Radio-induced gliomas: 20-year experience and ... - Springer Link

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


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


33

Maat-Schiemann

5/M

Craniopharyngioma

60

14


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


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


56

Ushio

2/F

Craniopharyngioma

54.6

4

Glioblastoma

123

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J Neurooncol (2008) 89:169–177

Table 1 continued Author (reference)

Age/sex

1st disease

Dose

Latency (years)


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


60

Fontana

6/F

ALL

24

10


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


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


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


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


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


103

Kato

54/F

Pituitary adenoma

50

20

Glioblastoma

104

Nishio

18/M

Pineal germinoma

30

9.5

Glioblastoma

123

J Neurooncol (2008) 89:169–177

173

Table 1 continued Author (reference)

Age/sex

1st disease

Dose

Latency (years)


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


–

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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J Neurooncol (2008) 89:169–177

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.

References 1. Albert RE, Omran AR, Brauer EW, Freed R (1966) Follow-up study of patients treated by X-ray for tinea capitis. Am J Public Health 56:2114–2120 2. Albo V, Miller D, Leiken S, Sather H, Hammond D (1985) Nine brain tumors (BT) as a late effect in children ‘‘cured’’ of acute

123

176

3. 4.

5.

6. 7.

8.

9.

10.

11.

12. 13.

14.

15.

16.

17. 18.

19. 20.

21.

22.

23.

J Neurooncol (2008) 89:169–177 lymphoblastic leukaemia (ALL) from a single protocol study. Proc Am Soc Clin Oncol 4:172 Anderson JR, Treip CS (1984) Radiation-induced intracranial neoplasms: a report of three possible cases. Cancer 53:426–429 Bachman DS, Ostrow PT (1978) Fatal long-term sequela following radiation ‘‘cure’’ for ependymoma. Ann Neurol 4:319– 321 Barnes ARE, Liwnicz BH, Schellhas HE, Altshuller G, Aron BS, Lippert WR (1982) Successful treatment of placental choriocarcinoma metastatic to brain followed by primary brain glioblastoma. Gynecol Oncol 13:108–114 Bazan C, New PZ, Kaghan-Hallet KS (1990) MRI of radiationinduced spinal cord glioma. Neuroradiology 32:331–333 Beute BJ, Fobben ES, Hubschmann O, Zablow A, Eanelli T, Solitare G (1991) Cerebellar gliosarcoma: report of a probable radiation-induced neoplasm. AJNR 12:554–556 Brat DJ, James D, Jedlicka AE, Connolly D, Chang E, Castellani R, Schmid M, Schiller M, Carson D, Burger PC (1999) Molecular genetic alterations in radiation-induced astrocytomas. Am J Pathol 154:1431–1438 Cahan WG, Woodard HQ, Higinbotham NL, Stewart FW, Coley BL (1948) Sarcoma arising in irradiated bone: report of 11 cases. Cancer 1:3–29 Chung CK, Stryker JA, Cruse R, Vanucci R, Towfighi J (1980) Glioblastoma multiforme following prophylactic cranial irradiation and intrathecal methotrexate in a child with acute lymphoblastic leukaemia. Cancer 47:2563–2566 Clifton MD, Amromin GD, Perry MC, Abadir R, Watts C, Levy N (1980) Spinal cord glioma following irradiation for Hodgkin’s disease. Cancer 45:2051–2055 Cohen MS, Kushner MJ, Dell S (1988) Frontal lobe astrocytoma following radiotherapy for medulloblastoma. Neurology 31:616–619 Diersse G, Alvarez G, Figols J (1988) Anaplastic astrocytoma associated with previous radiotherapy: report of three cases. Neurosurgery 6:1095–1097 Donson A, Erwin N, Kleinschmidt-DeMasters BK, Madden J, Addo-Yobo S, Foreman N (2007) Unique molecular characteristics of radiation-induced glioblastoma. J Neuropathol Exp Neurol 66(8):740–749 Fontana M, Stanton C, Pompili A et al (1987) Late multifocal gliomas in adolescents previously treated for lymphoblastic leukaemia. Cancer 60:1510–1518 Fukui K, Inamura T, Nakamizo A et al (2001) A case showing effective radiotherapy for a radiation-induced glioblastoma. No Shinkei Geka 7:673–677 Grabb PA, Kelly DR, Fulmer BB, Palmer C (1996) Radiationinduced glioma of the spinal cord. Pediatr Neurosurg 25:214–219 Guthjahr P, Dietrich E (1979) Risiko zweiter maligner neoplasien nach erfolgreicher Tumorbehadlung in Kindersalter. Deutch Med Wochenshr 104:969–972 Hall EJ (1994) Radiobiology for the radiologist, 4th edn. In: Lippincott JB (4 ed.) Philadelphia Haselow RE, Nesbit M, Dehner LP, Knam FM, McHugh R, Lewitt SH (1978) Second neoplasm following megavoltage radiation in a pediatric population. Cancer 42:1185–1191 Hegi ME, Diserens A-C, Godard S, Dietrich P-Y, Regli L, Ostermann S, Otten P, Van Melle G, de Tribolet N, Stupp R (2004) Clinical trial substantiates the predictive value of O-6Methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin Cancer Res 10:1871–1874 Hufnagel TJ, Kim JH, Lesser R et al (1988) Malignant glioma of optic chiasm eight years after radiotherapy for prolactinoma. Arch Ophtalmol 106:1701–1705 Jones A (1960) Supervoltage X-ray therapy after of intracranial tumors. Ann R Soc Surg Eng 27:310–354

123

24. Judge MR, Eden OB, O’Neill P (1984) Cerebral glioma after cranial prophylaxis for acute lymphoblastic leukaemia. Br Med J (Clin Res Ed) 289:1038–1039 25. Kaido T, Hoshida T, Uranishi R et al (2001) Radiosurgeryinduced brain tumor: case report. J Neurosurg 95:710–713 26. Kaschten B, Flandroy P, Reznik M, Hainaut H, Stevenaert A (1995) Radiation-induced gliosarcoma: case report and review of the literature. J Neurosurg 83:154–162 27. Kato N, Kayama T, Sakurada K, Saino M, Kuroki A (2000) Radiation-induced glioblastoma: a case report. No To Shinkei 52:413–418 28. Kitanaka C, Shitara N, Nakagomi T et al (1989) Postradiation astrocytoma: report of two cases. J Neurosurg 70:469–474 29. Kleriga E, Sher JH, Nallainathan SK, Stein SC, Sacher M (1979) Development of cerebellar malignant astrocytoma at site of medulloblastoma treated 11 years earlier. J Neurosurg 49:445–449 30. Komaki S, Komaki R, Chol H, Correa-Paz F (1977) Radiation and drug-induced intracranial neoplasm with angiographic demonstration. Neurol Med Chir (Tokio) 17:55–62 31. Kranzinger M, Jones N, Rittinger O et al (2001) Malignant glioma as a secondary malignant neoplasm after radiation therapy for craniopharyngioma: report of a case and review of the literature. Onkologie 24:66–72 32. Lacassagne A (1933) Conditions dans lesquelles ont ete obtenus, cher le lapin, des cancers par actions des raisons x sur des foyers inflammatoires. C R Soc Biol 67:244–251 33. Liwnicz BH, Berger TS, Liwnicz RG (1985) Radiation associated gliomas. A report of four cases and analysis of postradiation tumors of the central nervous system. Neurosurgery 17:436–445 34. Loeffler JS, Niemierko A, Chapman P (2003) Second tumors after radiosurgery: tip of the iceberg or a bump in the road? Neurosurgery 52:1436–1442 35. Maat-Schieman MLC, Bots GTAM, Thomeer RTWM (1985) Malignant astrocytoma following radiotherapy for craniopharyngioma. Br J Radiol 58:480–482 36. Malone M, Lumley H, Erdohazi M (1986) Astrocytoma as a second malignancy in patients with acute lymphoblastic leukaemia. Cancer 57:1979–85 37. Marus G, Levin V, Rutherford GS (1986) Malignant glioma following radiotherapy for unrelated primary tumors. Cancer 58:886–894 38. Matsumura H, Takimoto H, Shirata M, Hirata M, Ohnishi T, Hayakawa T (1998) Glioblastoma following radiotherapy in a patient with tuberous sclerosis. Neurol Med Chir (Tokio) 38:287– 291 39. McWhirter WR, Pearn JH, Smith H, O’Regan P (1986) Cerebral astrocytoma as a complication of acute limphoblastic leukaemia. Med J Aust 45:96–97 40. Muzumdar DP, Desai K, Goel A (1999) Glioblastoma multiforme following prophylactic cranial irradiation and intrathecal methotrexate on a child with acute lymphoblastic leukaemia: a case report. Neurol India 47:142–144 41. Nishio S, Morioka T, Inamura T et al (1998) Radiation-induced brain tumors: potential late complications of radiation therapy for brain tumors. Acta Neurochir 140:763–770 42. Okamoto S, Handa H, Yamashita J (1985) Post-irradiation brain tumors. Neurol Med Chir (Tokio) 25:528–533 43. Palma L, Vagnozzi R, Annino L, Ciappetta P, Maleci A, Cantore GP (1988) Post-radiation glioma in a child. Case report and review of the literature. Child’s Nervous System 4:296–301 44. Pearl GS, Mirra SS, Miles ML (1980) Glioblastoma multiforme occurring 13 years after treatment of a medulloblastoma. Neurosurgery 6:546–551 45. Pelloski C, Mahajan A, Maor M et al (2005) YKL-40 expression is associated with poorer response to radiation and shorter overall survival in glioblastoma. Clin Cancer Res 11(9):3326–3333

J Neurooncol (2008) 89:169–177 46. Piccirilli M, Di Norcia V, Frati A, Salvati M (2005) Glioblastoma in irradiated elderly patients: two case reports. Neurosurg Rev 28:226–228 47. Platt JH, Blue JM, Schold SC, Burger PC (1983) Glioblastoma multiforme after radiotherapy for acromegaly. Neurosurgery 13:85–89 48. Preissig SH, Bohmfalk GL, Reichel GW, Smith M (1979) Anaplastic astrocytoma following radiation for a glomus jugulare tumor. Cancer 43:2243–2247 49. Raffel C, Edwards MSB, Davis RL, Albin AR (1985) Postirradiation cerebellar glioma: case report. J Neurosurg 63:300–303 50. Rappaport ZH, Loren D, Ben-Ahron A (1991) Radiation-induced cerebellar glioblastoma multiforme subsequent to treatment of an astrocytoma of the cervical spinal cord. Neurosurgery 4:606–608 51. Rimm IL, Li FC, Tarbell NJ, Winston KR, Sallan SE (1987) Brain tumors after cranial irradiation for childhood acute lymphoblastic leukaemia: a 13-years experience from Dana-Farber Cancer Institute and The Children’s Hospital. Cancer 59:1506– 1508 52. Robinson RG (1978) A second brain tumor and irradiation. J Neurol Neurosurg Psychiatry 41:1005–1012 53. Ron E, Modan B, Boice JD Jr et al (1988) Tumours of the brain and nervous system after radiotherapy in childhood. N Eng J Med 319:1033–1039 54. Saenger EL, Silverman FN, Sterling FT, Turner ME (1960) Neoplasia following therapeutic irradiation for benign conditions in childhood. Radiology 74:889–904 55. Salvati M, Artico M, Caruso R, Rocchi G, Ramundo E, Nucci F (1991) A report on radio-induced gliomas. Cancer 67:392–397 56. Salvati M, Puzzilli F, Bristot R, Cervoni L (1994) Post-radiation gliomas. Tumori 80:220–223 57. Salvati M, Frati F, Russo N, Caroli E, Polli FM, Minniti G, Delfini R (2003) Radiation-induced gliomas: report of 10 cases and review of the literature. Surg Neurol 60:60–67 58. Sanders J, Sale GE, Ramberg R, Clift R, Buckner CD, Thomas ED (1982) Glioblastoma multiforme in a patient with acute lymphoblastic leukaemia who received a marrow transplant. Transplant Proc 14:770–774 59. Schmidbauer M, Budka H, Bruckner CD, Vorkapic P (1987) Glioblastoma developing at the site of a cerebellar medulloblastoma treated six years earlier. J Neurosurg 71:77–82 60. Shamisa A, Bance M, Nag S, Tator C, Wong S, Noren G, Guha A (2001) Glioblastoma multiforme occurring in a patient treated with gamma knife surgery: case report and review of the literature. J Neurosurg 94:816–821 61. Shapiro S, Mcaly JJ (1989) Late anaplastic glioma in children previously treated for acute lymphoblastic leukaemia. Pediatr Neurosci 15:176–189 62. Shapiro S, Mcaly JJ, Sartorius C (1989) Radiation-induced intracranial malignant gliomas. J Neurosurg 71:77–82

177 63. Shore RE, Albert RE, Pasternack BS (1976) Follow-up study of patients treated by X-ray epilation for tinea capitis. Arch Environ Health 31:21–28 64. Snead OC, Acker JD, Morawetz RW, Benton JW (1982) High resolution computerized tomography with coronal and sagittal reconstruction in the diagnosis of brain tumors in children. Childs Brain 9:1–9 65. Soffer D, Gomori JM, Pomeranz S, Siegal T (1998) Gliomas following low dose irradiation to the head: report of three cases. J Neurooncol 6:67–72 66. Sogg RL, Donaldson SS, Yorke CH (1978) Malignant astrocytoma following radiotherapy for craniopharyngioma. J Neurosurg 48:622–627 67. Stenbok P (1980) Spinal cord glioma after multiple fluoroscopies during artificial pneumotorax treatment of pulmonary tuberculosis. J Neurosurg 52:838–841 68. Tada M, Sawamura Y, Abe H, Iggo R (1997) Homozygous p53 gene mutation in a radiation-induced glioblastoma 10 years after treatment for an intracranial germ cell tumor: a case report. Neurosurgery 40:393–396 69. Tomita H, Nogaki H, Shibata Y, Tamaki N (1995) Brain stem glioma induced by radiotherapy: report of a case. No Shinkei Geka 23:151–155 70. Tsang RW, Lapierre NJ, Simpson WJ, Brierley MB, Panzarella T, Smyth S (1993) Glioma arising after radiation therapy for pituitary adenoma: a report of four patients and estimation of risk. Cancer 72:2227–2233 71. Ushio Y, Anta N, Yoshimine T, Nagatami N, Mogami H (1987) Glioblastoma after radiotherapy for craniopharyngioma: case report. Neurosurgery 21:33–38 72. Walter AW, Hancock ML, Pui C-H, Hudson MM, Ochs J, Rivera G, Pratt C, Boyett J, Kun L (1998) Secondary brain tumors in children treated for acute lymphoblastic leukaemia at St. Jude Children’s Research Hospital. J Clin Oncol 16(12):3761–3767 73. Walters TR (1979) Childhood acute lymphocytic leukemia with a second neoplasm. Am J Pediatr Hematol Oncol 1:285–287 74. You J, Young WH, Wilson D, Black KL (2000) Glioblastoma induction after radiosurgery for meningioma. Lancet 356:1576– 1577 75. Zampieri P, Zorat PL, Mingrino S, Soattin GB (1989) Radiationassociated cerebral gliomas. Report of two cases and review of the literature. J Neurosurg Sci 3:271–279 76. Zochodne DW, Cairncross JG, Arce FP et al (1984) Astrocytoma following scalp radiotherapy in infancy. Can J Neurol Sci 11:475–478 77. Zuccarello M, Sawaya R, DeCourten-Myers G (1986) Glioblastoma after radiation therapy for meningioma: case report and review of the literature. Neurosurgery 19:114–119

123