In recent years, the use of radiosurgery or radiotherapy for benign brain tumors has increased significantly. Although long-term follow-up from several centers suggests that radiosurgery or radiotherapy is effective and safe, there are particular concerns regarding development of radiation-induced tumors. This article reviews the use of radiosurgery and fractionated radiation therapy with particular regard to new tumor induction and malignant transformation. The authors have found that the risk of radiation associated tumors after radiosurgery or radiotherapy for benign brain tumors is very low. All patients should be informed about the risks and consequences of radiation and microsurgery. The current practice standards for radiosurgery should not be modified because of this very low risk.
The risk of a radiation-induced tumor is a controversial topic. Patients who undergo radiosurgery or fractionated radiation therapy may be at an increased risk for development of a second tumor. The role of concomitant environmental and genetic risk factors is not known. Radiation-induced oncogenesis is a special a concern when radiation is used to manage benign tumors where prolonged survival is expected. Typically, radiation-induced tumors occur several years after radiation exposure.
The concept of radiation oncogenesis was established in 1948 by Cahan and colleagues, who observed 11 patients who had sarcomas that developed after radiotherapy was administered for bone tumors and breast cancer. They outlined the following criteria that must be met for a tumor to be designated as a radiation-induced tumor:
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certain latency interval is required between delivery of the radiation and tumor development.
The new tumor must arise in the irradiated region.
The new tumor must be histologically distinct from the original irradiated tumor.
There must be imaging evidence that the second tumor was not present at the time of irradiation.
The patient must not have a genetic predisposition for developing cancer.
Second tumor after fractionated radiation therapy
Several large studies have documented an increased incidence of a second tumor in the body after radiation therapy. Brenner and colleagues reported data from the National Cancer Institute’s Surveillance Epidemiology and End Result (SEER) program, which contained information on 51,584 men who had prostate cancer treated by radiotherapy and 70,539 treated by surgery. The risk of a second tumor was found to be higher by about 6% in the radiotherapy group. Boice and colleagues studied the risk of a second malignancy in various organs in 150,000 patients who had carcinoma of uterine cervix treated with either surgery or radiotherapy. The overall conclusion of this study was that an increased cancer risk was associated with radiation therapy compared with surgery. Bhatia and colleagues reported that 17 of 483 women treated with radiation for Hodgkin’s disease later developed breast cancer.
There is evidence establishing radiation as a carcinogen in animal and human studies. Since Cahan’s publication, radiation-induced neoplasms affecting the central nervous system (CNS) after fractionated radiotherapy have been documented. The risk of developing a radiation-induced tumor after fractionated radiation therapy to the CNS is estimated to be 1% to 3%. Most of these tumors are meningiomas, but gliomas, sarcomas, and schwannomas have been reported. The term “radiation-induced,” however, seems inappropriate, because it implies that there is definitive evidence at a molecular level that radiation was the causative factor. Such information has not been reported definitely. Perhaps “radiation-associated” may be a better term.
Published data on the risks of oncogenesis after fractionated radiotherapy delivered to the brain suggests that even very low doses (less than 2 Gy) have been associated with development of a second tumor. Between 1948 and 1960, 10,834 children in Israel received scalp irradiation to induce alopecia as part of the management of tinea capitis. Mean doses to the brain in these children were estimated to be 1.5 Gy for the entire cohort. The relative risk of tumor formation at 30 years compared with the general population was 18.8 for schwannomas, 9.5 for meningiomas, and 2.6 for gliomas. A clear-cut dose–response effect was observed, with the relative risk approaching 20 after doses of approximately 2.5 Gy. The mean latency interval was histology-dependent. In this study, the mean latency interval was 21 years for meningiomas, 15 years for schwannomas, and 14 years for gliomas.
In a study of radiation-associated second tumors, Sadetzki and colleagues described 253 patients who developed meningiomas after radiation for tinea capitis. The mean time from exposure to meningioma diagnosis was 36 years (range 12 to 49 years). The authors found a higher incidence of multiple lesions, a younger age at diagnosis, and a higher percentage of calvarial lesions in this group of patients compared with those who developed meningiomas without previous exposure to ionizing radiation. Dalton and colleagues reported on 1597 children who were treated with or without 28 Gy of prophylactic whole-brain irradiation as part of management for acute lymphoblastic leukemia. Thirteen second tumors were reported in this group, with a median follow-up period of 7.6 years. Five second tumors were in the CNS (four astrocytomas and one meningioma). The median latency interval for astrocytoma development was 9 years compared with 16.6 years for meningioma detection. Among the irradiated children, there was a 0.085 incidence per 100 patient years of developing second tumors compared with 0 incidence for those not receiving cranial irradiation.
Brada and colleagues reported the risk of second brain tumor formation in 334 patients treated for pituitary tumors with surgery and fractionated small-field irradiation therapy using 45 Gy. Five patients developed second tumors (two astrocytomas, two meningiomas, and one meningeal sarcoma) in long-term follow-up. The latency period for the second tumor was 6 to 21 years, with malignant tumors developing earlier than benign tumors. 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 population. In these patients, the irradiated volumes were typically small. On the basis of this experience, it seems that the relative risk of second tumor formation is substantially less than that seen in patients treated with larger-volume radiation. Balasubramaniam and colleagues reported a radiation-associated glioblastoma multiforme (GBM) in the temporal lobe 5 years after stereotactic fractionated radiation therapy (25 fractions) for a vestibular schwannoma. The area where the GBM developed had received between 1.45 to 6.94 Gy.
Second brain tumors after radiosurgery
Physicians have speculated for years that second tumor formation would be a risk for patients after radiosurgery. It also was thought, however, that the risk would be quite low, for the following reasons:
The irradiated volume is very small compared with traditional radiotherapy techniques.
The high single doses of radiation given to the target volume during radiosurgery would lead to cytotoxicity and not mutagenicity, which is required for tumor formation.
Volumes and doses of radiation along the entrance and exit pathways in radiosurgery are so small that the likelihood of second tumors would be less.
Nonetheless, there have been case reports of second tumor detection after radiosurgery. Currently, the number of patients worldwide who have received radiosurgery is now likely in excess of 500,000. Reported cases of a second tumor after radiosurgery can be grouped under the following three categories.
Radiosurgery-Associated Malignant Tumors
At present, five case reports ( Table 1 ) of new malignant tumors after radiosurgery meet Cahan’ criteria for radiation-induced neoplasm. Each of these cases is summarized. The new malignant tumors were discovered from 5.3 to 9 years after radiosurgery. Each of the secondary tumors were high-grade gliomas.
| Author,Year | Patient Age/Sex | Original Diagnosis | Margin Dose | Postradiosurgery Management | Duration | New Tumor |
|---|---|---|---|---|---|---|
| Yu, 2000 | 63/F | Meningioma | 20 Gy | Resection 2 years later | 7 years | GBM |
| Shamisa, 2001 | 57/F | Vestibular Schwannoma | 11 Gy | Resection 6 months later | 7.5 years | GBM |
| Kaido, 2001 | 14/M | Arteriovenous malformation | 20 Gy | None | 6 years | GBM |
| McIver, 2004 | 43.F | Malignant Melanoma Metastases | 15 Gy | Whole-brain radiation therapy | 5.25 years | Anaplastic astrocytoma |
| Berman, 2007 | 34/F | Arteriovenous malformation | 15 Gy | None | 9 years | GBM |
Case report 1
A 63-year-old woman underwent gamma knife radiosurgery for an imaging-defined meningioma. She received 20 Gy to the tumor margin, with a maximal dose of 40 Gy. Two years later, she underwent tumor resection because of persistent neurological symptoms and edema. The final pathological finding was a benign meningioma with adjacent radiation necrosis. Seven years after radiosurgery and 5 years after microsurgical resection, she was found to have an enhancing lesion in her left occipital lobe. Surgical resection revealed a GBM. It was estimated that the site at which the GBM originated had received 5 to 10 Gy at the time of radiosurgery 7 years earlier.
Case report 2
A 57-year-old woman underwent gamma knife radiosurgery for a left-sided vestibular schwannoma. She was treated with 11 Gy to margin of an 8.6-cm 3 tumor. Six-month follow-up MRI showed cystic degeneration of the lesion with mass effect on the brainstem. The patient underwent microsurgical resection. Pathological study demonstrated a benign schwannoma. Seven and one-half years later, she presented with progressive headaches, confusion, and left hemiparesis. She was found to have a large cystic, enhancing lesion in the left temporal lobe. Microsurgery was performed. Histology showed a GBM. The site at which the second tumor arose had received 4 Gy (14% of the maximum dose of 27.5 Gy) at the time of the radiosurgical treatment 7.5 years earlier.
Case report 3
A 14-year-old boy underwent gamma knife radiosurgery for a right parietal arteriovenous malformation (AVM). He received 20 Gy to the tumor margin and 40 Gy maximum dose. Two years after radiosurgery, angiography confirmed that the AVM had been obliterated. The patient developed headaches and vomiting 6 years after radiosurgery and was found to have a new lesion in the previous area of radiosurgery. Surgery was performed, and a GBM was discovered. The tumor seemed to arise within the full-dose region of his AVM radiosurgical treatment.
Case report 4
A 43-year-old woman underwent radiosurgery for three brain metastases from malignant melanoma. Following radiosurgery, she underwent whole-brain radiotherapy (37.5 Gy). Twenty-two months later, a second radiosurgical procedure was performed for a recurrent right temporal lobe metastasis. Five years and 4 months after initial radiosurgery, the patient was diagnosed with a cerebellar anaplastic astrocytoma. The area of cerebellum where the glioma developed had received a maximum dose of 7.7 Gy and 1.5 Gy during the previous two radiosurgery procedures, respectively. The additional role of fractionated radiation therapy in the development of astrocytoma is not clear.
Case report 5
A 34-year-old woman underwent embolization followed by radiosurgery for a 4.5 × 3.0 cm × 3.0 cm AVM located in the pineal region. A margin dose of 15 Gy at 70% isodose line was delivered using linear accelerator linear accelerator (LINAC) radiosurgery. The patient was lost to follow-up after treatment until she presented with a change in mental status, nausea, headaches, and a generalized seizure 9 years later. MRI demonstrated a 55 mm × 45 mm enhancing, heterogenous mass in the splenium of the corpus callosum. Maximal debulking was performed. Pathological examination demonstrated an infiltrating glial neoplasm consistent with a GBM.
Radiosurgery-Associated Benign Tumors
Only four cases of new benign tumors after radiosurgery are reported ( Table 2 ) in the literature that meet Cahan’s criteria for radiation-induced neoplasms.
| Author, Year | Patient Age/Sex | Original Diagnosis | Margin Dose | Duration | New Tumor |
|---|---|---|---|---|---|
| Loeffler 2003 | 41/male | Growth hormone- secreting pituitary adenoma | 87 Gy via 25 separate beams using non-Bragg peak proton radiosurgery | 16 years | Tuberculum sellae meningioma |
| Loeffler 2003 | 53/male | Growth hormone- secreting pituitary adenoma | 104 Gy via 12 fields using Bragg peak proton radiosurgery | 19 years | Vestibular schwannoma |
| Sheehan 2007 | 7/male | Arteriovenous malformation | 20 Gy using gamma knife | 12 years | Meningioma |
| Sheehan 2007 | 12/female | Arteriovenous malformation | 25 Gy using gamma knife | 10 years | Meningioma |
Case report 1
A 41-year-old man was diagnosed with acromegaly associated with a pituitary macroadenoma. After trans-sphenoidal surgery, he underwent non-Bragg peak proton radiosurgery in Moscow, receiving 87 Gy by means of 25 separate 10 mm beams. The beams were centered on the sella, where the prescription dose was delivered. Sixteen years after radiosurgery, he was evaluated for decreased vision, and repeat MRI confirmed a Tuberculum sellae meningioma. Partial resection of a benign meningioma was performed. The lesion was at the immediate periphery of the previous full-dose irradiated volume. The site at which the tumor arose was estimated to have received 30% to 50% of the prescribed radiation dose.
Case report 2
A 53-year-old man underwent resection of a pituitary adenoma associated with acromegaly. Bragg peak proton radiosurgery followed. He received a peak dose of 104 Gy by means of 12 separate fields. Nineteen years later, MRI disclosed a left vestibular schwannoma. The second tumor site had received 4.4 Gy during proton radiosurgery. A CT scan performed in 1979 showed no evidence of a soft tissue mass within the posterior fossa or any widening of the internal auditory canal. Although this case meets the criteria for a radiation-associated second tumor, one might argue that if an MRI scan had been performed in 1979, a small intracanicular schwannoma might have been detected.
Case report 3
A seven-year-old boy underwent gamma knife radiosurgery in May of 1990 using a margin dose of 15 Gy (maximum dose of 30 Gy) to treat a right basal ganglia arteriovenous malformation. He underwent a second radiosurgery for persistent nidus in 1995 with a margin dose of 20 G (maximum, 40 Gy). Follow-up MRI in 2002 showed a small dural-based tumor consistent with meningioma. This area received 0.6 Gy and 0.25 Gy during first and second radiosurgery procedures.
Case report 4
A 12-year-old girl underwent gamma knife radiosurgery in November of 1992 using a margin dose of 25 Gy (maximum dose of 28 Gy) to treat a 1.2 cc right temporal arteriovenous malformation. She underwent a second radiosurgery for persistent nidus in 1995 with a margin dose of 20 G (maximum, 40 Gy). Follow-up MRI 10 years after radiosurgery showed a mass consistent with meningioma in the previously treated area, which had received 25 Gy.
Radiosurgery-Associated Tumor Dedifferentiation
Spontaneous malignant transformation of tumors has been described in the literature, especially for glioma. There have been few case reports of malignant transformation after radiosurgery, but such transformation is considered tumor dedifferentiation and does not meet Cahan’s criteria for a radiation-induced tumor. These tumors differ from radiation-associated tumors in that the tumor was not induced by radiation but rather showed evidence of malignant progression that involves the cellular evolution of a benign lesion to malignancy ( Table 3 ). Kubo and colleagues in their report contended that detailed histology prior to radiosurgery is essential, as biologically aggressive schwannomas are encountered in 0.14% of cases. These tumors exhibit local invasiveness, frequent recurrences, and systemic dissemination. If not identified before radiosurgery, an erroneous diagnosis of radiation-associated malignancy can be made easily.
| Author, Year | Patient Age/Sex | CP Angle Tumor | Histology | Margin Dose | Duration | Final Histology |
|---|---|---|---|---|---|---|
| Comey, 1998 | 50/male | Sporadic | No | 14.4 Gy | 5 years | Triton tumor |
| Harada, 2003 | 7/male | Sporadic | VS | RT 27 Gy | 2 years | Malignant schwannoma |
| Wilkinson, 2004 | 53/male | Sporadic | VS | RT | 7 years | Malignant schwannoma |
| Hanabusa, 2001 | 51/female | Sporadic | VS | 15 Gy | 6 months | Malignant schwannoma |
| Shin, 2002 | 26/female | Sporadic | VS | 17 Gy | 6 years | Malignant schwannoma |
| Kubo et al, 2004 | 51/male | Sporadic | VS | 14 Gy | 8 months | Malignant schwannoma |
Of the 11 reported cases (see Table 3 ; Table 4 ) of tumor dedifferentiation, prior histology was available only in five. On the other hand, even if the tumor exhibits unambiguous histological proof of a benign pattern, its malignant progression after radiosurgery is not caused by irradiation necessarily. In fact, after incomplete surgical resection, radiosurgery frequently is used only if residual neoplasm shows radiologically confirmed regrowth. By itself, however, tumor growth after prior resection may result in malignant transformation of the initially benign tumor, either spontaneous, or even induced by microsurgery. Hanabusa and collegues reported on a patient who had tumor recurrence 4 years after initial microsurgical resection for a vestibular schwannoma (pathologically proven from the first operation). The patient underwent radiosurgery for the recurrence. Six months later, a second microsurgical resection was performed. At reoperation, the tumor was found to be a malignant schwannoma. Whether the malignant transformation occurred because of radiosurgery or was a result the natural history of malignant phenotype change is unclear. It is common for a surgeon to resect a benign meningioma, only to find at a second resection for recurrence that the tumor is now atypical or even malignant.
