Radiation-induced supratentorial primitive neuroectodermal tumor after treatment for non-Hodgkin's lymphoma.
Secondary, radiation-induced tumors represent a significant risk to survivors of pediatric cancers, and comprise the leading cause of death for 15-year survivors of Hodgkin's lymphoma. (9) One of the rarest subsets of these tumors include radiation-induced central nervous system (CNS) tumors, which most commonly comprise tumors such as gliomas, meningiomas, and schwannomas. (4) A form of radiation-induced CNS tumor, which has only been described in case reports, is the secondary supratentorial primitive neuroectodermal tumor (PNET). We present a patient with a history of non-Hodgkin's lymphoma eleven years previously who presented with this lesion.
The patient is a sixteen year old male, who presented to our facility from a referring institution after experiencing a generalized tonic-clonic seizure three weeks previously. Workup at the referring institution included computed tomography (CT) scan, magnetic resonance imaging (MRI), and electroencephalogram (EEG).
He previously had Non-Hodgkin's Lymphoma (NHL) at age five, treated with chemotherapy as per the Pediatric Oncology Group (POG) protocol and 1800 cGy of whole brain radiation, without evidence of recurrence. Past medical history was also significant for behavior problems and cognitive decline since his radiation, as well as a seizure disorder treated with lamotrigine and levetiracetam between ages six and eight, after which all seizure medications were stopped and he experienced no further seizures until the current presentation.
Upon physical exam the patient was found to be alert and oriented, but somewhat developmentally delayed for his age, with decreased attention and fund of knowledge, and immediate recall of one object out of three. He demonstrated normal strength, no pronator drift, no sensory abnormalities or extinction, and no language difficulties.
Imaging revealed a hyperdense lesion on non-contrasted CT in the left frontal region. This was further evaluated by MRI, showing a 4cm contrast-enhancing lesion without restriction on diffusion weighted imaging. Due to the patient's history of NHL, a positron emission tomography (PET) scan of the whole body was performed, but did not demonstrate any other abnormal hypermetabolic lesions except for the left posterior frontal mass.
This patient was then taken to surgery for stereotactic biopsy of the lesion, with frozen pathology revealing a small, blue cell tumor. Final pathology revealed a primitive neuroectodermal tumour, and subsequent surgical resection was planned. Tractography revealed that the tumor was pushing the motor tracts posteriorly. Resection was accomplished with neuronavigation and intraoperative motor evoked potential monitoring through stimulation of motor tracts.
Adequate resection of tumor was accomplished, stopping just short of subcortical motor tracts and the sylvian fissure. He tolerated the surgery well, with only slight weakness (4+/5) in the right upper extremity. Post-operative MRI revealed some expected minimal residual tumor in the posterior aspect of the resection cavity, overlying the sylvian fissure (Figure 2).
Pathologic analysis revealed a densely cellular neoplasm with individual cell necrosis but no geographic necrosis observed (Figure 3). Vascular proliferation was present. Tumor cells demonstrated immunoreactivity for synaptophysin and failed to stain for lymphoid markers. Rare cells stained positively for glial fibrillary acidic protein GFAP). Epithelial membrane antigen (EMA) and CD99 stains were negative. Further immunohistochemistry revealed intact phosphatase and tensin homolog (PTEN--80% positive staining) and positive vascular endothelial growth factor (VEGF--60% positive staining), vascular endothelial growth factor receptor (VEGFr-KDR--50% positive staining), phosphorylated mitogen-activated protein kinase (pMAPK--70% positive staining), and phosphorylated serine/threonine-specific protein kinase (pAKT--25% positive staining). Endothelial growth factor receptor (EGFR) and O6-methylguanine-methyltransferase (MGMT) were negative on immunohistochemistry (0% and 5% positive staining, respectively). Final diagnosis was made of central nervous system primitive neuroectodermal tumor, World Health Organization (WHO) grade IV.
Additional radiation was possible based upon our patient's previous dosing and was offered to his family. They did elect to proceed with this treatment modality. It was also decided to treat our patient with bevacizumab and temozolomide.
This regimen of surgery, radiation, and chemotherapy was well-tolerated by the patient except for some nausea, weight loss, and radiation-induced skin irritation of the head and neck. The patient remains neurologically stable three years from his surgery date. Five-month follow-up imaging showed resolution of contrast-enhancement of the posterior aspect of the tumor bed, including the previously noted residual along the sylvian fissure. Three year follow-up imaging demonstrated calcification and encephalomalacia along the surgical site without evidence of tumor recurrence. The patient's right upper extremity weakness largely resolved.
The classification of a tumor as being radiation-induced must satisfy a number of requirements, as outlined by Cahan in 1948. (3) These include tumor location in a previously radiated area, pathologically-proven difference between the new tumor and the primary lesion, time lapse between radiation and tumor development, and finally no other predisposing conditions to tumor development. (3) Tumors which satisfy these requirements in the central nervous system may be either benign, such as meningioma or schwannoma, or more aggressive such as high-grade gliomas. (12)
These lesions are thought to develop most commonly in patients who are radiated at a young age or whose radiation therapy is coupled with methotrexate. (6) The K-ras oncogene has been implicated in development of these malignancies, although not widely investigated. (2,12) The most common primary malignancies include acute lymphoblastic leukemia (ALL) and other primary CNS lesions. Recent reviews of the literature by Hader, et al and Sobowale, et al revealed secondary PNETs after brain radiation for retinoblastoma, pilocytic astrocytoma, ependymoma, oligodendroglioma, and low grade astrocytomas. (8,12) More recently, a PNET after radiation for craniopharyngioma has been reported. (4) This recent report emphasizes the potential to develop these tumors with radiation alone, rather than coupled with methotrexate. (4) Only one previous case of PNET after NHL has been reported, as described by Brustle, et al. (2) However, the risk factors for NHL are similar to those for ALL and the primary CNS lesions listed above, specifically cranial irradiation with or without methotrexate.
The time to presentation of these secondary tumors was calculated by Sobowale to be an average of ten years after radiation, and the age of presentation for these tumors significantly higher than that for primary PNETs, with a mean presentation age of seventeen years. (12) This is consistent with our patient, who presented at age sixteen years and eleven months, and approximately eleven years after treatment for his primary malignancy.
Survival after these tumors is significantly shorter than primary PNETs, postulated to be due to both their different mechanism of development, and also due to limited treatment options in patients who have already received cranial irradiation. Accurate prognostication is difficult for this disease entity, complicated by both its rarity as well as wide variation in treatments based upon tumor location and prior radiation dose, as well as limited follow-up in the reported cases. Five of the reported cases in the literature do not report survival data. (12) Four of the reported cases in the literature reported that patients were still alive, however had less than 10 months of follow-up. (12) Two patients, both reported by Brustle and colleagues, had a reported survival of 48 months at last follow-up and were still alive at the time of the paper's publication. (2) Both of these patients were able to be treated with additional radiation (50 and 30 Gy) as well as chemotherapy. (2) Of the case reports which noted patient mortality, the average survival time was 10 months. (12) The various treatment methods as well as survival time for patients with radiation-induced PNETs in the literature is present in Table 1. Our patient is still alive and without evidence of disease progression at 36 months postoperatively, with a survival longer than average likely because radiation therapy was an option for him, along with chemotherapy and surgical resection.
Chemotherapy for secondary, radiation-induced PNETs has not been widely studied due to the rarity of the lesions. Previous case reports have described treatment with vincristine, lomustine, and prednisone, (4) vincristine alone, (12) and procarbazine, CCNU, and vincristine. (8) However, a number of case reports describe palliative measures only for these patients. It was decided to treat our patient with bevacizumab and temozolomide. Bevacizumab, an angiogenesis inhibitor, was used due to the tumor's positive VEGF expression. Temozolomide, an alkylating agent with cerebrospinal fluid penetration currently used in aggressive disease such as high-grade glioma and metastatic malignant melanoma, was thought to be appropriate due to the more highly aggressive nature of radiation-induced PNET versus primary PNET. Irinotecan was not deemed necessary because of the tumor's negative MGMT expression.
Radiation-induced PNETs are rare lesions which present unique difficulties to treatment because of previous radiation and an aggressive clinical course. Current treatment recommendations are few and the outcome not encouraging. Further study regarding the optimal treatment strategies of these tumors must be conducted as the incidence and length of survival of children after primary malignancy increases. In addition, with the compelling evidence that these lesions are radiation-induced, further study regarding the risk of other forms of radiation must be conducted. A study by Khan and colleagues reports no increased risk of PNET after diagnostic x-rays. (10) However, CT scans represent a significant increase in radiation exposure and are increasingly used in evaluation of such common childhood entities as appendicitis, concussion, etc. Evaluation of radiation exposure on the development of PNETs must be studied.
PNET: primitive neuroectodermal tumor
CNS: central nervous system
CT: computed tomography
MRI: magnetic resonance imaging
NHL: Non-Hodgkin's lymphoma
POG: Pediatric Oncology Group
PET: positron emission tomography
cGy: centi-Gray units
WHO: World Health Organization
ALL: Acute Lymphoblastic Leukemia
Cara L. Sedney, MD
Department of Neurosurgery, West Virginia University, Morgantown
Sanjay Bhatia, MBBS
Department of Neurosurgery, West Virginia University, Morgantown
Fahad Bafakih, MD
Department of Pathology, University of Virginia, Charlottesville, VA
Stephan Paul, MD
Department of Pediatrics, West Virginia University, Morgantown
Kymberly Gyure, MD
Department of Pathology, West Virginia University, Morgantown
Corresponding Author: Cara L. Sedney, MD, Department of Neurosurgery, Robert C. Byrd Health Sciences Center, PO Box 9183, Morgantown, WV 26506-9183. Email: email@example.com
(1.) Barasch ES, Altieri D, Decker RE, Ahmed S, Lin J, Primitive neuroectodermal tumour presenting as a delayed sequela to cranial irradiation and intrathecal methotrexate, J Paediatr Neruol, 1998;4, 375-378.
(2.) Brustle O, Ohgaki H, Schmitt HP, Walter GF, Ostertag H, Kleihues P, Primitive neuroectodermal tumors after prophylactic central nervous system irradiation in children. Association with an activated K-ras gene, Cancer, 1992;69, 2385-2392.
(3.) Cahan WG, Woodard HQ, Higinbotham NL, Stewart FW, Coley BL, Sarcoma arising in irradiated bone: report of eleven cases. 1948, Cancer, 1998;82, 8-34.
(4.) Chan M, Herrera SR, Neckrysh S, Wallace A, Valyi-Nagy T, Charbel FT, Primitive neruoectodermal tumor after radiation therapy for craniopharyngioma, Neurosurg Focus, 2011,30.
(5.) Chan MD, Attia A, Tatter SB, Lesser G, Zapadka ME, Mott RT, et al, Radiation-induced adulte medulloblastoma: a two-case report and review of the literature, J Neurooncol, 2011; 103, 745-749.
(6.) Chen AY, Lee H, Hartman J, Greco C, Ryu JK, O'Donnell R, et al, Secondary supratentorial primitive neruoectodermal tumor following irradiation in a patient with low-grade astrocytoma, Am J Neuroradiol, 2005;26, 160-162.
(7.) Dorfmuller G, Wurtz FG, Kleinert R, Lanner G, Cerebral primitive neuroectodermal tumour following treatment of a unilateral retinoblastoma, Acta Neurosurg, 1997;139, 749-755.
(8.) Hader WJ, Drovini-Zis K, Maquire JA, Primitive neuroectodermal tumors in the central nervous system following cranial irradiation, Cancer, 2003;97, 1072-1076.
(9.) Khadwal A, Biswas G, Arora B, Kurkure PA, Dshmukh C, and Shetty V, Primitive neuroectodermal tumor (PNET) as second malignancy after treatment of Hodgkin's disease, Indian J Pediatr, 2006;73, 437-438.
(10.) Khan S, Evans AA, Rorke-Adams L, Orjuela MA, Shiminski-Maher T, Bunin GR, Head injury, diagnostic X-rays, and risk of medulloblastoma and primitive neuroectodermal tumor: a Children's Oncology Group study, Cancer Causes Control, 2010;21,1017-1023.
(11.) Mackenzie JM, Franks AJ, Vanhille PT, Cameron MM, The evolution of an oligodendroglioma into a primitive neuroectodermal tumour, Neuropathol Apple Neurobiol, 1988;14, 71-79.
(12.) Sobowale OA, McCabe M, Pal P, Soh C, Karabatsou K, Radiotherapy-induced supratentorial primitive neuroectodermal tumor in a 17-year-old female: a case report and review of the literature, Acta Neurochir, 2010;153, 413-417.
(13.) Yoshida Y, Toma Y, Arai M, Higashi R, Kashihara K, Kaizaki Y, Primitive neuroectodermal tumor arising 8 years after chemotherapy and radiotherapy for acute lymphoblastic leukemia: case report, Neurol Surg, 2005;33, 717-722.
Table 1. Literature Review Author Chemotherapy Radiation Surgery Regimen for PNET for PNET for PNET Barasch  none 41Gy none Brustle  type not 50Gy none specified none 79Gy none type not 30Gy none specified Chan  vincristine, none complete lomustine, and resection prednisone Chan  none 36Gy with none 54 Gy boost none 54Gy none Chen  not specified none subtotal resection Dorfmuller  type not dose not none specified specified Hader  none none complete resection not specified none subtotal resection procarbazine, none subtotal CCNU, vincristine resection (PCV) pcv none subtotal resection Mackenzie  none none subtotal resection Sedney bevasizumab and 12.6 Gy with subtotal temozolomide 12.6 Gy boost resection Sobowale  PCV 54Gy subtotal resection Author Chemotherapy Outcome Regimen for PNET Barasch  none 14 month survival Brustle  type not 48 month survival specified and alive at publication none 10 months survival type not 48 months survival specified and alive at publication Chan  vincristine, 3 months then lomustine, and lost to followup prednisone Chan  none 1 month survival none 2 weeks survival Chen  not specified 4 months survival and alive at publication Dorfmuller  type not 9 months survival specified and alive at publication Hader  none 6 months survival not specified 11 months survival procarbazine, 18 months survival CCNU, vincristine (PCV) pcv 12 months survival Mackenzie  none 7 months survival Sedney bevasizumab and 36 months survival temozolomide and alive at publication Sobowale  PCV 8 months survival and alive at publication
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|Title Annotation:||Case Report & Literature Review|
|Author:||Sedney, Cara L.; Bhatia, Sanjay; Bafakih, Fahad; Paul, Stephan; Gyure, Kymberly|
|Publication:||West Virginia Medical Journal|
|Date:||Jul 1, 2015|
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