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J Neuropathol Exp Neurol Copyright Ó 2006 by the American Association of Neuropathologists, Inc. Vol. 65, No. 3 March 2006 pp. 204Y216 REVIEW ARTICLE The Burden of Radiation-Induced Central Nervous System Tumors: A Single Institution’s Experience B. K. Kleinschmidt-DeMasters, MD, Jennifer S. Kang, MD, and Kevin O. Lillehei, MD Abstract Radiation-induced tumors of the central and peripheral nervous systems are becoming a noticeable subset of tumors seen at referral institutions. This paper outlines a single institution’s experience with 22 examples of secondary meningiomas, gliomas, and sarcomas that developed in adults. These tumors are being increasingly encountered by physicians, but the greatest burden is on the patients themselves, who not only experience the life-altering effects of the original tumor and the subsequent delayed cognitive effects of radiotherapy, but later develop a second intracranial neoplasm. We detail a particularly poignant example of a 34-year-old man who developed a high-grade sarcoma with rhabdomyosarcomatous and osteogenic elements. Local control was difficult over the next year, and he eventually developed cerebrospinal fluid dissemination and succumbed. Although radiation-induced neoplasm remain relatively infrequent numerically, each case reminds us of the need for new, less toxic, and more targeted therapies for brain neoplasms. Key Words: Radiation-induced glioblastoma, Radiation-induced glioma, Radiation-induced meningioma, Radiation-induced sarcoma, Rhabdomyosarcoma. INTRODUCTION Radium, when discovered by Marie and Pierre Curie at the turn of the last century, showed such promise for alleviating human suffering from disease. The world applauded the discovery of radium and polonium, awarding the Curies half the 1903 Nobel Prize for Physics (shared with Henri Becquerel who discovered radioactivity in 1896) and Madame Curie (after her husband’s death) the 1911 Nobel Prize for Chemistry for the characterization of radium (1). Radiation therapy was soon embraced by physicians as a treatment for tuberculosis and a variety of benign and From the Departments of Neurosurgery (BKK-D, JSK, KOL), Neurology (BKK-D), and Pathology (BKK-D), University of Colorado Health Sciences Center, Denver, Colorado. Send correspondence and reprint requests to: B. K. KleinschmidtDeMasters, MD, Department of Pathology, Box B216, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262; E-mail: [email protected] 204 malignant conditions. Almost immediately, however, animal experiments in 1910 and 1929 established the link between irradiation and sarcoma development, and case reports of sarcoma induction in humans began appearing by 1922 (2). Another early indication of the potential deleterious effects of radiation exposure was the deaths of both Curies as a result of its side effects, with Madame Curie dying of leukemia in 1934. It took until 1948, however, for Cahan et al to formally establish criteria for tumors deemed to be Bradiationinduced^ (2). Since he originally outlined his findings for sarcomas arising in patients radiated for benign bone lesions, his criteria have since been modified slightly (3, 4). First, the new tumor has to arise within the field of irradiation. Second, there has to be a histologically proven difference between the initial and the second tumor. Third, a sufficient latency period must exist between the irradiation and the development of the second tumor, usually cited as greater than 5 years (2, 4). Recently suggested criteria have included the need for a significantly higher incidence of a tumor type in an irradiated cohort than in an adequate control group (3); Badditional support is found if an animal model exists and a doseYresponse relationship exists^ (3). In the intervening 50 years, the central and peripheral nervous systems (CNS, PNS) have become well-recognized sites for a significant percentage of radiation-induced tumors. Nevertheless, until recently, the number of cases of radiation-induced CNS/PNS tumors that any one institution encountered was generally low (3). In 2004, we saw an unprecedented number of patients at our adult referral hospital with radiation-induced brain tumors, prompting this review. In that year, seven patients were seen for radiation-induced meningiomas, five of whom underwent resection; these represented 13% of the meningiomas operated on that year at our institution. A search of our Pathology and Neurosurgery Department files from 1991Y2005 disclosed 22 patients with radiation-induced CNS tumors, including 15 meningiomas, four high-grade gliomas, and three sarcomas. Three of the gliomas and 2 of the sarcomas were also seen recently (Table 1). Although these numbers are obviously influenced by referral patterns, the number of cases we have encountered in the last 5 years has certainly gotten our attention. J Neuropathol Exp Neurol Volume 65, Number 3, March 2006 Copyright @ 2006 by the American Association of Neuropathologists, Inc. Unauthorized reproduction of this article is prohibited. Year First Seen at UCHSC/ Year of Surgery(s) Age of Initial Radiation Exposure, Gender Time Interval to Diagnosis of RIN Radiation-Induced Meningiomas 1992/1992, Child, M ~30Y35 1992, 2002 years Current Age, Karnofsky Score (KS) Previously Treated Condition Location and Type of Initial Radiation Exposure 54 years, KS 60 Left otitis media XRT to left ear Hard/soft palate, maxillary sinus, L middle fossa, orbit WHO grade I, meningothelial* WHO grade I, meningothelial* WHO grade I meningothelial 44 X,-Y, -22 (17) WHO II, atypical WHO grade I, with focal myxoid change (small biopsy) Size and Location of RIN at Diagnosis Pathologic Findings (each resection listed separately) 41 years, M 11 years 53 years, KS 60Y70 Craniopharyngioma (slides reviewed) XRT to suprasellar space L frontal L parietal 4 x 2.5 cm 1999/1999 2 weeks, F 39 years 45 years, KS 100 Scalp hemangioma over torcular region XRT scalp hemangioma Torcular region 2001/2000, 2001, 2003 12 years, F 45 years KS 0 Died Recurrent R optic nerve glioma (first resected at age 3, no XRT) XRT to right orbit Right frontal lobe WHO grade II, atypical WHO grade III, anaplastic WHO grade III, anaplastic 2003/2004 8 years, M 41 years 49 years, KS 70Y80 Large facial hemangioma XRT to face Dural-based, bifrontal, invading ethmoids WHO grade I, transitional (small biopsy) 1998/2004 multiple meningiomas 3 years, F 31 years 40 years, KS 50 WHO II cerebellar astrocytoma (slides not obtainable) XRT to cerebellum Left occipital parasagittal WHO grade I, transitional* 2004/1997, 2004 Child, M ~20Y25 years 35 years, KS 60Y70 Left temporal ganglioglioma XRT to left temporal lobe L frontal parasagittal First meningioma in same site (1997) unavailable for review WHO grade I, meningothelial complex karyotype, including abnormalities of 1p Tumor resections 3, XRT, and temozolomide; recurrent L temporal lesions, abscess, focal seizures; cognitive delay, cranial neuropathies, gait disturbance As of 8/04, improving aphasia Tumor resection 1999, SRS; posttherapy venous hypertension treated with steroids and acetazolamide; good recovery, now works full-time; no residual Tumor resections in 2000 and 2001, the last followed by SRS to two residual nodules, XRT total 6000 cGy in 30 fractions with concomitant hydroxyurea; another recurrence in 2002 treated again with SRS; continued tumor growth, additional resection, and death in 2003 Multiple social and psychiatric problems, including mental health admissions; persistent headache, chronic narcotic use Multiple meningiomas followed since 1998, one resected in 2004 residual mental disability, ataxia, retinal necrosis, poor healing of scalp wound Works part-time as a cashier, back to his preoperative baseline, which includes decreased cognitive function and short-term memory; he lives alone, but is assisted by his parents for major tasks Radiation-Induced CNS Tumors 205 1999/2000, 2004 multiple meningiomas Interval Follow Up J Neuropathol Exp Neurol Volume 65, Number 3, March 2006 Ó 2006 American Association of Neuropathologists, Inc. Copyright @ 2006 by the American Association of Neuropathologists, Inc. Unauthorized reproduction of this article is prohibited. TABLE 1. Twenty-Two Radiation-Induced Neoplasms Seen at UCHSC Year First Seen at UCHSC/ Year of Surgery(s) Age of Initial Radiation Exposure, Gender 2003/1999, 2004 multiple meningiomas 10 years, F 2002/2002, 2003 2002/1996, 2002, 2003 meningioma + glioma Time Interval to Diagnosis of RIN Pathologic Pathologic Location and Type Size and Location Findings (each Findingsresection (each listed Size and Location of Initial of RIN at resection listed of RINDiagnosis at Radiation separately) Interval Follow Up separately) Interval Follow Up Diagnosis Exposure Current Age, Karnofsky Score (KS) Previously Treated Condition 23 years 39 years, KS 70 Acute lymphocytic leukemia (ALL) XRT to skull base Right orbit First meningioma in same site (1999) unavailable for review WHO grade I, meningothelial* 20 mo, F 24 years 26 years, unknown ALL Whole brain radiation therapy, 18 Gy XRT in 10 fractions Midline falx and bilateral frontal lobes WHO grade III, anaplastic meningioma WHO grade III, anaplastic meningioma 3 years, M 12 years and 18 years 24 years, KS 70 WHO grade II posterior fossa ependymoma (slides reviewed) Cranio spinal XRT At age 15, left frontal lobe, at age 21, two lesions in left cerebellum Age 15, Btypical^ meningioma (not reviewed) Age 21,WHO IV glioma 2 years, F 35 years 37 years, KS 70 Posterior fossa tumor (original slides and report not obtainable) XRT to posterior fossa R temporalY parietal lobe, 9 cm in greatest diameter WHO grade I, transitional* Deletion 1p36 by FISH 2004 8 years, F 55 years 63 years, KS 90 Scalp ringworm XRT to scalp No tissue available (not biopsied) 1991/1993 Multiple meningiomas 5 years, F 63 years Unknown Right cerebellar tumor XRT to skin and cerebellum, calculated to be 3240 cGy and 4000 cGy, respectively 3 lesions: L sphenoid, 2 cm, L cavernous sinus, 4.5 cm, and L clivus, 2 cm 3 lesions: large, L occipital region tentorium, along R tentorial edge, 1 cm, and R falx, 2 cm WHO grade II, atypical Translocations 1q21, 3q21, 7q, 12q22 -24, 16p11, absence of monosomy 22 J Neuropathol Exp Neurol Volume 65, Number 3, March 2006 Ó 2006 American Association of Neuropathologists, Inc. 2005/2005 Multiple meningiomas Residual right proptosis and V1 hypersensitivity; stable residual right skull base and cavernous sinus mass, with two new enhancing dural nodules being followed radiographically Lost to follow up; as of 9/04, s/p resection 2 and XRT, 5040 cGy in 28 doses, to growing parafalcine lesion; refused adjuvant chemotherapy; neurologically stable but cognitively delayed L frontal mass resected in 1996; cerebellar lesions incidentally found on MRI, resected in 2002 and 2003; Gliadel wafers placed at second resection, followed by XRT and concurrent BCNU; currently on Iressa with episodic bouts of diarrhea; attends college part-time, no neurologic deficits Multiple meningiomas along tentorium increasing in size; mentally disabled but without focal neurologic deficits; unemployed and living with parents; she suffers from mild headaches History of Bmigraine^ headaches for 45 years; otherwise neurologically intact; three meningiomas were incidentally found after an auto accident in which she was driving Lost to follow up; as of 1995, she suffered from gait difficulties and imbalance; she had an uneventful postoperative course; at 4 months after resection of the large left tentorial lesion, there was no growth of the remaining lesions Kleinschmidt-DeMasters et al 206 Copyright @ 2006 by the American Association of Neuropathologists, Inc. Unauthorized reproduction of this article is prohibited. Table 1. (continued) 33 years 55 years, KS 90 2005/2005 17, F 34 years 49 years, KS 80 Radiation-Induced Gliomas 2002/1996, 3 years, M 2002, 2003 meningioma + glioma 12 years and 18 years 2002/2002 22 years, M 1993/1993 2004/2004 207 XRT to right neck R foramen magnum to C1, intradural No tissue available (not biopsied) ALL Craniospinal XRT 7 cm right sphenoid wing WHO I, meningothelial* Deletion 1p36 by FISH 24 years, KS 70 WHO grade II posterior fossa ependymoma (slides reviewed) Cranio spinal XRT At age 15, left frontal lobe, at age 21, 2 lesions in left cerebellum 1996, age 15, Btypical^ meningioma; 2002, 2003 age 21, WHO IV glioma No EGFR amp; 3Y10 copies of Ch. 7 5 years KS 0 Died (tumor at age 27 years) ALL Craniospinal XRT, thought to be on the order of 18Y24 Gy, but records are not available 3-cm right cerebellar enhancing lesion with smaller satellite lesions in the right pons and cerebellum WHO IV, glioblastoma 27 years, M 60 years Pilocytic astrocytoma XRT to cerebellum Cerebellum WHO IV glioblastoma MIB-1: 14.7%. TP 53: G5%. No EGFR amp; no gain of Ch. 7 54 years, M 20 years KS 0 Died (tumor at age 87 years) KS 0 Died (tumor at age 74 years) XRT to neck Enhancing, 6-cm-long mass in the spinal cord from C3 to C7 WHO III, anaplastic astrocytoma Underwent XRT to cervical spine with concomitant temozolomide; as of 4/05, there was no residual tumor on MRI; he died in 5/05 in home hospice Radiation-Induced Sarcomas 2001/2001, 23 years, M 2001, 2002 11 years XRT to left parietooccipital lesion Solid L parietooccipital region mass Grade IV sarcoma, fibrosarcoma with osteogenic Resection of sarcoma in 2/01, wound infection and abscess 7/01; no follow-up tumor KS 0 Died (tum- Non-Hodgkin lymphoma BThroat cancer,^ path unavailable Diagnosed as glioblastoma in 1990 (on review found to be Stable radiographic appearance of shape and size of mass; no focal neurologic deficits; intermittent R arm pain Loss of vision in right eye; residual tumor in resection cavity, possible SRS in future L frontal mass resected in 1996; cerebellar lesions incidentally found on MRI, resected in 2002 and 2003; Gliadel wafers placed at second resection, followed by XRT and concurrent BCNU; currently on Iressa with episodic bouts of diarrhea; attends college part-time, no neurologic deficits Underwent tumor debulking in 2002 complicated by postoperative cerebrospinal fluid leak; the residual was treated with temozolomide 14/28 days and XRT 50.4 Gy in 28 fractions; subsequently received SRS boost to the brainstem lesion and BCNU; he suffered mild imbalance and coordination problems with a gradual decline until death in 10/03 Experienced a rapid decline in clinical status and died in 12/ 93, 2 months after presenting to our hospital Radiation-Induced CNS Tumors 21, F J Neuropathol Exp Neurol Volume 65, Number 3, March 2006 Ó 2006 American Association of Neuropathologists, Inc. Copyright @ 2006 by the American Association of Neuropathologists, Inc. Unauthorized reproduction of this article is prohibited. 2004 Year First Seen at UCHSC/ Year of Surgery(s) Current Age of Initial Age, Time Interval Karnofsky Radiation to Diagnosis Score Exposure, of RIN Gender (KS) or at age 34 years) 22 years, F 15 years KS 0 Died (tumor at age 37 years) 2001/2001 26 years, F 19 years KS 0 Died (tumor at age 45 years) pleomorphic xanthoastrocytoma with anaplastic features) Diagnosed as malignant astrocytoma with focal oligodendroglioma, 1976 (on review, thought to be ganglioglioma with anaplastic oligodendroglial or neurocytic component) Diagnosed as oligodendroglioma, 1983 (slides unavailable for review, but residual, low-grade heavily calcified neoplasm adjacent to sarcoma in 2001 resection) Size and Location of RIN at Diagnosis extending into the adjacent lateral ventricle. XRT to right frontal resection cavity R frontal subcutaneous tissues, bone, and dura with lymphovascular and venous sinus invasion XRT to L parietooccipital resection cavity, 5940 rads in 33 fractions L parietooccipital resection cavity Pathologic Findings (each resection listed separately) sarcoma and rhabdomyosarcoma elements Grade IV sarcoma, malignant fibrous histiocytoma (undifferentiated high-grade pleomorphic sarcoma) with focal myxoid features Grade IV sarcoma, malignant fibrous histiocytoma (undifferentiated highgrade pleomorphic sarcoma) with extensive myxoid features Interval Follow Up therapy until referral to our institution in 10/01 at which point he had repeat resection and I-131 treatment through gliaSite balloon; subsequently had SRS and chemotherapy with ifosfamide and mesna; global aphasia, decreased attention, and right hemiparesis; he died in 8/02 Following diagnosis of the radiation-induced sarcoma, she had two resections and reconstruction procedures of her scalp and cranium; she suffered a rapid decline (2 months) in her neurologic and overall clinical state; she died in 3/98 Patient did reasonably well postoperatively; she went home and led a relatively independent lifestyle (~KS 70) until a more rapid decline near the time of death in 11/03 *, Meningioma with 1Y2 Batypical features^ such as small cell formation, prominent nucleoli, hypercellularity, or loss of architectural pattern, but insufficient to meet criteria for WHO grade II atypical meningioma. KS, Karnofsky score in 2005; current age is as of 2005; RIN, radiation-induced neoplasms; XRT, radiation therapy; WHO, World Health Organization; EGFR, epidermal growth factor receptor; Ch., chromosome; SRS, stereotactic radiosurgery; MRI, magnetic resonance imaging; BCNU, carmustine; FISH, fluorescent in situ hybridization. J Neuropathol Exp Neurol Volume 65, Number 3, March 2006 Ó 2006 American Association of Neuropathologists, Inc. 1998/1997, 1998 Previously Treated Condition Location and Type of Initial Radiation Exposure Kleinschmidt-DeMasters et al 208 Copyright @ 2006 by the American Association of Neuropathologists, Inc. Unauthorized reproduction of this article is prohibited. Table 1. (continued) J Neuropathol Exp Neurol Volume 65, Number 3, March 2006 Ó 2006 American Association of Neuropathologists, Inc. Radiation-Induced CNS Tumors 209 Copyright @ 2006 by the American Association of Neuropathologists, Inc. Unauthorized reproduction of this article is prohibited. Kleinschmidt-DeMasters et al The recent literature also suggests that radiationinduced CNS/PNS tumors are becoming a more noticeable subset of tumors seen at other referral centers, both in the United States and Europe (4, 5). These tumors can be a treatment challenge for radiation oncologists, given that some of these patients have already received maximal doses of radiation to that brain region at the time of their original lesion. However, most importantly, these tumors are a burden for the individual patient who with great relief overcomes and survives the rigors of surgery, radiation therapy, and often chemotherapy for their original tumor, only to have inflicted on them, years later, another tumor of iatrogenic, albeit currently nonpreventable, origin. In addition, many of these patients suffer from years’ worth of severe cognitive deficits primarily as a result of the original radiation therapy. We detail the unfortunate case history from one such recent patient to underscore the suffering that such patients experience. Illustrative Case History This 34-year-old man first presented in 1989 at the age of 23 years with seizures and headaches. He was treated by his primary care physician with phenytoin and no imaging studies were acquired. One year later, he developed a right visual field cut, prompting a visit to an ophthalmologist who ordered a computed tomography scan and discovered a left parietal tumor. The patient was referred to a neurosurgeon. The left parietal tumor was resected on February 3, 1990, and diagnosed as glioblastoma multiforme. He received postoperative radiation therapy but no chemotherapy. He underwent yearly serial magnetic resonance imaging (MRI) studies for approximately 4 years, which were negative for recurrence. He was then lost to follow up but was able to find work as a dishwasher. He experienced significant cognitive deficits attributable to his cranial external beam radiation therapy. In October 2000, 10 years after his first tumor was resected, the patient developed headaches and numbness on the right side of his body. He did not seek medical attention until he started having difficulty with speech, for which he consulted a different neurosurgeon in January 2001. An MRI scan revealed a recurrent enhancing mass in the same region as his original tumor. The patient underwent surgical excision of the mass on February 2, 2001; it was unclear from the operative report whether this was a gross total or subtotal resection. High-grade sarcoma with osteogenic differentiation J Neuropathol Exp Neurol Volume 65, Number 3, March 2006 was documented (Fig. 1A, B). The patient received no adjuvant therapy. In July 2001, the patient experienced recurrent symptoms and MRI showed abnormalities in the site of the resection bed. Surgery revealed an abscess in the region of his previous operation. The abscess was drained, and blood cultures grew out Staphylococcus aureus; he was treated with 6 weeks of antibiotics. He had persistent expressive aphasia but did well until a follow-up scan on October 8, 2001, showed recurrence of the tumor. He was referred to our institution, the fourth hospital and fourth neurosurgeon involved in his care. On admission, MRI scan showed a very large parietooccipital tumor that had rapidly regrown within the site of the operative bed, extending from the dura to the left lateral ventricle. A separate nodule was seen in the choroid plexus. A gross total resection was performed on November 7, 2001. Histologically, the tumor was a high-grade, complex sarcoma with a predominantly herringbone fibrosarcomatous pattern and focal osteogenic differentiation, similar to that seen on the previous resection specimen from 2001 (Fig. 1A, B). Additional rhabdomyosarcomatous differentiation was present in the new specimen, evidenced by cells with abundant eosinophilic cytoplasm (Fig. 1C) and vague cross-striations (Fig. 1D). These cells were strongly immunoreactive for desmin (Fig. 1E), myo-D1 (Fig. 1F), and myogenin. Mitotic activity was very brisk (Fig. 1A, C). There was no immunoreactivity for S-100 protein and no evidence of nerve sheath origin. No residual glioma was found in material from either resection. A GliaSite balloon was placed into the resection cavity with delivery of 50 Gy to a depth of 1 cm over 72 hours using radioactive iodine. After treatment, the radioactive iodine and the balloon were removed. The resection bed on follow-up MRI scanning appeared clean (Fig. 1G). Unfortunately, several months after resection, he developed a left cerebellopontine angle subarachnoid metastasis for which he received gamma knife therapy on March 14, 2002. A subcutaneous mass along his occipital incision appeared and was excised on April 24, 2002. Over the ensuing months, he developed cerebrospinal fluid dissemination of his tumor with enhancing masses developing along the ependymal surfaces of the ventricle, within the subarachnoid space overlying the frontal lobe (Fig. 1H) and adjacent to the pons (Fig. 1I). Smaller lesions were found in the cerebellum, in the left internal auditory canal, and along the spine. Several cycles of chemotherapy with ifosfamide and mesna proved ineffective and he died on August 18, 2002. FIGURE 1. (A–I) Thirty-four-year-old man (patient from the illustrated case history) with a postradiation complex sarcoma manifesting a fibrosarcoma pattern and brisk mitotic activity ([A] and [H, E], 200), foci of osteogenic differentiation ([B] and [H, E], 200), and rhabdomyosarcomatous differentiation (C–F). Note the large cells with abundant eosinophilic cytoplasm ([C] and [H, E], 600) that contained ill-defined cross-striations at high power ([D, H], and [E], 1250) and were strongly immunoreactive for desmin ([E], 600) and Myo-D1 ([F], 600). Neuroimaging studies (T1-weighted, with gadolinium) chronicle the unfortunate progression of his tumor. Despite a relatively clean resection bed after his second resection (G), he developed tumor regrowth, cerebrospinal fluid dissemination over the surface of the frontal lobe (H), and adjacent to pons (I), as well as cerebellar lesions; he died shortly thereafter. 210 Ó 2006 American Association of Neuropathologists, Inc. Copyright @ 2006 by the American Association of Neuropathologists, Inc. Unauthorized reproduction of this article is prohibited. J Neuropathol Exp Neurol Volume 65, Number 3, March 2006 Ó 2006 American Association of Neuropathologists, Inc. Radiation-Induced CNS Tumors 211 Copyright @ 2006 by the American Association of Neuropathologists, Inc. Unauthorized reproduction of this article is prohibited. Kleinschmidt-DeMasters et al DISCUSSION This illustrative case represents one of the more graphic examples of the 22 patients we have seen at our institution with secondary, radiation-induced CNS neoplasms (Table 1). The recurring left parietooccipital lesion in this patient was diagnosed as a complex radiation-induced sarcoma, with rhabdomyosarcomatous and osteogenic foci of differentiation, clearly arising in the site of his original tumor. We obtained his original 1990 slides from the outside hospital and, on review, discovered that the original resected tumor diagnosed as glioblastoma was actually a pleomorphic xanthoastrocytoma (PXA) with anaplastic features, a tumor type that was not characterized until the late-1990s (6, 7). This patient’s slides from 1990 showed pleomorphic tumor cells and copious numbers of eosinophilic granular bodies with more focal lymphocytic collections, xanthic cells, Rosenthal fibers, and elongate spindle tumor cells, all features of PXA, but with superimposed necrosis, microvascular proliferation, and mitoses. PXA with anaplastic features is a tumor with behavior similar to a grade 3 anaplastic astrocytoma. Long-term survival with glioblastoma is rare and slides from the original resection should be rereviewed whenever possible, because in over 40% of instances, an alternate diagnosis explains the patient’s better outcome (8). Obtaining old slides and records is becoming more of a challenge, because patients are now often seen at multiple institutions (as shown here) and slides from 20 years ago are often no longer available. Nevertheless, we were able to review this patient’s original surgical pathology material and the alternate diagnosis likely accounts for his 11-year interval before diagnosis of his radiation-induced sarcoma (8). Radiation-induced brain sarcoma is one of several radiation-induced tumors types that can be seen in the central and peripheral nervous systems, along with meningiomas, high-grade gliomas, schwannomas (9), and malignant peripheral nerve sheath tumors (Table 1). Kaschten et al, in their 1995 review of the literature on radiation-induced glial and CNS sarcomatous tumors, found that of the sarcomas, 58% were diagnosed as fibrosarcomas, 22% as meningeal sarcomas, and 14% as osteogenic sarcomas (10). Case reports of malignant fibrous histiocytomas, chondrosarcomas, mesenchymal chondrosarcomas, Bfibrochondrosarcoma^ (11), and other unusual Bmixed^ forms have also appeared (12Y14). Our other two radiation-induced sarcomas were undifferentiated high-grade pleomorphic sarcomas (malig- J Neuropathol Exp Neurol Volume 65, Number 3, March 2006 nant fibrous histiocytoma, myxoid type) (Fig. 2A). The literature seems to suggest that radiation-induced sarcomas are more likely to contain mixed mesenchymal elements compared with spontaneous primary CNS sarcomas, but this is difficult to prove because of the case-report nature and relative rarity of all primary CNS sarcomas. The life-altering effects of the original tumor, the subsequent delayed effects of radiation therapy that resulted in cognitive deficits, and the eventual development of a second radiation-induced tumor illustrate the obvious burden suffered by the patient we illustrate in the case history, his family, and his physicians. We were acutely aware that, as physicians, we were unwittingly responsible for this scenario. All three of the patients with radiation-induced sarcoma seen at our institution have died from their tumors (Table 1). However, on a more optimistic note, the patients with radiation-induced meningioma treated at our institution have generally had better clinical outcomes than much of the literature on radiation-induced meningiomas would have led us to believe. Indeed, many clinicians have taken the message from the literature that all patients with radiationinduced meningiomas do poorly and are difficult to manage surgically and medically. In 2004, seven patients with radiation-induced meningiomas were seen by our neurosurgical service, five of whom underwent surgical resection of their tumor. Two patients are being followed expectantly with stable MRI scans (Table 1), including one with multiple skull base meningiomas 6 decades after receiving radiation treatment for tinea capitis (Fig. 2B, C). Several other of the 15 total patients with meningiomas had been followed for 5 to 10 years before their tumors required first excision or reresection, underscoring the fact that a significant percentage of radiationinduced meningiomas can be relatively indolent in their behavior (Table 1). In general, our patients with radiation-induced meningioma have been managed with individually tailored treatment regimens, including gross total resection whenever possible, reresection when necessary, and occasionally stereotactic radiosurgery. There has thus far been only one known death among our meningioma patients (Table 1). However, several patients live with significant cognitive disabilities primarily related to their original radiation therapy. Hence, although an inordinately high number of FIGURE 2. (A) The other two radiation-induced sarcomas were undifferentiated high-grade pleomorphic sarcomas, with focal myxoid features, and did not contain mesenchymal elements (hematoxylin and eosin [H&E], 200). (B, C) Neuroimaging studies (coronal views, T1-weighted, with gadolinium) from one of our postradiation meningioma cases in which the woman had received low-dose radiation for tinea capitis decades earlier; note the multiplicity of lesions. (D–F) Neuroimaging studies (coronal views, T1-weighted, with gadolinium) from a woman who had received high-dose therapeutic radiation for a posterior fossa tumor (unknown type) decades earlier; again note multiplicity of lesions. Although the ominous-appearing, largest lesion was aggressively resected ([D], preoperative scan; [E], postoperative scan), it was a World Health Organization grade I meningioma ([F], H&E, 100), albeit with loss of chromosome 1p. (G–I) Radiation-induced gliomas can occur in unusual locations and at unusual ages, as illustrated by an anaplastic astrocytoma occurring in the cervical spinal cord of a 74-year-old man ([G], H&E, 600), a glioblastoma in the cerebellum of an 87-year-old man ([H], H&E, 200), and a glioblastoma in the cerebellum of a 21-year-old man ([I], H&E, 200). 212 Ó 2006 American Association of Neuropathologists, Inc. Copyright @ 2006 by the American Association of Neuropathologists, Inc. Unauthorized reproduction of this article is prohibited. J Neuropathol Exp Neurol Volume 65, Number 3, March 2006 patients with radiation-induced meningiomas indeed Bdo not do well,^ confirming some clinicians` impression, the patients` problems are not solely the result of their radiation-induced meningioma(s). Our experience has been that even with recurrence, many of the tumors can be controlled effectively. The link between radiation and meningioma development is a strong one. Meningiomas were the most frequent cranial tumor type to develop in the atomic bomb survivors of Hiroshima and Nagasaki. The most recent Life Span Study (LSS), published in Cancer in 2004, demonstrated a doserelated excess of tumors of the CNS and pituitary gland among a cohort of 80, 160 survivors (15). All examples were reviewed by pathologists to verify diagnoses. Meningiomas were followed in frequency by neuroepithelial tumors, schwannomas, and pituitary tumors. The overall incidence of tumors increased steadily with age and was stable over time. Tumors were histologically similar to their spontaneously occurring counterparts. Recent studies have confirmed earlier work showing that persons who underwent six or more full mouth dental x-rays over a lifetime also have a significantly increased risk of meningioma (16). Other types of dental x-rays, i.e. posterior bitewings, lateral cephalometric, and panoramic radiographs, are not statistically associated with increased risk. The risk is especially pronounced in patients who had full-mouth series 15 to 40 years ago, at a time when radiation exposure was much greater that it currently is today in dental practice (16). The majority of meningiomas in the past have been attributable to low-dose irradiation to the scalp for tinea capitis. Recently, more examples of meningiomas arising after moderate (1000Y2000 rads) to high-dose therapeutic radiation (>2000 rads) have been reported (3). Generally, the lower the dosage of radiation the patient receives, the longer the interval to development of the meningioma. Radiation-induced meningiomas in patients previously treated with low-dose radiation for tinea capitis (mean 1.4Y1.8 Gy [17]) have been recognized for decades and show a strong doseYresponse relationship, with the relative risk approaching 20 after doses of approximately 2.5 Gy (18). Treatment of large numbers of immigrants between 1948 and 1960 subsequently lead to BAn Iatrogenic Epidemic of Benign Meningioma^ in Israel (19). Sadetzki et al, in a large study of 253 radiation-induced meningiomas developing after tinea capitis treatment, found a mean latency period of 36 years (range, 12Y49 years), multiplicity in 16% of cases, calvarial location in 59%, and a nonsignificant higher recurrence rate compared with the control meningioma group (17). Other recent studies have shown similar figures for multiplicity (15%) and a relatively low recurrence rate, but have additionally shown a high percentage of malignant meningiomas (29%) and second neoplasms other than meningioma (28%) (20). Radiation-induced meningiomas occurring after therapeutic moderate- or high-dose cranial radiation therapy (XRT) often occur in patients who received their therapy in childhood and develop their tumors after a shorter latency period (5Y20 years) than those who received low-dose scalp Ó 2006 American Association of Neuropathologists, Inc. Radiation-Induced CNS Tumors irradiation for tinea capitis. An inverse relationship exists between radiation dose and interval to second tumor development and supports a doseYresponse relationship (21). Younger children treated with high-dose radiotherapy may be particularly vulnerable to chromosomal injury and occasionally have developed radiation-induced meningiomas at intervals as short as 12 and 14 months after therapy (reviewed in [21]). The patients we have encountered at our institution received their radiation in childhood for a potpourri of benign and malignant conditions and all have developed tumors many years after therapy (Table 1). This assortment of background conditions, including facial hemangioma (22), parallels that found in several other series (23, 24) and reinforces the idea that the original condition for which the patient received radiation therapy has little or no influence on the host’s tendency to develop a radiationinduced neoplasm. Children with acute lymphoblastic leukemia (ALL) are another group well known to be at risk for secondary brain tumors as a result of the administration of prophylactic cranial irradiation (20, 22, 25). One group of authors felt the problem was significant enough to suggest that BBecause of the possibility of benign, potentially curable brain tumors occurring after cranial irradiation, it may be wise to carry out occasional cranial imaging in the follow-up of these patients. No routine imaging follow-up is needed after chemotherapy alone^ (26). Numerous reports document adults with radiationinduced meningiomas after cranial irradiation for pituitary adenomas and craniopharyngiomas (although radiationinduced meningiomas are only one of several adverse side effects attributable to radiotherapy in this cohort such as visual deterioration and pituitary dysfunction) (27, 28). Follow-up studies of patients with pituitary adenoma suggest that the risk for a given patient receiving radiation is relatively low. No secondary brain tumors were found in one study of 325 pituitary tumor patients in Sweden (29), and one malignant brain tumor (expected 0.3) and one meningioma were encountered in 296 patients with pituitary tumors in Edinburgh from 1962 to 1990 (30). However, the actual numbers of patients with radiation-induced meningiomas, especially following high-dose radiation therapy, seen at a given institution is starting to increase, as we have illustrated. A British group recently cited radiation-induced meningiomas occurring after highdose irradiation as accounting for 3.7% of the meningiomas seen at their institution over a 10-year time period (5). AlMefti et al last year published his findings on 16 radiationinduced meningiomas seen from 1992 to 2001 at his institution; 14 of these were secondary to high-dose radiation the patients had received (4). No signature histologic features of radiation-induced meningiomas have been identified thus far. Although early studies suggested that radiation-induced meningiomas were Ba recognizable entity^ (31) as a result of their cytological atypia, the majority of tumors meet current criteria for World Health Organization (WHO) grade I (32). Al Mefti et al noted the lack of correlation between histologic features 213 Copyright @ 2006 by the American Association of Neuropathologists, Inc. Unauthorized reproduction of this article is prohibited. Kleinschmidt-DeMasters et al and tumor behavior (4). His series was comprised entirely of referral cases, and hence 100% had had a first recurrence after initial resection elsewhere by the time they were seen at his institution (4). Of this already recurrent group, 62% went on to have a second and 17% a third recurrence, but only 38% were either WHO grade II atypical or WHO grade III anaplastic meningiomas. Progesterone receptor status and low proliferation index did not correlate with benign tumor behavior in his study. He attributed the aggressive behavior in his cohort to the presence of multiple clonal aberrations in all tumors studied with chromosomal alterations on 1p (89% of cases) and 6q (67% of cases) (4). Others have also noted loss of 1p, 7p, and 6q by CGH (33) and a gene on 1p13 has been implicated (34). Although loss of 1p is the most common alteration in radiation-induced meningiomas, it is also found in approximately 30% of spontaneous meningiomas (35, 36) and hence is not a signature genetic hallmark of radiationinduced lesions. Mutations in NF2 gene, seen in up to 50% of spontaneous meningiomas, are generally not observed in radiation-induced meningiomas (37, 38), nor are mutations in the PTEN, TP53, HRAS, KRAS, and NRAS genes (38). On review, many of our meningiomas possessed one or two of the cytologic features seen in WHO grade II atypical meningiomas (i.e. small cell formation, hypercellularity, macronucleoli, or sheeting architecture) but fell short of diagnostic criteria for atypical meningioma; these cases are denoted by an asterisk (*) in Table 1. This finding may well reflect the increased genetic aberrations in these tumors. Location and size are also problems with radiationinduced tumors. Al Mefti et al noted that skull base location might preclude gross total removal (4). We concur with this interpretation and note the increasing number of patients who originally received radiation therapy for posterior fossa tumors and later developed skull base meningiomas compared with the predominance of more surgically accessible calvarial tumors in patients radiated for tinea capitis (17). This, along with multiplicity (Fig. 2B, C) and enormous size (Fig. 2D), further add to the difficulties in surgical management. Aggressive surgical resection can be performed in some patients (Fig. 2E postoperative scan from patient illustrated in Fig. 2D). Despite the ominous preoperative neuroimaging features, this was a grade I meningioma (Fig. 2F). Fluorescence in situ hybridization studies showed deletion of 1p36. On occasion, we have been able to supplement surgical resection or biopsy with postoperative radiosurgery for tumor residual with successful control on short-term follow up (Table 1). Like radiation-induced meningiomas, radiation-induced gliomas may occur after low-dose irradiation for tinea capitis or after high-dose therapeutic cranial radiation therapy for pituitary adenomas, acute lymphoblastic leukemia, or various types of brain tumors such as ependymoma, medulloblastoma, and astrocytomas. Tsang et al estimated the relative risk for glioma arising after radiation therapy for patients with pituitary adenomas to be 16 times greater than the general population in Ontario, with secondary glioma occurring at a risk of 1.7% at 10 years and 2.7% at 15 years (39). Radiation-induced gliomas are usually glioblastomas or anaplastic astrocytomas, although radiation-induced gliosar- 214 J Neuropathol Exp Neurol Volume 65, Number 3, March 2006 comas, low-grade astrocytomas (40), primitive neuroectodermal tumors (41, 42), and oligodendroglioma (43) have been reported. Tumors develop 5 to 25 years postradiation, with an average of 9.6 years (40). Similar to the situation with radiation-induced meningiomas, there are no signature histologic features unique to radiation-induced gliomas. Brat et al recently assessed radiation-induced highgrade gliomas for possible alterations in p53, PTEN, KRAS, EGFR, and p16 and found molecular alterations similar to those seen in spontaneously arising, primary (de novo) highgrade astrocytomas, with the possible exception of an absence of PTEN mutations in the radiation-induced group (44). Young age is a distinctive feature in some radiationinduced gliomas (40, 44). All but one of the nine patients reported by Brat et al were less than 34 years of age, whereas the 10 patients in the series by Salvati et al ranged in age from 18 to 63 years (40). Two of our four gliomas were very old and developed tumors in unusual locations, including a 74-year-old man with anaplastic astrocytoma of the cervical spinal cord after radiation therapy for Bthroat cancer^ (Fig. 2G) and an 87-year-old man with a glioblastoma of the cerebellum after radiation therapy for a pilocytic astrocytoma decades previously (Fig. 2H). The latter patient with a 52-year interval and one of our meningiomas with a 63-year latency period have been previously reported (45, 46). These two patients illustrate the disquieting fact that some radiated patients may never outlive the risk for developing secondary neoplasms. Unusual locations are, of course, a byproduct of which area of brain was originally radiated. Our other two patients with gliomas were young and also had cerebellar glioblastomas (Fig. 2I). Interestingly, one of our patients with radiation-induced glioblastoma multiforme (GBM) still survives, paralleling a recently reported case report citing response to chemotherapy in a radiation-induced GBM who survived 44 months (47). Recent animal studies provide the strongest evidence that gliomas are directly radiation-induced (48, 49). In a recent study of 3-year-old male primates that received fractionated WBRT (350 cGy for 5 days per week for 2 weeks to a total dose of 3500 cGy), nine of 11 animals developed glioblastomas. Tumors occurred at intervals of 2.9 to 8.3 years after radiation and comparative genomic hybridization showed deletions in the primate chromosome (Ch.) corresponding to human Ch. 9 (50). Thus far, at least five cases of radiation-induced neoplasms have been reported after stereotactic radiosurgery (39, 51, 53), although the risks for these appear lower after radiosurgery than after fractionated radiation therapy (54). Loeffler et al have suggested that the proper term for new, histologically different tumors arising in previously irradiated resection cavities is Bradiationassociated^ because there is Bno definitive evidence at a molecular level that radiation [was] the causative factor. Such information is simply not available in [these] patients^ (52). Given the track record with external beam cranial radiation therapy and the number of years it took to appreciate the full oncogenic effects of radiation, it will take time before the long-term effects of radiosurgery as a carcinogen are fully realized. It should be noted, however, Ó 2006 American Association of Neuropathologists, Inc. Copyright @ 2006 by the American Association of Neuropathologists, Inc. Unauthorized reproduction of this article is prohibited. J Neuropathol Exp Neurol Volume 65, Number 3, March 2006 that the types of tumors thus far anecdotally reported after stereotactic radiosurgery are identical in type to those reported after inadvertent radiation exposure (atomic bomb survivors, people receiving dental x-rays), after low-dose radiation therapy for tinea capitis, and after high-dose therapeutic radiation doses. Hence, it is highly likely that CNS/PNS tumors occurring after stereotactic radiosurgery are radiation-induced as well. Many thousands of patients around the world have received efficacious treatment with either external beam cranial XRT or stereotactic radiosurgery (>200,000 patients over the past 30 years [54])Vtherapy that undoubtedly saved numerous lives or prolonged survival. Fortunately, a very small number of such individuals have had the burden of developing a second, radiation-induced CNS/PNS neoplasm. Currently, we know little about what individual host factors might influence such an occurrence (except for children with neurofibromatosis or Li-Fraumeni syndrome who appear to be at increased risk for developing their second malignancies within the radiation portals [55]). The suffering of even one patient as a result of an iatrogenic therapy regimen should prompt us to seek safer, equally efficacious therapeutic alternatives. Neuropathologists play an important role as Bwatchdogs^ for a variety of new and innovative treatment regimens, especially for gliomas. We need to continue to advocate for full autopsies to be performed on each and every patient who dies after a new treatment protocol and we strongly believe that provision for autopsy follow up should be written into every clinical trial. We need to continue to document the adverseVand favorableVeffects of each new variation in therapy bravely attempted by our clinical colleagues. This documentation, of course, needs to be made in nonjudgmental fashion, recognizing that for many desperate patients with brain tumors, we have little else to currently offer them except experimental therapy. Most patients enter these trials fully cognizant of the risks they are taking and know that they will most assuredly die if no therapy is given. Nevertheless, neuropathologists Bstand in the gap^ and must provide autopsy or surgical pathology feedback in a timely fashion, so that treatment regimens can be modified, improved, and in rare cases, discarded, to optimize care for the next patient who comes along. There is little doubt that in the future, radiation therapy will be of historic interest only and replaced entirely by safer and more effective alternatives. At that time, young physicians may shake their heads (as we do today when recalling some of the early treatments used for multiple sclerosis or syphilis) and ask how in the world we physicians in the year 2006 could have ever used the best-known carcinogenVradiationVas a therapy for cancer. ACKNOWLEDGMENTS The authors thank Dr. Arie Perry for helpful comments and gratefully acknowledge Ms. Susan Peth for expert manuscript preparation, Ms. Amy Kendall in the University of Colorado Tumor Registry for obtaining survival data, and Ms. Lisa Litzenberger for photographic assistance. This study Ó 2006 American Association of Neuropathologists, Inc. Radiation-Induced CNS Tumors was supported in part by funds from the Michele PlachyRubin Foundation for Brain Tumor Research at UCHSC. 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