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Show ORIGINAL CONTRIBUTION Intracranial Malignancies Occurring More Than 20 Years After Radiation Therapy for Pituitary Adenoma Wen Ying Wu- Chen, MD, Dina A. Jacobs, MD, Nicholas J. Volpe, MD, Joseph O. Dalmau, MD, PhD, and Mark L. Moster, MD Abstract: A 37- year- old woman developed a left third cranial nerve palsy 28 years after radiation for a nonsecreting pituitary adenoma. Imaging disclosed a left parasellar mass and a midbrain/ pontine signal abnormality. Biopsy of the parasellar mass revealed a malignant sarcoma. The brainstem abnormality was presumptively diagnosed as a malignant glioma. A 63- year- old man developed a malignant astrocytoma of the left optic nerve and chiasm 23 years after partial excision and radiation of a nonsecreting pituitary adenoma. Both patients died of their malignancies. Although secondary malignancies have been described in this setting, such long latencies have not been reported. ( J Neuro- Ophthalmol 2009; 29: 289- 295) R adiation therapy is a mainstay of treatment for many nervous system tumors. Among them are pituitary adenomas, which may be treated with fractionated radiation or single- dose radiosurgery to control tumor growth and hormone hypersecretion ( 1). Complications of radiotherapy include neurovascular damage, radionecrosis, progressive fibrosis, deletion of oligodendroglial and neural stem cell populations, alterations in cytokine expression, and dis-ruption of cellular DNA ( 2). Radiation- associated tumors are a late complication 2. They may arise within the brain, dura, cranial bones, or spinal and peripheral nerves. We present two patients who developed secondary malignancies 23 and 28 years after radiotherapy. Such long latencies have not been reported previously. CASE REPORTS Case 1 A 37- year- old woman had a pituitary adenoma at age 9 years. The tumor was resected and the final pathologic identification was a nonsecreting adenoma. After the surgery, she underwent a course of radiation therapy at an unknown dose with resolution of a visual field defect and no evidence of optic neuropathy at that time. She had a recent diagnosis of hypertension. Twenty- eight years later, she developed left upper lid ptosis and diplopia. At the onset of diplopia, examination elsewhere was notable for a dilated and sluggishly reactive left pupil, left upper lid ptosis, and complete left adduction, supraduction, and infraduction deficits. The findings were considered to be reflective of a left third cranial nerve palsy. Brain MRI was interpreted as showing abnormal T2 signal bilaterally in the pons extending to the medulla, believed to be consistent with chronic ischemic change, inflammation, or demyelination. Lumbar puncture revealed a normal opening pressure and normal constituents, and results of a cerebral angiogram were also normal. We examined her 8 months later. Visual acuity was 20/ 20 in both eyes, visual fields were full to confrontation, and color plates were fully identified. There was no afferent pupillary defect. Results of dilated ophthalmoscopy were unremarkable. There was a complete left third cranial nerve palsy with a mydriatic pupil that did not constrict to direct light. The remainder of the neurologic examination was normal. Repeat brain MRI ( Fig. 1) revealed focal enhance-ment in the left parasellar region and in the left midbrain at the site of exit of the left third cranial nerve. The MRI T2 signal change in the caudal brainstem described on the earlier MRI was still present. Magnetic resonance spectroscopy showed elevation of choline with respect to creatinine and depression of Department of Neurology ( WYW- C), Temple University Hospital, Philadelphia, Pennsylvania; Departments of Neurology and Neuro-ophthalmology ( DAJ, NJV, JOD), Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania; and Division of Neuro-ophthalmology ( MLM), Albert Einstein Medical Center, Wills Eye Institute and Thomas Jefferson University School of Medicine; Philadelphia, Pennsylvania. The authors have no financial interest relevant to the subject of the manuscript. Address correspondence to Mark L. Moster, MD, Einstein at Elkins Park, 60 East Township Line Road, Elkins Park, PA 19027; E- mail: markmoster@ gmail. com J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 289 N- acetylaspartate ( NAA) in the parts of the lesion involving the pons and midbrain. Portions of the lesion also demonstrated elevated lactate. The appearance was con-sidered consistent with a primary neoplasm of the brainstem. She was given a presumptive diagnosis of a post- radiation brainstem glioma and treated with temozolomide. The parasellar lesion was biopsied with the final pathologic analysis revealing a highly malignant sarcoma. Despite receiving several cycles of intravenous cyclophosphamide, vincristine, and doxorubicin over 8 weeks, the brainstem lesion progressed and she died a few months later. Case 2 A 62- year- old man had undergone resection of a nonsecreting pituitary adenoma via a left frontal craniotomy at age 39, followed by 5,400 rads of radiotherapy. Visual function normalized at that time, and periodic examinations and brain imaging revealed no evidence of tumor recurrence. Twenty- three years after radiotherapy, he awoke with painless blurred vision in the left eye. Examination elsewhere disclosed visual acuities of 20/ 20 in both eyes with a left afferent pupillary defect, a nasal step defect on Humphrey visual field testing, and a swollen left optic disc. An initial diagnosis of nonarteritic anterior ischemic optic neuropathy ( NAION) was made, but later review of a brain MRI showed that the left optic nerve was enlarged ( Fig. 2A). He came to our attention when, over the next several weeks, visual acuity worsened in the left eye as did the left eye visual field defect and optic disc edema. Cerebrospinal fluid evaluation revealed 7 white blood cells ( 90% lymphocytes and 10% monocytes), 9 red blood cells, FIG. 1. Case 1. A. Axial FLAIR MRI demonstrates increased signal in the pons, which was more prominent on the right side. B. Postcontrast T1 MRI demonstrates an enhancing mass in the left parasellar and interpeduncular regions. FIG. 2. Case 2. A. Precontrast coronal MRI demonstrates an enlarged left optic nerve ( arrow). B. One year later, postcontrast coronal MRI demonstrates an enhancing mass extending into the parasellar region ( arrow). 290 q 2009 North American Neuro- Ophthalmology Society J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 Wu- Chen et al ( Continued on next page) TABLE 1. Published cases of second intracranial tumors developing after radiation therapy for pituitary adenoma Publication Hormonal Secretion by Initial Tumor Age at Treatment of Initial Tumor ( years), Sex Radiation Dose ( Gy) Latency ( years) Clinical Presentation Secondary Tumor Terry et al, 1959 ( 23) None 26, F 120 12 Progressive visual loss with olfactory and gustatory hallucinations Fibrosarcoma None 44, M 158.25 3 Left hemiparesis and left seventh central palsy Fibrosarcoma None 47, F 131.5 7 Change in mental status and headache Fibrosarcoma Meredith et al, 1960 ( 32) None 51, F 20.52 6 Painless left temporal mass Osteogenic sarcoma Newton et al, 1962 ( 33) NA 39, F 39.10 10 NA Fibrosarcoma Goldberg et al, 1963 ( 34) GH 24, F NA 30 NA Anaplastic epidermoid carcinoma GH 30, F 23.25 15 NA Hemangioendothelioma GH 28, F 39.40 10 NA Fibrosarcoma GH 31, F 42 20 NA Sarcoma Wheelock, 1962 ( 35) PRL 50, F NA 12 NA Sarcoma Greenhouse, 1964 ( 36) GH 24, F 72.2 10.4 Headache and right visual loss Sarcoma Waltz and Brownell, 1966 ( 37) None 42, M 45 5 Progressive bilateral visual loss and left ophthalmoplegia Fibrosarcoma None 38, M 35 8 Headache, left VI and right III nerve palsy Sarcoma Chang and Poole, 1967 ( 38) NA NA NA 27 NA Sarcoma Sparagana et al., 1972 ( 5) None 50, M 250.7- 360.2 21 Seizures and confusion Osteogenic sarcoma Rubinstein, 1972 ( 39) NA 32, F NA 18 NA Fibrosarcoma Bogdanowicz and Sachs, 1974 ( 40) NA 16, F 61.14 16 NA Meningioma Amine and Sugar, 1976 ( 41) NA 16, F 51 10 NA Osteogenic sarcoma Gonzalez- Vitale et al, 1976 ( 6) None 26, M 36 1 14 ( 5 months later) 11 Disorientation and stuporous Malignant fibrous histiocytoma Powell et al, 1977 ( 42) NA 52, M 50 13 Confusion, blurred vision and weight loss Pituitary sarcoma Ahmad and Fayos, 1978 ( 7) None 56, M 40.92 10 Contralateral visual loss, fourth cranial nerve palsy and visual field defect Fibrosarcoma Averback, 1978 ( 8) None 52, F 54 1 Papilledema, generalized weakness, disorientation Mixed sarcoma-glioblastoma 291 Radiation- Associated Intracranial Malignancies J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 TABLE 1. Continued Publication Hormonal Secretion by Initial Tumor Age at Treatment of Initial Tumor ( years), Sex Radiation Dose ( Gy) Latency ( years) Clinical Presentation Secondary Tumor Coppeto and Roberts, 1979 ( 9) GH 46, M 100 8 Ophthalmoplegia Fibrosarcoma Gerlach and Janisch, 1979 ( 43) NA NA NA NA NA Sarcoma Shin et al, 1980 ( 44) PRL 56, F 50 3 NA Fibrosarcoma Martin et al, 1980 ( 10) None 18, F 45 5 Ptosis and complete ophthalmoplegia Fibrosarcoma Pieterse et al, 1982 ( 45) None 48, M 45 20 Progressive visual loss and recurrent bitemporal hemianopsia Sarcoma Piatt et al, 1983 ( 46) None 25, M 45 10 Right hemiparesis Memory loss, delusions, anxiety and confusion Glioblastoma GH 38, M 49 14 Glioblastoma Nagatani et al, 1984 ( 11) PRL 55, F 50 7 Left hemiparesis and lethargy Fibrosarcoma Shi et al, 1984 ( 12) None 54, M 50 8 Headache, left third and fourth cranial nerve palsies with decreased vision Fibrosarcoma Kolodny and Dluhy, 1985 ( 13) PRL 23, M 40 1 27 ( 17 years later) 19 Unsteady gait, headache, and left arm weakness Meningioma Pages et al, 1986 ( 47) NA 23, M 54 27 Frontal headache and transient aphasia Fibrochondrosarcoma Marus et al, 1986 ( 14) GH 52, F 45 6 Rapid deterioration of consciousness Malignant astrocytoma Huang et al, 1987 ( 15) GH 26, M 66 12 Memory loss, lethargy, right- sided weakness, right homonymous hemianopia, and optic atrophy Anaplastic oligodendroglioma Shapiro et al, 1989 ( 26) None 27, M 45 1 50 ( 12 years later) 22 Seizures, right seventh cranial nerve palsy, right hemiparesis, dysarthria Glioblastoma Flickinger et al, 1989 ( 16) None 55, M 47.5 7.5 NA Glioblastoma Suda et al, 1989 ( 17) GH 38, F 50 4.5 Headache and vomiting Malignant astrocytoma Al- Mefty et al, 1990 ( 18) GH 32, F 40 32 Uncontrolled acromegaly Meningioma Tamura et al, 1992 ( 28) GH 43, F 60 14 Headache and recent memory loss Anaplastic astrocytoma Tsang et al, 1993 ( 21) None 26, M 45 10 Vertigo, left face numbness and weakness Glioma* GH 34, F 42.5 10 Headache and aphasia Glioblastoma None 42, M 50 15 Headache, syncope, and dysarthria Glioblastoma PRL 38, M 50 8 Confusion and aphasia Malignant astrocytoma 292 q 2009 North American Neuro- Ophthalmology Society J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 Wu- Chen et al TABLE 1. Continued Publication Hormonal Secretion by Initial Tumor Age at Treatment of Initial Tumor ( years), Sex Radiation Dose ( Gy) Latency ( years) Clinical Presentation Secondary Tumor Simmons and Laws, 1998 ( 22) GH, PRL 17, M 50 11 Seizures Glioblastoma GH 23, F 45 18 Headache, left sided weakness Glioblastoma Alexander et al, 1998 ( 25) None 22, M 30.5 31 Syncope Ependymoma, meningioma, cavernous malformation Kato et al, 2000 ( 27) None 34, F 50 20 Aphasia and right hemiparesis Glioblastoma Gnanalingham et al, 2002 ( 4) None 67, F 52.2 14 Right visual loss and third cranial nerve palsy Osteosarcoma Loeffler et al, 2003 ( 24) GH 41, M 87 16 Left visual loss Meningioma GH 53, M 104 19 Left hearing loss Vestibular schwannoma Minniti et al, 2004 ( 20) None 54, M 40- 50 6 NA Astrocytoma None 40, F 40- 50 9 NA Astrocytoma None 48, F 40- 50 7 NA Meningeal sarcoma GH 19, F 40- 50 10 NA Meningioma NA 58, F 40- 50 21 NA Meningioma None 22, M 40- 50 34 NA Meningioma NA 22, F 40- 50 22 NA Meningioma None 39, F 40- 50 7 NA Astrocytoma None 39, F 40- 50 29 NA Meningioma GH 51, M 40- 50 6 NA Astrocytoma GH 31, M 40- 50 6 NA Primitive neuroectodermal tumor Present study None 9, F NA 28 Left third cranial nerve palsy Sarcoma None 39, M 54 23 Sudden left eye visual loss Anaplastic astrocytoma * Clinical diagnosis. NA, not available; GH, growth hormone; PRL, prolactin. 293 Radiation- Associated Intracranial Malignancies J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 29 mg/ dl of protein, and negative VDRL, acid- fast bacilli, cryptococcal antigen, cultures, and cytology. He underwent optic nerve biopsy via a frontotemporal craniotomy. The pathologic analysis revealed inflammatory changes with many mononuclear cells. Visual acuity in the left eye transiently improved after treatment with corticosteroids, but over the next 8 months it gradually deteriorated to finger counting. Repeat brain MRI showed an enhancing mass that extended inferiorly into the sella and superiorly into the left frontal lobe ( Fig. 2B). A craniotomy revealed tumor emanating from the optic nerve and lateral aspect of the optic chiasm. The exophytic portion of the tumor was removed, and pathologic analysis revealed an anaplastic astrocytoma. Despite treatment with chemotherapy, visual acuity deteriorated to no light perception, the tumor grew, and the patient died 7 years after presentation. DISCUSSION We have presented two cases of presumptive radiation- induced tumors occurring long after radiotherapy for pituitary adenoma. The first patient developed a para-sellar sarcoma and a presumed brainstem glioma 28 years after radiotherapy; the second patient developed a malignant astrocytoma of the optic nerve and chiasm 23 years after radiotherapy. Both patients died of their malignancies despite chemotherapy. The latencies are long, but we presume that the radiation caused these malignancies, given that they would be unusual spontaneous occurrences, they lay within the radiation field, and they developed in patients without an obvious genetic predisposition to cancer ( 3). Although third cranial nerve palsy has been reported along with other visual findings in a radiation- associated sarcoma ( 4) in the pituitary fossa with spread to the chiasm, cavernous sinuses, and nasopharynx, a presentation with isolated third nerve palsy has not been previously described. The second patient was also unusual in having an acute onset of vision loss and a swollen optic disc, features that initially suggested NAION. In that patient, the first biopsy showed only inflammatory cells, leading to a diagnosis of optic neuritis. Sarcomas are the most commonly reported intracra-nial tumors presumed to be radiation- induced, followed by gliomas and meningiomas ( Table 1, 4- 28). The latency period ranges from 1 year to > 30 years ( 4- 28). In a review of brain tumors after radiation for pituitary adenomas, Brada et al ( 19) found that 11 ( 2.4%) of 426 patients developed a second intracranial tumor. Of the 426 patients, 76% had received 40- 50 Gy in 20- 30 fractions; 23% had received $ 50 Gy. Based on that study, the cumulative likelihood of developing a secondary tumor was 2.0% within the first 10 years and 2.4% within 20 years, with an overall relative risk of 10.5 compared with that of the gen-eral population ( 19,20). The authors noted a median latency of 7.0 years ( range 1- 22 years) for glioma, 9.7 years ( range 5- 27 years) for sarcoma, and 13.8 years ( range 7- 34 years) for meningioma 19,20. Tsang et al ( 21) reported 4 cases of gliomas arising after radiation therapy for pituitary ade-noma with latencies between 8 and 15 years. The malig-nancies in our 2 patients were identified much later. There is a strong correlation between radiation dose and the risk of development of a secondary tumor, with the relative risk approaching 20 after doses of 2.5 Gy or higher ( 29). Higher doses are associated with shorter latency periods ( 30,31). REFERENCES 1. Stieber VW. 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