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Radiation-induced glioma following CyberKnife® treatment of metastatic renal cell carcinoma: a case report
© Abedalthagafi and Bakhshwin; licensee BioMed Central Ltd. 2012
Received: 16 February 2012
Accepted: 21 June 2012
Published: 3 September 2012
Post-stereotactic radiation-induced neoplasms, although relatively rare, have raised the question of benefit regarding CyberKnife® treatments versus the risk of a secondary malignancy. The incidence of such neoplasms arising in the nervous system is thought to be low, given the paucity of case reports regarding such secondary lesions.
Here we describe a case of a 43-year-old Middle Eastern woman with primary clear cell renal cell carcinoma and a metastatic focus to the left brain parenchyma who presented with focal neurologic deficits. Following post-surgical stereotactic radiation in the region of the brain metastasis, the patient developed a secondary high-grade astrocytoma nearly 5 years after the initial treatment.
Although the benefit of CyberKnife® radiotherapy treatments continues to outweigh the relatively low risk of a radiation-induced secondary malignancy, knowledge of such risks and a review of the literature are warranted.
Given the advent of new stereotactic radiosurgery techniques, important questions have arisen regarding the risk of secondary malignancy following such treatments. On the basis of previous case reports, the incidence of such a secondary malignancy following CyberKnife® therapy has been estimated at between 0.7% and 1.9% [1, 2]. Specifically, reports of post- stereotactic radiation-induced central nervous system (CNS) tumors have been few, and reflect a higher incidence in patients with a predisposition to cancer, such as those with neurofibromatosis. Typically, such a secondary malignancy is thought to arise within a period of 5 to 10 years post-treatment, given a review of the literature involving such patients. Here we present a case of radiation-induced glioma in a patient following treatment with stereotactic radiosurgery for a metastatic renal cell carcinoma focus to the brain. It should be noted that although there remains a notable risk of developing a secondary CNS malignancy following radiotherapy treatment, it is thought that the overall benefits of such treatments outweigh the risk of developing a secondary neoplasm.
A year later, the patient began developing neurological symptoms including right arm tremor, weakness, dizziness, and abnormal sensation on her right cheek. An MRI scan of her brain revealed a large left frontal mass stemming from the insular that subsequently enlarged and grew upwards, creating a midline shift. After 5 months, she underwent resection of the mass. Pathology showed radiation necrosis with sheets of foamy macrophages and gliosis of the surrounding brain tissue with focal perivascular chronic inflammation. IHC staining was negative for keratin, with no evidence of viable tumor cells. IHC staining was positive for CD68 indicating the histiocytic nature of many of the foamy cells.
The criteria for a radiation-induced neoplasm as originally outlined by Cahan et al. in 1948  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. Our patient’s case seems to fulfill all of these criteria. Extensive imaging was performed at the time of the original diagnosis and no evidence of a lesion was found in the left occipital-parietal area. Although 5 years is the generally accepted minimum latency period for developing a radiation-induced malignancy, cases with shorter latency periods have been reported. This case is complicated by the fact that the patient received both whole brain irradiation as well as Gamma Knife stereosurgery, but the affected secondary location was definitely within the irradiated field. Tumor markers show the histologic disparity between the original brain metastases and the new lesion. Finally, the patient was not known to have any genetic conditions that predispose toward carcinogenesis.
The risk of developing a secondary nervous system cancer, particularly meningiomas, following conventional fractionated radiation exposure has been well established. Studies of the survivors of the atomic bombings of Hiroshima and Nagasaki indicate an increased incidence of meningiomas in this population [4–6]. Epidemiological data derived from child immigrants to Israel after World War II who received radiation for the treatment of tinea capitis showed an increase of up to 6.9-fold in nervous system neoplasms (including meningiomas, gliomas, and nerve sheath tumors) . There has also been some suggestion of greater numbers of meningiomas and gliomas in adults who underwent radiotherapy for pituitary adenomas [8, 9]. Finally, experiments on primates given therapeutic doses of fractionated whole-brain radiation resulted in high rates of induction of glioblastoma multiforme , and over 100 human cases in which a glioma appeared after radiotherapy have been identified . Nevertheless, the absolute risk of developing a radiation-induced neoplasm after receiving radiotherapy to the CNS remains relatively low and it is generally thought that the overall benefits of the treatment outweigh the negative complication rate of alternative treatments .
The risk of oncogenesis due to stereotactic radiosurgery has generally been believed to be lower than that of conventional radiotherapy. Although traditional practices involve low-dose radiation delivered to a high volume of tissue, stereotactic methods allow for high-dose, low-volume radiation with a steep drop in dosage outside the targeted zone. The perception of increased safety in radiosurgery has been supported by an analysis of nearly 5000 English patients who underwent Gamma Knife therapy . This study found only one new case of astrocytoma following radiation in comparison to a predicted incidence of 2.47 in the general population. A major criticism of the study has been that the mean follow-up interval was only just over 6 years. However, the follow-up of over 1200 of the patients was greater than 10 years.
Case reports of secondary malignancy following stereotactic radiosurgery
Indication for radiation
Location of primary lesion
Location of secondary lesion
Comey 1998 
Noren 1998 
Thomsen 2000 
Yu 2000 
Kaido 2001 
Right parietal lobe
Right parietal lobe
Shamisa 2001 
Inferior temporal lobe
Bari 2002 
Malignant nerve sheath tumor
Salvati 2003 
Right frontal region
Right frontal, corpus callosum
Shin 2002 
Malignant nerve sheath
McIver 2004 
Left parietal parasagittal region
Sanno 2004 
Right parietal lobe
Sheehan 2006 
Right basal ganglia
Assumed meningioma (?)
Right lateral middle cranial fossa
Sheehan 2006 
Assumed meningioma (?)
Right temporal lobe
Balasubramaniam 2007 
Right temporal lobe
Berman 2007 
Corpus callosum and/or right parietal lobe
Carlson 2009 
Bilateral posterior fossae
Inferior right medulla and cerebellomedullary cistern
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
We would like to thank Dr Norio Azumi for his support of this work.
- Sheehan J, Yen CP, Steiner L, Sheehan J, Yen CP, Steiner L: Gamma Knife surgery-induced meningioma. Report of two cases and review of the literature. J Neurosurg. 2006, 105 (2): 325-329. 10.3171/jns.2006.105.2.325.View ArticlePubMedGoogle Scholar
- Brada M, Rajan B, Traish D, Ashley S, Holmes-Sellors PJ, Nussey S, Uttley D: The long-term efficacy of conservative surgery and radiotherapy in the control of pituitary adenomas. Clin Endocrinol (Oxf). 1993, 38 (6): 571-578. 10.1111/j.1365-2265.1993.tb02137.x.View ArticleGoogle Scholar
- Cahan WG, Woodard HQ, Higinbotham NL, Stewart FW, Coley BL: Sarcoma arising in irradiated bone; report of 11 cases. Cancer. 1948, 1 (1): 3-29. 10.1002/1097-0142(194805)1:1<3::AID-CNCR2820010103>3.0.CO;2-7.View ArticlePubMedGoogle Scholar
- Shibata S, Sadamori N, Mine M, Sekine I: Intracranial meningiomas among Nagasaki atomic bomb survivors. Lancet. 1994, 344 (8939–8940): 1770-View ArticlePubMedGoogle Scholar
- Shintani T, Hayakawa N, Hoshi M, Sumida M, Kurisu K, Oki S, Kodama Y, Kajikawa H, Inai K, Kamada N: High incidence of meningioma among Hiroshima atomic bomb survivors. J Radiat Res (Tokyo). 1999, 40 (1): 49-57. 10.1269/jrr.40.49.View ArticleGoogle Scholar
- Yonehara S, Brenner AV, Kishikawa M, Inskip PD, Preston DL, Ron E, Mabuchi K, Tokuoka S: Clinical and epidemiologic characteristics of first primary tumors of the central nervous system and related organs among atomic bomb survivors in Hiroshima and Nagasaki, 1958–1995. Cancer. 2004, 101 (7): 1644-1654. 10.1002/cncr.20543.View ArticlePubMedGoogle Scholar
- Ron E, Modan B, Boice JD, Alfandary E, Stovall M, Chetrit A, Katz L: Tumors of the brain and nervous system after radiotherapy in childhood. N Engl J Med. 1988, 319 (16): 1033-1039. 10.1056/NEJM198810203191601.View ArticlePubMedGoogle Scholar
- Erfurth EM, Bülow B, Mikoczy Z, Svahn-Tapper G, Hagmar L: Is there an increase in second brain tumours after surgery and irradiation for a pituitary tumour?. Clin Endocrinol (Oxf). 2001, 55 (5): 613-616. 10.1046/j.1365-2265.2001.01385.x.View ArticleGoogle Scholar
- Minniti G, Traish D, Ashley S, Gonsalves A, Brada M: Risk of second brain tumor after conservative surgery and radiotherapy for pituitary adenoma: update after an additional 10 years. J Clin Endocrinol Metab. 2005, 90 (2): 800-804.View ArticlePubMedGoogle Scholar
- Lonser RR, Walbridge S, Vortmeyer AO, Pack SD, Nguyen TT, Gogate N, Olson JJ, Akbasak A, Bobo RH, Goffman T, Zhuang Z, Oldfield EH: Induction of glioblastoma multiforme in nonhuman primates after therapeutic doses of fractionated whole-brain radiation therapy. J Neurosurg. 2002, 97 (6): 1378-1389. 10.3171/jns.2002.97.6.1378.View ArticlePubMedGoogle Scholar
- Salvati M, Frati A, Russo N, Caroli E, Polli FM, Minniti G, Delfini R: Radiation- induced gliomas: report of 10 cases and review of the literature. Surg Neurol. 2003, 60 (1): 60-67. 10.1016/S0090-3019(03)00137-X.View ArticlePubMedGoogle Scholar
- Muracciole X, Régis J: Radiosurgery and carcinogenesis risk. Prog Neurol Surg. 2008, 21: 207-213.View ArticlePubMedGoogle Scholar
- Rowe J, Grainger A, Walton L, Silcocks P, Radatz M, Kemeny A: Risk of malignancy after Gamma Knife stereotactic radiosurgery. Neurosurgery. 2007, 60 (1): 60-65.View ArticlePubMedGoogle Scholar
- Comey CH, McLaughlin MR, Jho HD, Martinez AJ, Lunsford LD: Death from a malignant cerebellopontine angle triton tumor despite stereotactic radiosurgery. Case report. J Neurosurg. 1998, 89 (4): 653-8. 10.3171/jns.1998.89.4.0653.View ArticlePubMedGoogle Scholar
- Noren G: Long-term complications following Gamma Knife radiosurgery of vestibular schwannomas. Stereotact Funct Neurosurg. 1998, 70 (suppl 1): 65-73.View ArticlePubMedGoogle Scholar
- Thomsen J, Mirz F, Wetke R, Astrup J, Bojsen-Møller M, Nielsen E: Intracranial sarcoma in a patient with neurofibromatosis type 2 treated with Gamma Knife radiosurgery for vestibular schwannoma. Am J Otol. 2000, 21 (3): 364-70. 10.1016/S0196-0709(00)80046-0.View ArticlePubMedGoogle Scholar
- Yu JS, Yong WH, Wilson D, Black KL: Glioblastoma induction after radiosurgery for meningioma. Lancet. 2000, 356 (9241): 1576-7. 10.1016/S0140-6736(00)03134-2.View ArticlePubMedGoogle Scholar
- Kaido T, Hoshida T, Uranishi R, Akita N, Kotani A, Nishi N, Sakaki T: Radiosurgery- induced brain tumor. Case report. J Neurosurg. 2001, 95 (4): 710-3. 10.3171/jns.2001.95.4.0710.View ArticlePubMedGoogle Scholar
- Shamisa A, Bance M, Nag S, Tator C, Wong S, Norén G, Guha A: Glioblastoma multiforme occurring in a patient treated with Gamma Knife surgery. Case report and review of the literature. J Neurosurg. 2001, 94 (5): 816-21. 10.3171/jns.2001.94.5.0816.View ArticlePubMedGoogle Scholar
- Bari ME, Forster DM, Kemeny AA, Walton L, Hardy D, Anderson JR: Malignancy in a vestibular schwannoma. Report of a case with central neurofibromatosis, treated by both stereotactic radiosurgery and surgical excision, with a review of the literature. Br J Neurosurg. 2002, 16 (3): 284-289. 10.1080/02688690220148888.View ArticlePubMedGoogle Scholar
- Shin M, Ueki K, Kurita H, Kirino T: Malignant transformation of a vestibular schwannoma after Gamma Knife radiosurgery. Lancet. 2002, 360 (9329): 309-10. 10.1016/S0140-6736(02)09521-1.View ArticlePubMedGoogle Scholar
- McIver JI, Pollock BE: Radiation-induced tumor after stereotactic radiosurgery and whole brain radiotherapy: case report and literature review. J Neurooncol. 2004, 66 (3): 301-5.View ArticlePubMedGoogle Scholar
- Sanno N, Hayashi S, Shimura T, Maeda S, Teramoto A: Intracranial osteosarcoma after radiosurgery–case report. Neurol Med Chir (Tokyo). 2004, 44 (1): 29-32. 10.2176/nmc.44.29.View ArticleGoogle Scholar
- Balasubramaniam A, Shannon P, Hodaie M, Laperriere N, Michaels H, Guha A: Glioblastoma multiforme after stereotactic radiotherapy for acoustic neuroma: case report and review of the literature. Neuro Oncol. 2007, 9 (4): 447-453. 10.1215/15228517-2007-027.View ArticlePubMedPubMed CentralGoogle Scholar
- Berman EL, Eade TN, Brown D, Weaver M, Glass J, Zorman G, Feigenberg SJ: Radiation-induced tumor after stereotactic radiosurgery for an arteriovenous malformation: case report. Neurosurgery. 2007, 61 (5): E1099-10.1227/01.neu.0000303207.92617.4e. discussion E1099View ArticlePubMedGoogle Scholar
- Carlson ML, Babovic-Vuksanovic D, Messiaen L, Scheithauer BM, Neff BA, Link MJ: Radiation-induced rhabdomyosarcoma of the brainstem in a patient with neurofibromatosis Type 2. J Neurosurg. 2010, 112 (1): 81-87. 10.3171/2009.6.JNS09105.View ArticlePubMedGoogle Scholar
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