
10/M 36/M
Pineal Teratoma Meningioma
40 27.5
26 21
M astrocytoma M astrocytoma
13
Kleriga
1/M
Medulloblastoma
50
50
Cerebellar M astrocytoma
14
Halesow
0.75/?
Histiocytosis
6
6
INFT ependymoma
15
Preissig
43/M
Chemodectoma
44.8
8
Cerebellar M astrocytoma
16
Gutjahr
4/F
Craniopharyngioma
60
8
Glioblastoma
17
Walters
3/F
ALL
26.2
6
Astrocytoma
18
Clifton
21/M
Hodgkin’s disease
49.7
6
Spinal glioblastoma
19
Pearl
5/M
Medulloblastoma
30
13
Glioblastoma
20
Steinbock
20/F
Lung Tbc
Fluo
25
Spinal astrocytoma
21
Cohen
4/F
Medulloblastoma
45
16
Astrocytoma
22
Chung
2/M
ALL
24
5
Glioblastoma
23
Barnes
17/F
Choriocarcinoma
40
6
Multiple glioblastoma
24
Sanders
4/F
All
24
5
Glioblastoma
25
Snead
9/F
Retinoblastoma
28
6
Glioblastoma
26
Piatt
38/M
Pituitary adenoma
49
14
Glioblastoma
27 28
Piatt Anderson
25/M 3/F
ALL ALL
45 24
10 6
Glioblastoma Multiple astrocytoma
29
Anderson
25/F
Medulloblastoma
42
6
INFT ependymoma
30
Zochodne
24/F
Scalp hemangioma
16.1
15
M Astrocytoma
31
Judge
3/F
ALL
24
9
Multiple M astrocytoma
32
Raffel
13/F
ALL
24
7
Cerebellar M astrocytoma
33
Maat-Schiemann
5/M
Craniopharyngioma
60
14
Cerebellar M astrocytoma
34
Liwnicz
11/M
Craniopharyngioma
59
25
Glioblastoma
35
Liwnicz
2/M
M ependymoma
35
14
Glioblastoma
36
Liwnicz
2 wk/M
Retinoblastoma
55
12
Glioblastoma
37
Liwnicz
5/M
Burkitt’s lymphoma
18
5
Glioblastoma
38
Okamoto
39/F
Pituitary adenoma
50
5
Glioblastoma
39
Okamoto
25/F
Medulloblastoma
42
6
INFT ependymoma
40–8
Albo
5 M-4F
ALL
24
6.5
4 Astroc + 1 ependym + 1 gliom
49
Malone
8/F
ALL
20
3.5
INFT and spinal astrocytoma
50 51
Malone Malone
19/M 6/F
ALL ALL
25.2 24
4.5 5
Astrocytoma M astrocytoma
52
Marus
10/M
ALL
32
7
Cerebellar M astrocytoma
53
Marus
52/F
Pituitary adenoma
45
6
M astrocytoma
54
Zuccarello
32/M
Meningioma
56
10
Glioblastoma
55
McWhirter
2/M
ALL
24
10
Cerebellar M astrocytoma
56
Ushio
2/F
Craniopharyngioma
54.6
4
Glioblastoma
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Table 1 continued Author (reference)
Age/sex
1st disease
Dose
Latency (years)
Radio-induced glioma
57
Schmidbauer
13/M
Medulloblastoma
60
6
Glioblastoma
58
Rimm
6/M
ALL
24
11
Multiple GBM or PNET
59
Fontana
6/M
ALL
24
11
Multiple glioblastoma
60
Fontana
6/F
ALL
24
10
Multiple glioblastoma
61
Hufnagel
41/M
Pituitary adenoma
55
8
M astrocytoma
62
Palma
3/M
ALL
24
11
Mixed glioma
63
Kitanaka
13/M
Pineal germinoma
54
7
M astrocytoma
64
Kitanaka
7/F
Craniopharyngioma
60
16
M astrocytoma
65
Shapiro
27/M
Pituitary adenoma
95
22
Glioblastoma
66
Shapiro
3/M
ALL
48
7
M astrocytoma
67 68
Shapiro Shapiro
2/F 5/F
ALL ALL
24 24
9 6
Multiple M astrocytoma M astrocytoma
69
Shapiro
4/M
ALL
24
4
M astrocytoma
70
Shapiro
6/F
ALL
24
4
Glioblastoma
71
Shapiro
25/F
Optic glioma
60
4
Glioblastoma
72
Rappaport
22/F
Spinal astrocytoma
40
1
Glioblastoma
73
Zampieri
11/M
Sarcoma
40 + 16
8
Anaplastic astrocytoma
74
Zampieri
45/F
Pituitary adenoma
50
9
Anaplastic astrocytoma
75
Dierssen
16/F
Fibrosarcoma
50
11
Astrocytoma
76
Dierssen
15/M
Ear chronic disease
18
11
Astrocytoma
77
Dierssen
28/F
Pituitary adenoma
66
6
Glioblastoma
78
Soffer
2/F
Tinea capitis
?
61
Glioblastoma
79
Soffer
?/F
Tinea capitis
?
?
Cerebellar astrocytoma
80
Soffer
4/F
Tinea capitis
?
36
Fibrillary astrocytoma
81
Bazan
19/M
Hodgkin’s disease
40
6
Astrocytoma II-III
82
Beute
26/F
Paroth mucoep carc
50
8
Gliosarcoma
83 84
Walter Walter
2/M 15/M
ALL ALL
24 24
9.2 9
Oligodendroglioma Glioblastoma
85
Walter
2/F
ALL
24
9.8
Malignant glioma
86
Walter
2.7/M
ALL
24
7.6
Glioblastoma
87
Walter
2/F
ALL
24
13.2
Anaplastic astrocytoma
88
Walter
3.8/M
ALL
24
7.6
Malignant glioma
89
Walter
2/M
ALL
18
11
Glioblastoma
90
Walter
3/M
ALL
40
10.5
Malignant glioma
91
Walter
2/F
ALL
24
8.5
Anaplastic astrocytoma
92
Walter
5/F
ALL
48
5.9
Glioblastoma
93
Walter
2/M
ALL
18
14.1
A oligodendroglioma
94
Grabb
20/F
Medullomyoblastoma
30
17
Anaplastic astrocytoma
95
Tsang
26/M
Pituitary adenoma
45
11
Glioma
96
Tsang
34/F
Pituitary adenoma
42.5
10
Glioblastoma
97
Tsang
42/M
Pituitary adenoma
50
15
Glioblastoma
98 99
Tsang Kaschten
38/M 13/M
Pituitary adenoma ALL
50 24
9 12
Astrocytoma Gliosarcoma
100
Matsumura
26/M
Giant cell astrocytoma
8
Glioblastoma
101
Tomita
44/F
Astrocytoma
60
20
Fibrillary astrocytoma
102
Kranzinger
14/F
Craniopharyngioma
4
Anaplastic astrocytoma
103
Kato
54/F
Pituitary adenoma
50
20
Glioblastoma
104
Nishio
18/M
Pineal germinoma
30
9.5
Glioblastoma
123
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173
Table 1 continued Author (reference)
Age/sex
1st disease
Dose
Latency (years)
Radio-induced glioma
105
Kaido
20/M
AVM
40 Rs
6
Glioblastoma
106
Shamisa
57/F
Vestibular schwannoma
17.1 Rs
7
Glioblastoma
107
You
70/F
Meningioma
40 Rs
7
Glioblastoma
108
Muzumdar
12/M
ALL
20
6
Glioblastoma
109
Donson
14/M
Burkitt’s lymohoma
7
Glioblastoma
110
Donson
11/M
Medulloblastoma
3
Glioblastoma
111
Donson
19/M
Low-grade astrocytoma
15
Glioblastoma
112
Donson
23/F
Ependimoma
12
Glioblastoma
113
Donson
14/F
ALL
10
Glioblastoma
114
Present series
22/F
ALL
24
12
Glioblastoma
115 116
Present series Present series
42/M 19/M
Tinea capitis ALL
3 24
25 6
Glioblastoma Glioblastoma
117
Present series
21/F
ALL
24
11
Glioblastoma
118
Present series
34/M
Tinea capitis
3
26
Glioblastoma
119
Present series
41/M
Tinea capitis
3
25
Glioblastoma
120
Present series
51/M
Medulloblastoma
30 + 45 on PCF
11
Glioblastoma
121
Present series
63/F
Scalp emangioma
30
20
Glioblastoma
122
Present series
52/M
Scalp emangioma
30
12
Glioblastoma
123
Present series
79/F
Cavernous angioma
30 Rs
13
Glioblastoma
124
Present series
78/M
Tinea capitis
3
25
Glioblastoma
125
Present series
72/M
Cutaneous emangioma
30
18
Glioblastoma
126
Present series
57/F
Scalp emangioma
30
10
Glioblastoma
127
Present series
37/M
ALL
24
11
Glioblastoma
128
Present series
32/M
ALL
18
22
Astrocytoma
129
Present series
34/F
ALL
24
26
Astrocytoma
ALL = Acute lymphoblastic leukemia; fluo = fluoroscopies; M = malignant; astroc = astrocytoma; epend = ependymoma; INFT = infratentorial; PCF = posterior cranial fossa; AVM = arterovenous malformation; RS = patients treated with radiosurgery; wk = weeks
might also play an etiological role, or that leukemia itself might favor tumors of the glia [13, 55]: however, nowadays these hypotheses are still far from being confirmed. Furthermore, some authors postulated the existence of a relationship between the doses of radiation delivered and histotype of the induced tumor [25, 41], but without confirmation. Conversely, the severity of the glioma appears not to be dose-related: it has been reported that a neoplasia induced by a small dose of radiation is not less harmful than a neoplasia induced by a large dose [19]. With respect to life expectancy, in our series the overall survival for GBM patients was 10.4 months. To compare overall survival with that of so-called ‘‘spontaneous’’ones,‘‘ we prefer to consider GBM cases that were at least subtotally resected in both groups: for the radiation-associated group overall survival was 20.1 months, whereas for the spontaneous group it was 15.2 months. So far, neither specific radiographic nor histopathological features nor genetic alterations capable of differentiating between radio-induced gliomas and so-called ‘‘spontaneous ones’’ have been identified in adults. Brat et al. [8] studied
nine radio-induced gliomas, six glioblastomas, and three anaplastic astrocytomas, but were not able to find any specific pattern. The mutations observed, particularly those of the p16-gene (MTS1/CDKN2) and that of the usually associated codifying gene for methyladenosin-phosphorilasis (MTAP), did not differ from those observed in primary lesions. On the other hand, none of the tumors examined presented any mutation of the oncosuppressor gene PTEN, usually observed in ‘‘spontaneous’’ gliomas with a high degree of malignancy, and only one of the nine cases examined displayed a mutation involving exon 8 of the p53 gene. Moreover, a recently published study by Donson et al. [14] reports five cases of radio-induced glioblastomas occurring in children and young adults with unique molecular characteristics. These authors analyzed surgical specimens from glioblastoma patients using gene expression microarray, and they surprisingly found the following: (1) in radiation-induced glioblastomas the clinical course was more aggressive and treatment-refractive than in pediatric ‘‘de novo’’ cases; (2) gene amplification of tumor cells showed homogeneous pattern among the five cases, compared
123
123
RP
LT
LT
RF
LF
RF
LF
LF
19/M 21/F
34/M
41/M
51/M
63/F
52/M
3 4
5
6
7
8
9
10 79/F
11 78/M
12 72/M
13 57/F
14 37/M
15 32/M
16 34/F
A
A
GBM: MGMT = not met; YKL-40 = 2+
GBM: MGMT = met; YKL-40 = 0
GBM: MGMT = not met; YKL-40 = 1+
GBM: MGMT and YKL-40 analysis not performed GBM: MGMT = met; YKL-40 = 0.
GBM
GBM
GBM: MGMT = not met; YKL-40 = 0
GBM
GBM
GBM GBM
GBM
GBM
Histhology
B
GT
P
GT
GT
GT
B
B
-
GT
B
–
B ST
GT
–
–
–
Conformational (60 Gy) in 6 weeks Conformational (60 Gy) in 6 weeks
Conformational (64 Gy) in 6 weeks
Conformational (64 Gy) in 6 weeks
–
WB tct (60 Gy) in 6 weeks
-
WB tct (60 Gy) in 6 weeks
WB tct (60 Gy) in 6 weeks
–
WB tct (60 Gy) in 6 weeks WB tct (60 Gy) in 6 weeks
WB tct (60 Gy) in 6 weeks
–
Surgery RTh
9.5
13
–
–
–
13
–
–
1 12
13.5
–
PFS (months)
–
–
–
–
TMZ conc. (75 mg/m2) + 18 cycles adj. [36 (200 mg/ m2) PCV (6 weeks) for 3 cycles 3
TMZ conc. (75 mg/m2) + 6 cycles adj. (200 mg/ m2)
TMZ conc. (75 mg/m2) + 6 cycles adj. (200 mg/ m2)
–
–
–
–
–
–
– –
–
–
CTh
–
–
7.6
[36
13.2
19
–
2
2
14
5
3
5 14
14
1
OS (months)
A = astrocytoma (grade II WHO); GBM = glioblastoma; F = frontal, T = temporal, P = parietal, O = occipital, M = mesencephalic; MGMT = promoter metylation status for the gene of the methyl-guanine-methyl-transferase enzyme: met = methylated (protein not expressed); not met = not methylated (protein expressed); GT = grossly total (residual disease \2% at 48 h postoperative MRI), ST = subtotal(residual disease \10%), P = partial (residual disease \50%), B = biopsy (residual disease [50%); WB = whole brain; TMZ = temozolomide, PCV = procarbazine-CCNU-vincristine (vincristine not used); PFS = progression-free survival, OS = overall survival
RTeM
RP
R F; R P; L O
RF
L FT RF
RF
42/M
RF
22/F
2
Site
1
Age/ gender
Table 2 Patients treatment results
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with the great heterogeneity of de novo GBM tumor cells, and this fact ‘‘may suggest a common, shared tumorigenic origin and pathway’’ for radiation-induced GBM; (3) gene amplification showed a significant overlap with pilocytic astrocytomas (37%), suggesting a common precursor cell. In our study we analyzed MGMT gene promoter methylation status and YKL-40 staining level in five cases, but no peculiarities were identified (Table 1), with the only longterm survivor showing methylated MGMT promoter and negative immunostaining for YKL-40. On the other hand, Kitanaka et al. [28] and Kleriga et al. [29] were able to identify some peculiar clinical features. Generally, patients harboring a radiation-induced neoplasia are younger than those affected by primary forms. Radioinduced neoplasms usually have a malignant histotype and could be situated in all cerebral locations, comprising the suprasellar region and the cerebellar fossa. On the basis of data collected from published series, the median age of the patient population is 19.2 years, and the average dose delivered is 32 Gy, consistent with the estimate made by Kaschten et al. [26]. However, in 15 cases, namely in 12.5% of radio-induced glioma patients, first irradiation was employed to treat tinea capitis, with an average total dose ranging from 3 to 8 Gy, which is considerably lower than previously reported. In another 12 cases (10%), radiation therapy was performed as an adjuvant to surgery for a pituitary adenoma. Because of the long life expectancy in this kind of patient, the possible risks connected with radiotherapy should be carefully evaluated [70]. The 16 cases we describe had received total doses ranging from 3 to 45 Gy, with single doses ranging from 1.5 to 20 Gy and a median dose of 20.5 Gy. Six of them had suffered from ALL, four were treated for tinea capitis, and four were previously irradiated for a scalp hemangioma, a pathology in which the possible complications of radiotherapy had only been reported by Zochodne et al. [76]; one case was treated for medulloblastoma, and the last one developed a glioblastoma in the area of a frontal cavernous angioma treated by radiosurgery at doses of 25 Gy. According to our review of the literature, this is the fourth case of glioblastoma secondary to c-knife radiosurgery [26, 60, 74]. Some considerations about radiosurgery are now necessary. There were three other cases of radiosurgery-associated tumors: two malignant schwannomas and one meningioma (see Loeffler et al. [34] for details), leading to a total of seven radiosurgery-associated tumors. The highest risk of developing a secondary tumor appears to be related more to the extension of irradiation than to high dosages; in fact, the carcinogenic effect does not rise in linear proportion to the dose of radiation, because high doses of radiation may lower or even eliminate the possibility of carcinogenic mutations by killing the cells. Only those cells that are not killed may progress toward
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malignant transformation by accumulating a series of mutations. The dose–response curve for radiation-induced secondary tumors is not yet clear, although some experiments on small animals suggest that the incidence increases with an average dosage from 3 to 10 Gy as single delivering doses, and for higher dosages there is a monotone decrease: clinical evidence supports this biphasic relationship [34]. Presumably, for patients treated by radiosurgery the borders around the irradiated area receive a dose of radiation compatible with mutation [34, 60]. Shamisa et al. [60] calculated that the amount of peripheral radiation received was 8 Gy at the most. Table 1 summarizes the data regarding the other three cases. The latency period was fairly short in comparison to gliomas induced by conventional radiotherapy, 7 years in the two cases described by Shamisa et al. [60] and Kaido [25], 6 years in the one reported by You et al. [74], and 13 in our case. Some authors believe that the possible risks of radiosurgery may be underestimated because of its relatively recent introduction [26, 34, 60, 74]. You et al. [74], who reported the case of a GBM that developed after c-knife resection of an occipital lesion in 2001, expressed the fear that his case may be the first of a long series and emphasizes the need for a scrupulous assessment of the risks and benefits of this method, especially for treatment of benign pathologies such as meningiomas. Shamisa et al. [60] also stress the need for a precise evaluation of the long-term complications of radiosurgical procedures, particularly in light of their use in the treatment of benign, congenital pathologies, particularly in light of the long life expectancy of young patients. The effectiveness of radiosurgery coupled with the very few cases of complications reported to date should be interpreted to mean that it cannot be employed indiscriminately, since there is never a safe dosage threshold. We conclude that safe, routine use of both traditional radiotherapy and radiosurgical techniques must depend on an accurate evaluation of their relative risks. Finally, we stress the need to collect and publish all radioinduced cases. In fact, only the observation and study of more cases can help the scientific community to clarify the biological and clinical properties of such a particular category of glioma, not only to establish the best treatment for these particular patients, but also to improve our understanding of the pathogenetic features of all gliomas.
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