The treatment of childhood cancer is one of the great

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1 A Review of Secondary Central Nervous System Tumors After Treatment of a Primary Pediatric Malignancy Asher M. Marks, MD,* and Roger J. Packer, MD,,, Despite remarkable strides in the treatment of pediatric malignancies over the last 50 years, long-lasting sequelae and secondary malignancies continue to plague this population. This article reviews the incidence, diagnosis, and etiology of secondary central nervous system tumors in the setting of a history of primary pediatric malignancy. Particular attention is paid to central nervous system tumors presenting after treatment of leukemia and primary brain tumors, as well as the role of treatment and underlying cancer predisposition syndromes in the risk of developing these secondary tumors. Semin Pediatr Neurol 19: Elsevier Inc. All rights reserved. *Department of Hematology/Oncology, Children s National Medical Center, Washington, DC. Center for Neuroscience and Behavioral Medicine, Children s National Medical Center, Washington, DC. Brain Tumor Institute, Children s National Medical Center, Washington, DC. Gilbert Family Neurofibromatosis Institute, Children s National Medical Center, Washington, DC. Division of Neurology, Children s National Medical Center, Washington, DC. Address reprint requests to Roger J. Packer, MD, Department of Neurology, Children s National Medical Center, 111 Michigan Avenue, Northwest Washington, DC rpacker@cnmc.org The treatment of childhood cancer is one of the great medical success stories of the 20th century. The American Cancer Society s most recent 2012 Cancer Facts and Figures 1 notes that for all childhood cancers combined, the 5-year relative survival rate has improved markedly over the past 30 years, from 58% in the mid-1970s to 83% today. Although these numbers are encouraging, these 5-year survivors are not without significant sequelae. One of the most concerning sequela lies in the occurrence of secondary central nervous system (CNS) tumors. The British Childhood Cancer Survivor Study 2 reviewed 17,981 5-year survivors of childhood cancer and found the overall standardized incidence ratio (SIR) of subsequent primary neoplasms to be 4 times more than expected, with the most frequently observed subsequent neoplasms after a median follow-up time of 24.3 years being located in the CNS. There is also evidence that the frequency of secondary malignant neoplasms, in general, is increasing. A Surveillance, Epidemiology, and End Results (SEER) 3 database review of secondary malignant neoplasms among long-term survivors of childhood brain tumors supports this trend. Compared with treatment before 1979, patients treated between 1979 and 1984 had a 4.7-fold increase in risk, whereas those treated after 1985 had a 6.7-fold increase in risk. The causes of secondary CNS tumors in patients previously treated for childhood cancer include CNS radiation, treatments with mutagenic chemotherapies, and underlying genetic abnormalities. Given the increasing use of postsurgical adjuvant radiotherapy and chemotherapy for children with brain tumors, it is important that signs and symptoms of secondary CNS tumors are sought and patients are aware of the risks. Incidence Review of 14,361 5-year survivors from the Childhood Cancer Survivor Study (CCSS) 4 revealed a total of 116 CNS tumors that developed after treatment of a childhood cancer. The most common subsequent CNS neoplasm was meningioma (n 66, with 3 being malignant), followed by glioma (n 40), primitive neuroectodermal tumor (PNET; n 6), and CNS lymphoma (n 1). Three of the tumors were of unknown histology, and in four instances, the pathology report was unavailable. Subsequent CNS tumors occurred from 5 to 28 years after the date of the original cancer diagnosis, with a median time to the occurrence of subsequent CNS tumor being 14 years. The majority of subsequent gliomas (21 of 40 [52.5%]) occurred during the initial 5 years of follow-up (5-9 years from cancer diagnosis), with an overall mean time of 9 years /12/$-see front matter 2012 Elsevier Inc. All rights reserved. doi: /j.spen

2 44 A.M. Marks and R.J. Packer and only 4 being diagnosed after 15 years. The median age at diagnosis of the new glioma was 15 years, and 70% were diagnosed before age 20. This trend of relatively early subsequent glioma corresponds to a similar study done by the British Childhood Cancer Survivor Study group. 2 Meningiomas tended to appear later, with 71.2% (n 47) of cases diagnosed 15 or more years after the primary cancer diagnosis. The study investigators noted no sign of a decline in the numbers of new cases with increasing time. The median age at diagnosis of the new meningioma was 25.5 years, and 74% were diagnosed after age 20. The CCSS review included patients previously diagnosed with leukemia, CNS cancer, Hodgkin lymphoma, non-hodgkin lymphoma, kidney tumor, neuroblastoma, soft tissue sarcoma, or bone sarcoma and noted that subsequent CNS tumors were most common in patients previously treated for acute lymphoblastic leukemia (ALL; SIR 16.9) and primary tumors of the CNS (SIR 14.2). Younger age at the time of childhood cancer diagnosis, as well as radiation exposure, were associated with increased risk of a subsequent CNS tumor. The SIR for children who were younger than 5 years at their original diagnosis was Treatment with chemotherapy and radiation was associated with a SIR of 12.9, whereas radiation alone was Figure 1 Flair axial image of large, biopsy proven left frontal, necrotic high-grade glioma with surrounding edema. Tumor occurred 8 years after treatment of a medulloblastoma. Presentation and Diagnosis The clinical presentation of secondary brain tumors does not differ from presentation of such lesions in newly diagnosed patients. Clinical manifestations are dependent on location of the tumor, aggressivity of the lesion, the degree of associated peritumoral edema, and the general growth pattern of the mass. By definition, secondary brain tumors occur years after successful treatment of the primary neoplasms and are histologically different from the first tumor. However, there are some difficulties in using these guidelines to determine if a tumor is truly a secondary neoplasm, rather recurrence of the first tumor. Although secondary neoplasms occur years after initial diagnosis, some forms of childhood brain cancer, especially low-grade gliomas, ependymomas, and, to a lesser extent, embryonal tumors, may recur years after initial diagnosis and apparent successful treatment. Such late relapses may be difficult to separate from the development of a secondary brain tumor. In almost all cases, histological confirmation is required to distinguish a secondary brain tumor from relapse. However, given the histological complexity of embryonal neoplasms, such as medulloblastoma, histological distinction can be difficult. Medulloblastoma may have areas of apparent glial differentiation, and it is often difficult to separate a differentiated or clonal expansion of the glial element of the medulloblastoma from that of a secondary malignant glial neoplasm, especially a small-cell glioma. Another factor making diagnosis difficult may be the reluctance to biopsy secondary diffuse infiltrative lesions occurring in the diencephalon or the brainstem. In these cases, diagnosis is usually based on neuroimaging features. Distinguishing an infiltrating secondary glioma from primary tumor recurrence of a medulloblastoma within the brain stem can be difficult. The pattern of tumor relapse and associate symptomatology can be quite variable. Because radiation-induced tumors usually occur within the radiation portal, especially the edge of the portal, the tumors may recur within or adjacent to the primary tumor site. Diagnosis of cortical high-grade gliomas with associated edema occurring at the edge of the radiation field is usually not difficult (Fig. 1). Such lesions commonly present with symptoms associated with masses in the cortex, such as headaches, nausea, vomiting, and focal neurologic deficits, dependent on the location of the tumor. Seizures may occur, and as is in the case of primary gliomas, seizures are more frequent early in the course of illness in low-grade tumors as compared with higher-grade tumors. A second presentation of a more diffuse infiltrating mass, akin to gliomatosis cerebri, may occur as a secondary tumor phenomenon. In these cases, diagnosis may be delayed, especially in survivors of childhood brain tumors who may have residual chronic headaches, seizures, or neurologic dysfunction (Fig. 2). Secondary high-grade gliomas of the brainstem can be difficult to clinically separate, early in the course of illness, from tumor recurrence of a posterior fossa primary tumor (Fig. 3). Although the radiographic features ultimately may be used to distinguish the two processes, histological confirmation is required to document that the lesion is a secondary tumor rather than a relapse of the medulloblastoma. Because of the poor prognosis of patients, physicians are often reluctant to recommend further surgery, including biopsy, because of the possibility of further neurologic damage. Probably, the most difficult separation is when the tumor occurs in the primary

3 Secondary central nervous system tumors 45 Figure 2 T2 image of infiltrative, biopsy-proven grade 3 astrocytoma involving the thalamic, basal ganglionic, parietal, and occipital region occurring 10 years after treatment of leukemia (patient had received craniospinal radiotherapy as part of initial treatment). tumor site with radiographic features consistent either with a secondary neoplasm or tumor recurrence (Fig. 4). In such cases, neuroradiographic comparison to the original tumor is helpful, but once again, histological confirmation is required. Meningiomas are much easier to distinguish clinically from primary tumor recurrence. Their location on the surface of the brain, often far from the primary tumor site, makes diagnosis relatively easy. However, initial symptomatology may be vague, as nonspecific headaches and partial seizures are common in children with meningiomas. Ten percent, or Figure 3 An intrinsic brain-stem mass, noted on enhanced sagittal image arising 5 years after treatment of a medulloblastoma lesion was not biopsied. Figure 4 Enhanced sagittal image of solid and cystic cerebellar mass. Mass was histologically a high-grade glioma occurring 7 years after diagnosis of a medulloblastoma, treated with radiotherapy and chemotherapy. more, of children surviving primary CNS tumors have a seizure disorder or chronic headaches, once again complicating diagnosis. Meningiomas are also commonly diagnosed on posttreatment surveillance studies, before they become symptomatic. Primary Cancers As previously noted, recent research shows a large number of subsequent brain tumors in patients previously treated for ALL or a primary tumor of the CNS. That is not to say, however, that there are not reported cases of subsequent CNS tumors after other solid tumors or lymphomas. These include two reported cases of CNS tumor after treatment for osteosarcoma. One case was that of an astrocytoma appearing 3 years after diagnosis and treatment of osteosarcoma in an 11-year-old boy, 5 and a second case involved diagnoses of a PNET 5 years after the diagnosis and treatment of osteosarcoma in a 16-year-old boy. 6 Notably, neither case involved the use of cranial radiation. A larger analysis of pediatric malignant bone tumors treated on legacy Children s Cancer Group/Pediatric Oncology Group protocols from 1976 to 2005 has been done. 7 The total number of patients reviewed was 2842 (1686 treated for osteosarcoma and 1156 treated for Ewing sarcoma), and of these nearly 3000 patients, only 1 was found to have a subsequent CNS tumor. The patient was a 24 year old found to have an anaplastic astrocytoma 10 years after initial diagnosis of osteosarcoma. A retrospective chart review of patients with secondary tumors after soft tissue sarcomas showed that of the 20 patients identified, only 3 had secondary tumors of the CNS. 8 These included an astrocytoma identified 6 years after a fibrosarcoma of the face (treated with radiation), an oligodendroglioma identified 13 years after treatment of a rhabdomyosarcoma of the nasopharynx, and a glioblastoma identified 20

4 46 A.M. Marks and R.J. Packer years after treatment of a rhabdomyosarcoma of the nose. Of interest, all 3 of these cases involved radiation to the site of the initial tumor, which was invariably located on or around the face. Given the history of craniospinal and cranial radiation, as well as systemic chemotherapy use in ALL patients, children surviving ALL are at considerable risk of developing secondary brain tumors. One of the most recent studies to evaluate these patients was a retrospective study of 2169 patients with acute lymphoblastic leukemia treated between 1962 and 1998 at St. Jude Children s Research Hospital, Memphis. 9 All the patients achieved complete remission, and the median follow-up time was 18.7 years (range, years). Twenty-four of these patients developed meningioma, and another 24 developed another type of CNS tumor (glioblastoma multiforme [n 10], astrocytoma [n 9], oligodendroglioma [n 2], dysembryoplastic neuroepithelial tumor [n 1], ependymoma [n 1], and primitive neuroectodermal tumor [n 1]). When these patients were further separated into those without meningioma who presented with CNS tumor after the first complete remission, but before relapse, it was found that 21 of 22 of these patients received cranial/craniospinal radiation, resulting in a significant impact on the SIR for CNS tumors (SIRs, 45.8 vs 4.3). This significant increase in SIR of patients treated with radiation is disconcerting; however, current strategies of leukemia treatment are moving away from prophylactic CNS radiation in ALL patients. Patients who receive CNS radiation today are those who present with or develop active CNS disease or those diagnosed with T-cell ALL at initial presentation. The treatment of pediatric CNS tumors still heavily relies on the use of CNS radiation and systemic chemotherapy. Analysis of secondary CNS tumors in this population reflects this trend. In the SEER database review of secondary malignant neoplasms among long-term survivors of childhood brain tumors, patients were reviewed, and 6 were found to develop a secondary astrocytoma, 1 developed a subsequent PNET, 4 developed other glioma, and 1 developed a miscellaneous intracranial/intraspinal tumor. Compared with glioma, it is notable that secondary PNET appears to be a far less common secondary tumor in this population. A review of 2387 CNS tumor patients treated with radiation therapy between 1990 and 1999 at Vancouver General Hospital proposes that secondary PNET after treatment for a different CNS tumor is more common than previously thought. 10 The review notes 4 patients that developed a subsequent PNET. Three patients were diagnosed with primary posterior fossa tumors in childhood: 1 pilocytic astrocytoma, 1 low-grade astrocytoma, and 1 malignant ependymoma. The fourth patient was diagnosed and treated for a temporal astrocytoma at 37 years of age. This patient eventually developed a posterior fossa PNET, 5 years after initial treatment. A more common presentation of secondary CNS tumor in patients previously treated for a primary CNS tumor, however, is the occurrence of astrocytoma or meningioma. This phenomenon is well described in a review of the 14 medulloblastoma patients who experienced second malignant neoplasms after treatment on Children s Oncology Group study A Of these patients, 5 children had high-grade gliomas. The majority of these second malignant neoplasms occurred 5 years after diagnosis and treatment of the primary tumor. There is a trend in the literature of secondary CNS tumors occurring more than 5 years after initial treatment, with many secondary CNS tumors in the literature noted to occur around 10 years after treatment. Although it is clear that ALL and primary CNS tumor are both risk factors for the development of a secondary CNS tumor, it is important to look specifically at the inciting events that result in these tumors. Namely, the primary treatments of these malignancies: intensive systemic chemotherapy and cranial radiation. Treatment-Induced Malignancy Chemotherapy is the mainstay of cancer treatment and acts by killing rapidly dividing cells. Many of these agents work through disruption of the DNA helix itself. Two examples include alkylating agents and topoisomerase inhibitors. Alkylating agents, including cisplatin, carboplatin, cyclophosphamide, and ifosfamide, work by attaching an alkyl group (C n H 2n 1 ) to the guanine base of DNA, resulting in damage of the DNA and destruction of the cell involved. Topoisomerase is essential for the proper winding and unwinding of DNA. Upon binding to DNA, topoisomerase cuts the phosphate backbone allowing the DNA to be untangled or unwound. Topoisomerase inhibitors, including topotecan, irinotecan, and etoposide, prevent this process from occurring and result in interference of transcription and replication. Because cancer cells divide faster and with less efficient repair mechanisms than healthy cells, they are more susceptible to damage caused be these types of therapies. Secondary malignancies become a concern because of the inherent mutagenic properties that these therapies posses. Although it is clear that the use of cytotoxic therapy increases the rate of acute myelogenous leukemia and myelodysplastic syndrome in the pediatric population, the full contribution of chemotherapeutic agents to the development of secondary CNS tumors is less clear. The previously noted Neglia review of the CCSS database 4 attempts to assign the risk associated with chemotherapy versus that associated with radiation therapy in 14,361 5-year survivors of childhood cancers. They note, After adjustment for radiation dose and original diagnosis, no statistically significant associations were seen between risk of second or subsequent CNS tumors and chemotherapy exposure overall or exposure to alkylating agents, anthracyclines, epipodophyllotoxins, platinum agents, or antimetabolites specifically. They do note nonstatistically significant increases in the odds ratios (ORs) for glioma associated with previous epipodophyllotoxin and platinum exposure, but that antimetabolite exposure (6-mercaptopurine or 6-Thioguanine) was not associated with an increased risk of glioma (OR 0.75, 95% confidence interval [CI] ). Statistically nonsignificant increases in ORs were observed among patients with meningioma who had previous epipodophyllotoxin or platinum exposure. The aforementioned SEER data 3 does not prove absolute second-

5 Secondary central nervous system tumors 47 ary tumor causation as a result of chemotherapy; however, the study does note a steadily increasing incidence of secondary malignant neoplasms over time that the authors note does correlate with the increased use of chemotherapy in the treatment of primary brain tumors. The mutagenic, and therefore carcinogenic, potential of radiation therapy is well illustrated in the literature. The primary carcinogenic effects of radiation therapy are believed to be its ability to ionize atoms in the human body. This ionization results in breaks in the DNA helix, which can result in one of several outcomes. In the case of radiation therapy, the goal is cell death. Rapidly dividing cells are more likely to succumb to death than normal healthy cells. If cells do not die, there is potential for self-repair. The concern arises when cells do not succumb to death and are not properly repaired. Cells that experience a nonlethal dose of ionizing radiation and are not repaired appropriately can accumulate DNA mutations that are passed on to subsequent cell divisions. As these mutations accumulate, the risk of damaging a tumor suppressor gene or proto-oncogene increases along with the potential for oncogenesis. Some of the first evidence to show a direct correlation between ionizing radiation and CNS tumors comes from a study looking at children who underwent radiation therapy for tinea capitis in the 1950s. 12,13 A matched population and sibling review of 10,834 patients who were radiated with a mean of 1.5 gray (Gy) (range Gy) showed a significantly increased risk of meningioma (relative risk 9.5, 95% CI: ) and glioma (relative risk 2.6, 95% CI: ). 14 After a median long-term follow-up of 40 years, it was found that the excess relative risk per gray was 4.63 (95% CI: ) for meningioma and 1.98 (95% CI: ) for malignant brain tumors. Of the second neoplasms in a cohort of 9720 ALL patients, 39 out of 43 of these neoplasms occurred in patients who had received radiation at some point in therapy. 15 Ten years after the diagnosis, the estimated risks of a second neoplasm among the irradiated and nonirradiated patients were 1.6% and 0.3%, respectively. Of the 43 second neoplasms, 23 were CNS tumors in children 5 years of age or younger at the time of ALL diagnosis, and all 23 occurred in patients who had received cranial (22) or wholebody irradiation (1), accounting for a 22-fold risk of CNS neoplasms subsequent to the treatment of childhood ALL. 16 This trend was reinforced again, 10 years later, in a review of 13,581 patients in the aforementioned CCSS cohort. 17 These results are similar to the previously noted St. Jude experience. 9 Diffuse high-grade gliomas presenting as second malignant neoplasms after radiotherapy have been assessed at a clinical, histological, and molecular level. These tumors show some unique traits when compared with primary gliomas, and may offer a window into the cellular changes brought on by ionizing radiation. Secondary gliomas tend to be more aggressive with median survival of only 12 months despite intensive treatment. At a histological level, they are mainly composed of small undifferentiated or stellate cells. They rarely show gemistocytes or spindle cells and have a higher frequency of atypical mitoses as well as lower cellularity when compared with primary gliomas. Dedifferentiation of many of the small cells with sparse cytoplasm is supported by a lack of expression of glial fibrillary acidic protein on immunohistochemistry. 18 Cancer Predisposition Syndromes Although the treatment of primary malignancies plays a major role in the development of secondary brain tumors, underlying genetic cancer predisposition syndromes cannot be ignored. Medulloblastoma is associated with multiple cancer predisposition syndromes, including Li Fraumeni syndrome (LFS), Gorlin syndrome, and Turcot syndrome. 19 LFS is an autosomal-dominant disorder caused by a germ line P53 mutation and is characterized by susceptibility to a wide range of malignancies, with the most common being sarcomas and early onset breast cancer. In addition to medulloblastoma, LFS is also associated with malignant glioma and supratentorial PNET. Gorlin syndrome or Nevoid basal cell carcinoma syndrome is an autosomal dominant syndrome with a predisposition for medulloblastoma, meningioma, and basal cell carcinoma. It is further characterized by various skeletal and developmental anomalies, including scoliosis, cleft palate, broad nose, and wide-set eyes. The mutation that causes Gorlin syndrome is located around the patched (PTCH) gene, which encodes a protein that downregulates the sonic hedgehog receptor a major culprit in the development of medulloblastoma. Turcot syndrome encompasses two separate genetic disorders: familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer (HNPCC). These disorders are caused by several different mutations that result in a familial predisposition to colorectal cancer syndromes that are associated with nervous system tumors, including medulloblastoma, astrocytoma, and ependymoma. Familial adenomatous polyposis is also known as brain tumor polyposis syndrome type 2, whereas HNPCC is also known as brain tumor polyposis syndrome type 1. HNPCC tends to result in fewer colon polyps, but a higher risk of developing colonic adenocarcinoma, if the colon is not removed. HNPCC is also referred to as Lynch syndrome and involves a single germ line mutation in the mismatch repair genes, including hpms, hmsh6, hmsh2, hmlh1, and hmlh3. More recently, biallelic germ line mutations in mismatch repair genes have been identified. These patients have been given the diagnosis of constitutional mismatch repair deficiency syndrome and have been shown to present with a wide range of hematologic and solid-tumor malignancies, including glioma, PNET, and medulloblastoma. 20 Pituitary adenomas are rare in childhood ( 1:1 million), but are often associated with multiple endocrine neoplasia syndrome. In addition to pituitary adenomas, multiple endocrine neoplasia type 1 can result in parathyroid adenoma, enteropancreatic tumors, and adrenocoritcal tumors.

6 48 A.M. Marks and R.J. Packer von Hippel Lindau (VHL), an autosomal dominant disorder caused by mutations in the VHL tumor suppressor gene, is associated with renal cell carcinoma, pancreatic neuroendocrine tumors, pheochromocytoma, and cerebellar and retinal hemangioblastomas. These hemangioblastomas are cystic benign neoplasms that tend to be found in the posterior fossa, retina, and spinal cord. They affect 60%-80% of patients with VHL. 19 Neurofibromatosis 1 (NF1), neurofibromatosis 2, and tuberous sclerosis (TS) are each inherited as a single mutated copy of a given tumor suppressor gene, and therefore, much like inherited retinoblastoma, only inactivation of the one remaining functional copy of the gene is required for tumorigenesis. 19 NF1 is the most common predisposition syndrome with an incidence of 1:2500-1:3000 and is diagnosed by the presence of at least 2 of 7 diagnostic criteria. Neurofibromas are the most common tumors found in these patients. They are benign peripheral nervous system tumors that can appear anywhere in the body. However, plexiform neurofibromas, are more diffuse neurofibromas that can transform into aggressive malignant peripheral nerve sheath tumors. The second most common tumor in NF1 patients is the optic pathway glioma. They are seen in 15% of children with NF1, tend to present between 2 and 6 years of age, and are usually grade I pilocytic astrocytomas. Radiation in NF1 patients with these tumors should be avoided given their generally indolent nature and a high rate of secondary brain tumors in this population. Neurofibromatosis 2 predisposes patients to schwannoma, meningioma, and ependymoma with bilateral vestibular schwannoma being pathognomonic for the syndrome. TS patients often present with mental retardation, epilepsy, and hypopigmented macules. TS is unique in that it predisposes patients to subependymal giant-cell astrocytoma. Conclusions Although great strides have been made and continue to be made in the treatment of childhood cancers, there is still much improvement needed in the prevention of long-term side effects of these often toxic treatments. As radiation prophylaxis is phased out in leukemia treatment and doses are reduced in CNS tumor treatment, it is hoped that the incidence of secondary malignancies will be reduced. However, often this reduction in radiotherapy is coupled with intensification of potentially mutagenic chemotherapy, so risk may not decrease, and may even increase. With the maturation of molecularly targeted therapies and proton beam therapy, there is further hope for a reduction in the incidence of therapy-related secondary tumors. In the interim, it is important to closely follow childhood cancer survivors in specialized long-term follow-up clinics and have a high index of suspicion for secondary CNS tumors in patients who are at risk for this potentially devastating sequela of cancer treatment. References 1. The American Cancer Society Cancer Facts and Figures. Available at: cancer-facts-figures Accessed January 9, Reulen RC, Frobisher C, Winter DL, et al: Long-term risks of subsequent primary neoplasms among survivors of childhood cancer. JAMA 305: , Peterson KM, Shao C, McCarter R, et al: An analysis of SEER data of increasing risk of secondary malignant neoplasms among long-term survivors of childhood brain tumors. Pediatr Blood Cancer 47:83-88, Neglia JP, Robison LL, Stovall M, et al: New primary neoplasms of the central nervous system in survivors of childhood cancer: A report from the childhood cancer survivor study. 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