cranial irradiation has been widely used as a therapeutic method treating a wide variety of lesions , particularly neoplasms . though radiation therapy of central nervous system is usually well - tolerated
, it does occasionally cause clinically significant long - term toxicity such as late delayed radiation necrosis and irradiation - related arteriopathy with stroke14 ) . among other complications induction of neoplasm
radiosurgery is not free from this problem although there are only a few reported cases14 ) .
we report a case of glioblastoma which was developed after gamma knife radiosurgery ( gks ) for meningioma .
a 47-year - old woman presented with headache , anosmia , and visual dimness . large extra - axial mass originating from olfactory groove and both frontal base was found on mri ( fig .
she underwent gross total tumor removal , and the pathological diagnosis of meningotheliomatous meningioma was confirmed . approximately 1 year after surgery
she underwent gks with 16 gy of marginal dose at 50% isodose line ( fig .
three years after initial radiosurgery , the subsequent mri scan revealed tumor progression at a location different from the previous recurrence .
she underwent radiosurgery with 13 gy of marginal dose and she was subjected to third gks with 15 gy of marginal dose on local recurrent lesion after 2 years from second gks ( fig .
2b , c ) . at 58 months from the initial gks , which is also
72 months from the first operation the patient experienced severe headache with vomiting and a huge new lesion was found in the area of the previous radiosurgery ( fig .
she was treated with concomitant chemo - radiotherapy ( total dose of irradiation 6000 cgy over 30 fractions and oral temozolomide 75 mg / m / day during the radiotherapy period ) followed by adjuvant chemotherapy with oral temozolomide .
first cycle was consisted of 150 mg / m / day temozolomide for 5 days , and subsequent 5 cycles were maintained with 200 mg / m / day for 5 days with 4 weeks interval between each cycle .
the tumor progression was significant at 11 months from the diagnosis of glioblastoma with neurological deterioration .
currently , she is alive at the time of this writing ( 15 months after diagnosis of glioblastoma ) with only supportive management .
there is now increasing concern regarding the potential for radiation - induced neoplasm , because of the intensive use of radiotherapy under a wide range of doses and treatment conditions resulting in a longer survival of brain tumor patients2,14,24 ) . despite the reported documents about the safety of radiosurgery , additional reports of glioma induction after radiosurgery
may temper its use in the treatment of benign lesions , such as meningiomas , particularly in younger patients10,12 ) .
the following criteria for radiation - induced neoplasms have been previously described7,11 ) : 1 ) a second tumor occurs within the field of irradiation used to treat the primary disease ; 2 ) the tumor is not present prior to irradiation , and there has been a reasonable interval between radiotherapy and the detection of the second tumor ( usually several years ) ; 3 ) a histological difference exists between the primary and subsequent tumor ; and 4 ) no known genetic or predisposing conditions to secondary malignancy are observed . in other
series , the criterion of latent period in radiation induced tumor was set to 5 years5,6,13 ) .
however , the " 5 year " period is not accepted as an absolute standard due to insufficient biologic evidence .
therefore , the present case could be considered as radiation induced tumor . in this way , the present case fits the all criteria and deserves to be diagnosed as radiation - induced malignancy .
however , radiation is now well recognized to be a trigger , not only a treatment , for cancer .
when the cells are irradiated , the probability of malignancy increases with dose , most likely with no threshold .
this view is based on experimental data showing that even a single photon can cause a base change leading to mutations that eventually can cause malignancy .
that is , a cancer induced by a small dose of radiation is not less harmful than a cancer induced by a large dose .
but , in the concept of biological equivalent dose , it is not a low - dose treatment , thus it could cause radiation induced tumor .
the lower incidence of radiation induced tumor in radiosurgery , could be explained by relatively smaller volume of normal tissue exposed to radiation compared to conventional radiation .
brada et al.4 ) reported the risk of second brain tumor formation in 334 patients treated for pituitary tumors with surgery and fractionated small - field irradiation ( median dose , 45 gy ) . with a cumulative follow - up period of 3760 years
, five patients developed second tumors ( two astrocytomas , two meningiomas , and one meningeal sarcoma ) .
the latency period is similar to what has been seen with fractionated therapy in the several years period after radiosurgery , and malignant tumors occur earlier than their benign tumor counterparts .
the cumulative risk of developing second brain tumors was 1.3% at 10 years and 1.9% at 20 years .
the relative risk of a second brain tumor was 9.38 compared with the normal population4 ) .
concerning the risk of developing a secondary neoplasm , several factors such as patient age , tissue vulnerability , radiation type and dose , underlying disease , and additional chemotherapy may all play an important role2,4,17,24,25 ) .
the relative risk of a secondary tumor following cranial irradiation in children has been estimated to be from 2.6 to 38.8 compared with the risk in the standard population8,15,22 ) while in the adult population it was estimated to be from 9.38 to 164,24 ) . in some cases ,
sadetzki et al.16 ) described 253 patients who developed meningiomas after radiation for tinea capitis .
the mean time from exposure to meningioma diagnosis was 36 years ( range , 12 - 49 year ) .
the authors found a higher incidence of multiple lesions , a younger age at diagnosis , and a higher percentage of calvarial lesions than in control patients who developed meningiomas without previous exposure to ionizing radiation16 ) .
in fact , the opposite may be more accurate , because high dose of radiation may sterilize the carcinogenic potential of a tissue by killing cells . only in those cells that are not killed deoxyribonucleic acid repair errors
the efficiency of tumor induction varies inversely with repair capacity , which in turn depends on the integrity of cell cycle check - points3,9 ) .
the general form of the dose - response curve for radiation associated second tumors is not clear , but several experiments on small animals suggest that the incidence increases with dose up to a maximum usually occurring between 3 and 10 gy , followed by a subsequent monotonic decrease3 ) .
there are also studies reporting that the highest incidence of radiation associated second tumors occurs at field peripheries , where the dose is less than at the field center9 ) .
most of the reported cases of radiation - associated tumor were related to conventional radiotherapy .
there were small number of malignant neoplasms after treatment of vestibular schwannoma , meningioma or arteriorvenous malformation ( table 1 ) .
considering that carcinogenetic potential is not necessarily dose - dependent and sublethal damage and repair errors are required for development of secondary tumors , single session radiosurgery may be relatively safer than fractionated radiotherapy with repeated chance of sublethal damage .
however , it seems that radiation - induced malignancy can occur within very low - dose peripheral regions as well as the full - dose regions . because the number of the patients who underwent radiosurgery and long - term follow up is much smaller than that treated with fractionated radiotherapy , relative safety of radiosurgery needs to be proven by further accumulation of clinical data .
as cumulative level of radiation increases by the repeated gks , so does the oncogenic opportunity . in the present study , the cumulative radiation dose of three repeated gks is higher than that of conventional radiotherapy , leading to oncogenic change . in our series ,
clinical outcome was not different and as poor as primary glioblastoma treated with standard treatment of surgery , radiotherapy and chemotherapy .
although malignancy after radiosurgery is very rare , its impact is not acceptable considering the benign nature of the primary disease .
no one knows for sure that how much dose of the radiation causes oncogenic transformation .
therefore , the possibility of this fatal complication should be balanced always in case of radiosurgery .
we experienced a case of radiosurgery - associated glioblastoma that developed after gks for meningioma .
although the risk of radiosurgery - associated tumor is very low , application of radiosurgery for benign tumors should be very cautious because its occurrence is fatal to the patients .
 we report a patient who underwent gamma knife radiosurgery to treat recurrent meningioma after microsurgery and thereafter developed secondary malignancy adjacent to the original tumor . 
 a 47-year - old woman had underwent resection of the olfactory groove meningioma . 
 then radiosurgery was done three times over 4 year period for the recurrent tumor . after 58 months from the initial radiosurgery , she presented with headache and progressive mental dullness . 
 huge tumor in bifrontal location was revealed in mri . 
 subsequent operation and pathological examination confirmed diagnosis of glioblastoma . 
 this case fits the criteria of radiation - induced tumor and the clinical implication of the issue is discussed . 
INTRODUCTION
CASE REPORT
DISCUSSION
CONCLUSION