24 Risk of Radiation-Associated Tumorigenesis in the Treatment of Vestibular Schwannoma

10.1055/b-0039-169178

24 Risk of Radiation-Associated Tumorigenesis in the Treatment of Vestibular Schwannoma

Michael J. Torrens

24.1 Introduction

There has been increasing use of both fractionated radiotherapy (FRT)s. Literatur ^, s. Literatur and more conformal, stereotactically directed radiosurgerys. Literatur ^, s. Literatur for benign intracranial lesions over the last 20 years. In the case of vestibular schwannoma (VS), it has produced high control rates with few side effects compared to open surgery. Only around 60 cases were treated in North America by radiosurgery in 1990 but a prediction that over 1,000 cases per annum would be treated by 2010 has been fulfilled.s. Literatur One of the possible disadvantages of radiosurgery has been the unknown frequency of radiation-induced secondary tumors.

The association of secondary neoplasia with therapeutic radiation is well known. A recent studys. Literatur estimated that about 0.45% of the 298,000 new cancers registered in the United Kingdom in 2007 were associated with radiotherapy for a previous cancer. It is not so certain, however, that the conformal higher dose radiation used in radiosurgery has a similar effect. An important, prospective, controlled study from Sheffield, England,s. Literatur followed 5,000 radiosurgery patients over 30,000 patient-years of follow-up and detected no increased risk of malignancy. However, sporadic case reports that suggest induction of malignancy by radiosurgery have been published, and in particular several cases of malignant transformation in VS (MTVS) have occurred. The purpose of this chapter is to evaluate the significance of these reports.

24.2 Radiation-Induced Tumors

The criteria for radiation-induced neoplasia as originally defined by Cahan et als. Literatur include: (1) the tumor must not be present at the time of irradiation; (2) there must be a prolonged latency period between radiation delivery and tumor development; (3) the tumor must arise in the irradiated region; (4) the tumor must be histologically distinct from the original tumor; and (5) the patient must not have a genetic predisposition to the development of cancer.

In the case of specific treatment of VS, the risk may be firstly of MTVS and secondly the induction of a separate secondary neoplasia in other tissue within the field of radiation.

24.3 Radiation Treatment of Vestibular Schwannoma

In this context, radiation has been delivered in three principal ways. FRT involves repeated small doses, usually less than 2 Gy and not with high conformality, being delivered over a period of weeks. Fractionated stereotactic radiotherapy (FSRT) requires more precise direction and conformality and may involve a hypofractionated regime of fewer and larger doses. Stereotactic radiosurgery (SRS) is highly selective and conformal with, classically, only one dose of around 12 Gy to the tumor margin (though the definition allows for up to five doses).

FRT has been used for the treatment of VS from at least 1945, at first usually in incompletely resected tumors, and such postoperative irradiation has been shown to decrease the chance for recurrence following subtotal resection from 46 to 6%.s. Literatur

SRS for VS was first suggested by Leksells. Literatur in 1971 but did not become widespread until after 1990 when the improved delineation provided by MRI allowed conformal targeting. A recent studys. Literatur of 440 patients followed for more than 10 years after SRS showed progression-free survival of 93% at 5 years and of 92% at 10 years, with 100% facial nerve preservation if the prescription dose was less than 13 Gy.

FSRT became an alternative after the success of SRS had been demonstrated, perhaps with the aim of improving hearing preservation. A recent large reviews. Literatur of 449 cases from Germany showed local control was 97% at 36 months, 95% at 60 months, and 94% at 120 months, with no statistical difference between FSRT and SRS. “Useful hearing” was preserved in 85% of the patients. Loss of useful hearing was observed in 14% in the FSRT group and in 16% in the SRS group.

In another recent review, Conley and Hirschs. Literatur also concluded that SRS and FRT are equally effective treatment modalities and that current evidence supports use of radiation for small-to-medium-sized primary and recurrent VSs with optimal dosing below 13 Gy. It is also recommended in poor surgical candidates and for those who do not desire observation or surgery.

24.4 Malignant Transformation in Vestibular Schwannoma

There have been, to date, 29 reports of MTVS after radiation (Table 24‑1 ).s. Literatur However, the quantitated significance of this presumed radiation induction has not been clarified except in neurofibromatosis type 2 (NF2) where the incidence of malignancy is high in relation to the numbers treated.s. Literatur

Table 24.1 Malignant transformation following radiation treatment
Authors and year	Age (y), sex	NF	Type of RT	Histological type	Cahan’s criteria	Latency (mo)
Akamatsu et al 2010s. Literatur	67, F	No	SRS	MPNST	Yes	90
Bari et al 2002s. Literatur	28, F	Yes	SRS	MPNST		48
Baser et al 2000s. Literatur	NS, NS	Yes	SRS	MPNST		NS
	NS, NS	Yes	SRS	MPNST		NS
	NS, NS	Yes	SRS	MPNST		NS
Carlson et al 2010s. Literatur	25, F	Yes	SRS	Triton		120
Comey et al 1998s. Literatur	50, M	No	SRS	Rhabdomyosarcoma		60
Demetriades et al 2010s. Literatur	37, M	No	SRS	MPNST	Yes	120
Hanabusa et al 2001s. Literatur	51, F	No	SRS	Sarcoma	Yes	6
Hasegawa et al 2013s. Literatur	NS, NS	NS	SRS	MPNST		NS
Ho and Kveton 2002s. Literatur	14, F	Yes	SRS	NS		7
Kubo et al 2005s. Literatur	55, M	No	SRS	MPNST		NS
Maire et al 2006s. Literatur/Markou et al 2012	45, F	No	CRT	MPNST		231
McEvoy and Kitchen 2003s. Literatur	22, M	Yes	SRS	NS		24
Muracciole et al 2004s. Literatur	61, F	No	SRS	Triton		72
Newell and Pollack 2012s. Literatur	50, M	No	Yes	MPNST		NS
Norén 1998s. Literatur	18, F	Yes	SRS	MPNST		60
Pollock et al 1998s. Literatur	NS, NS	NS	SRS	Triton		NS
Puataweepong et al 2012s. Literatur	34, F	No	SRS	MPNST		72
Scheithauer et al 2009s. Literatur	32, M	Yes	CRT	MPNST		324
Schmitt et al 2011s. Literatur	51, M	No	SRS	Sarcoma		87
Shin et al 2002s. Literatur; Kurita 1997	26, F	No	SRS	MPNST	Yes	72
Tanbouzi Husseini et al 2011s. Literatur	20, M	Yes	SRS	MPNST		60
Thomsen et al 2000s. Literatur	19, F	Yes	SRS	Sarcoma	Yes	72
Van Rompaey et al 2009s. Literatur	53, F	No	SRS	MPNST		96
Wilkinson et al 2004s. Literatur	53, M	No	SRS	MPNST	Yes	48
Yanamadala et al 2013s. Literatur	51, F	No	SRS	MPNST	Yes	60
Yang et al 2010s. Literatur	74, M	No	SRS	Sarcoma	Yes	72
Seferis et al 2014s. Literatur	34, F	No	SRS	MPNST	Yes	72
Abbreviations: CRT, conformal radiotherapy; MPNST, malignant peripheral nerve sheath tumor; NF, evidence of neurofibromatosis; NS, not stated; RT, prior exposure to radiation; SRS, stereotactic radiosurgery. Source: Used with permission from Seferis C, Torrens M, Paraskevopoulou C, Psichidis G. Malignant transformation in vestibular schwannoma: report of a single case, literature search, and debate. J Neurosurg. 2014; 121 Suppl:160–166.s. Literatur

A total of 59 cases of malignant peripheral nerve sheath tumor (MPNST) of the vestibular nerve have been found reported in the literature, 29 cases occurring after radiation treatment, 25 cases arising spontaneously, and 5 cases occurring after surgery for benign disease (Table 24‑1 , Table 24‑2 , Table 24‑3 ).s. Literatur In those irradiated cases with prior benign histology and therefore totally conforming to Cahan’s criteria,s. Literatur the mean delay to malignant expression was 68 months. A greater proportion of patients with NF2 in the irradiated group is compatible with the increased susceptibility of NF2 cases to radiation, having multiple tumors. Of the 29 cases after radiation, 11 of 26 (42%) with available information were suffering from neurofibromatosis, and of the 30 cases occurring without prior radiation, the equivalent proportion was 5 of 29 (17%).

Table 24.2 Spontaneous occurrence of malignant vestibular nerve tumors
Authors and year	Age (y), sex	NF	RT	Histological type
Best 1987s. Literatur	24, F	Yes	None	Triton
Caporlingua et al 2014s. Literatur	50, F	No	None	Triton (?)
Chen et al 2008s. Literatur	62, F	No	None	MPNST
Earls et al 1994s. Literatur	NS, NS	NS	NS	Melanotic
Gong et al 2012s. Literatur	55, F	No	None	Triton
Gonzalez et al 2007s. Literatur	43, F	No	NS	MPNST
Gruber et al 1994s. Literatur	61, F	No	None	MPNST
Han et al 1992s. Literatur	47, F	No	None	Triton
Harada et al 2000s. Literatur	10, M	No	None	MPNST
Hernanz-Schulman et al 1986s. Literatur	NS, child	No	None	MPNST
Higami et al 1998s. Literatur	45, F	Yes	None	MPNST
Hong et al 2014s. Literatur	25, M	No	None	MPNST
Karami et al 2011s. Literatur	23, F	No	None	MPNST
Kudo et al 1983s. Literatur	54, M	No	None	MPNST
Kuzmik et al 2013s. Literatur	73, F	No	None	MPNST
Maeda et al 1993s. Literatur	38, M	No	None	MPNST
Matsumoto et al 1990s. Literatur	54, M	No	None	MPNST
Miller et al 1986s. Literatur	74, M	Yes (?)	None	Melanotic
Mrak et al 1994s. Literatur	40, M	No	None	MPNST
Saito et al 2000s. Literatur	69, M	No	None	Melanotic
Scheithauer et al 2009s. Literatur	32, M	Yes	None	MPNST
	26, F	No	None	MPNST
	5, M	No	None	MPNST
Suresh et al 2003s. Literatur	NS, NS	Yes	None	MPNST
Wei et al 2012s. Literatur	41, F	No	NS	MPNST
Abbreviations: MPNST, malignant peripheral nerve sheath tumor; NF, evidence of neurofibromatosis; NS, not stated; RT, prior exposure to radiation. Source: Used with permission from Seferis C, Torrens M, Paraskevopoulou C, Psichidis G. Malignant transformation in vestibular schwannoma: report of a single case, literature search, and debate. J Neurosurg. 2014; 121 Suppl:160-166.s. Literatur

Table 24.3 Malignant transformation of a benign entity
Authors and year	Age (y), sex	NF	RT	Histological type	Prior benign histological type	Latency (mo)
Gousias et al 2010s. Literatur	64, M	No	None	MPNST	No^a	120
McLean et al 1990s. Literatur	75, M	No	None	MPNST	Yes	11
Scheithauer et al 2009s. Literatur	67, M	No	None	MPNST	Yes	9
	56, M	No	None	MPNST	Yes	7
Son et al 2001s. Literatur	33, F	No	None	MPNST	Yes	2
Abbreviations: MPNST, malignant peripheral nerve sheath tumor; NF, evidence of neurofibromatosis; RT, prior exposure to radiation. Source: Used with permission from Seferis C, Torrens M, Paraskevopoulou C, Psichidis G. Malignant transformation in vestibular schwannoma: report of a single case, literature search, and debate. J Neurosurg. 2014; 121 Suppl:160-166.s. Literatur ^aNo histology report available, but MRI over 120 months clearly shows a benign process that progressed to malignant disease.

An independent studys. Literatur in patients with neurofibromatosis has revealed that in a population of 1,348 NF2 patients, 106 would have received radiosurgery. Malignant transformation occurred in five of these cases. This corresponds to a risk of 4,717 × 10^– ⁵, a very substantially greater risk than in non-NF2 patients.

However, it is less easy to quantify the risk in non-NF2 cases because the condition is very rare and the true incidence depends on the accuracy of reporting of individual cases. In particular, there may be a tendency to report MTVS after radiation more readily than cases arising spontaneously.

There are several reasons to assume that MTVS after radiation is a genuine entity. The first is the delay or latency from diagnosis to malignant expression. In the irradiated group, this is 68 months (in those with confirmative initial benign histology) or 85 months (all cases) compared with 7.2 months in those nonirradiated cases where there was a prior histological diagnosis. This would suggest that the irradiated cases are showing the delay required by the Cahan criteria for malignant induction, whereas the nonirradiated cases are already in the process of malignant expression. Secondly, the irradiated group has a larger proportion of cases in which the histology shows a sarcomatous element (8/27, or 29.6%) compared with the nonirradiated group (4/30, or 13.3%).s. Literatur Sarcomatous differentiation is known to be associated with irradiation and the overall incidence of postradiation sarcoma in patients who survive longer than 5 years following radiation therapy is about 0.1%.s. Literatur Thirdly, there has been a threefold increase in the number of case reports of MTVS since the year 2000 (Table 24‑4 ).s. Literatur If a delay period of 5 to 8 years, according to Cahan’s criteria, is added to the decade of 1990 when significant numbers of radiosurgical treatments began to be performed, then an increase in reported cases of MTVS would be expected from 2000 onward if radiation is a significant predisposing factor.

Table 24.4 Cases of malignant VSs presenting over time
Dates of publication of MPNST cases	No. of cases recorded
1983–1989	4
1990–1994	6
1995–1999	5
2000–2004	14
2005–2009	11
2010–2014	18
Abbreviation: MPNST, malignant peripheral nerve sheath tumor. Source: Used with permission from Seferis C, Torrens M, Paraskevopoulou C, Psichidis G. Malignant transformation in vestibular schwannoma: report of a single case, literature search, and debate. J Neurosurg. 2014; 121 Suppl:160-166.s. Literatur

The most important question is to evaluate the quantitative significance of radiation in the induction of MTVS. In relation to the number of VS presenting worldwide per annum of between 72,000 and 114,000,s. Literatur it has been calculateds. Literatur that there is a risk of developing a spontaneous malignancy between 1.32 × 10^– ⁵ and 2.08 × 10^– ⁵. If only the 25 cases not associated with NF2 are considered, then the chance becomes between 1.09 × 10^– ⁵ and 1.74 × 10^– ⁵.

Extrapolation from the records of the Leksell Gamma Knife Societys. Literatur and a survey by the Acoustic Neuroma Associations. Literatur suggests that a very provisional total number of VS cases treated by radiation worldwide could be 115,333. In relation to the 29 patients with postirradiation MTVS recorded over 20 years, the risk is 29 in 115,333 or 25.1 × 10^– ⁵. If patients with neurofibromatosis are excluded from this analysis, there remain 18 patients with MPNST associated with radiation and so the risk for malignant transformation in the absence of neurofibromatosis is reduced to 15.6 × 10^–5. This represents a 9 to 14 times increased probability of malignancy in relation to the spontaneous incidence of between 1.09 × 10^–5 and 1.74 × 10^–5. Compared with MTVS, the frequency of reporting other induced malignancies is smaller.

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