Imaging of Metastatic CNS Neuroblastoma

Pediatric Imaging Pictorial Essay D mbrosio et al. Metastatic CNS Neuroblastoma Pediatric Imaging Pictorial Essay Downloaded from www.ajronline.org by 46.3.204.53 on 12/12/17 from IP address 46.3.204.53. Copyright RRS. For personal use only; all rights reserved FOCUS ON: Nicholas D mbrosio 1 John K. Lyo Robert J. Young Sophia S. Haque Sasan Karimi D mbrosio N, Lyo JK, Young RJ, Haque SS, Karimi S Keywords: CNS metastases, dural metastases, neuroblastoma, pediatric neuroradiology, skull metastases DOI:10.2214/JR.09.3203 Received June 17, 2009; accepted after revision October 25, 2009. 1 ll authors: Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York, ve., New York, NY 10065. ddress correspondence to N. D mbrosio (dambrosn@hotmail.com). JR 2010; 194:1223 1229 0361 803X/10/1945 1223 merican Roentgen Ray Society Imaging of Metastatic CNS Neuroblastoma OJECTIVE. lthough neuroblastoma is a common childhood malignancy, which frequently metastasizes, involvement of the CNS is rarely reported in the literature. However, over the past several years, we have encountered an increasing number of cases of metastatic neuroblastoma to the CNS. This metastatic potential and changing metastatic pattern may, in part, be due to advances in medical treatment, leading to prolonged survival. This article will review the common and uncommon manifestations of metastatic neuroblastoma with an emphasis on the skull, dura, brain, ventricles, and leptomeninges. CONCLUSION. Neuroblastoma has diverse manifestations including masquerading as primary neurologic disease. This disease must be considered in a child with any unexplained neurologic disorder. Realizing that neuroblastoma may represent the cause of neurologic disease in a child will lead to earlier diagnosis. N euroblastoma is the third most common malignancy in children after leukemia and primary CNS brain tumors. It accounts for 10 15% of childhood malignancies. The primary tumor commonly arises in the adrenal gland or along the sympathetic chain, usually in the abdomen. The recognition of neuroblastoma may be difficult because of its many different manifestations hence, the term, the great imitator. Metastases are present in up to 70% of patients with neuroblastoma at the time of diagnosis [1]. Secondary craniocerebral neuroblastoma manifests most often as osseous metastases involving the calvaria, orbit, or skull base [2]. Metastatic CNS neuroblastoma may also occur anywhere in the CNS as a parenchymal, intraventricular, or spinal cord mass. Materials and Methods Study Group We retrospectively reviewed neuroimaging examinations of 90 neuroblastoma patients whose cases were presented at neurooncology tumor board rounds over the previous 3 years at Memorial Sloan-Kettering Cancer Center (MSKCC). This series of patients does not represent the entire population of neuroblastoma patients treated at our institution, but represents a selected subset of patients with CNS manifestations. Most of these patients had primary or metastatic neuroblastoma confined to the spinal cord and paraspinal regions. These particular manifestations of the disease will not be emphasized in this review. Instead, this article will focus on the unusual manifestations of metastatic neuroblastoma involving the brain, skull, dura, and leptomeninges. Metastatic CNS Neuroblastoma Skull Metastatic involvement of the skull has been found in up to 25% of patients with neuroblastoma. Neuroblastoma is the most common malignant metastasis to the skull in children [3]. These calvarial lesions often extend to produce epidural deposits. Metastatic involvement of the skull produces several possible radiographic findings: thickened bone, the so-called hair-on-end periosteal reaction, lytic defects, and separation of sutures. The differential diagnosis of multiple lytic skull lesions in a child includes Langerhans cell histiocytosis, leukemia, lymphoma, and sarcoma metastases [2, 4]. The sutural separation secondary to direct involvement of neuroblastoma is different from that found with generalized increased intracranial pressure. In neuroblastoma, the sutural separation is not uniform and the margins of the sutures are somewhat indistinct [3, 5] (Fig. 1). Extension of epidural deposits along the sutures produces erosion of the suture that then results in split sutures [4]. The hair-on-end appearance is a periosteal response to tumor cells extending from a calvarial JR:194, May 2010 1223

D mbrosio et al. Downloaded from www.ajronline.org by 46.3.204.53 on 12/12/17 from IP address 46.3.204.53. Copyright RRS. For personal use only; all rights reserved metastasis (Fig. 2). The inner aspect of the periosteum is particularly resistant to penetration by tumor cells so the tumor, as it breaks out of the bone, lifts the periosteum, thereby producing plaquelike epidural deposits of tumor [2]. Skull metastases are often very subtle. Scalp lesions are a common accompaniment of calvarial metastases [4, 6] (Fig. 3). Dura Metastatic neuroblastoma has a predilection to metastasize to the dura (Fig. 4). Dural metastases tend to favor the external surface of the dura, spreading diffusely over both the convexities and base of the skull. The dura acts as a barrier to direct invasion, so involvement of the brain parenchyma is rarely seen [1]. Dural metastases are almost always associated with osseous metastases and can be hemorrhagic. Dural metastases may respond favorably to treatment (Fig. 5). Neuroblastoma commonly metastasizes to the base of the skull and orbits late in the disease. oth Langerhans cell histiocytosis and metastatic neuroblastoma characteristically involve the posterolateral part of the orbit where the frontal bone and greater wing of the sphenoid meet [7] (Fig. 6). Parenchymal metastases Despite the high frequency of dissemination to the bone marrow, metastatic spread to the CNS, including involvement of either brain parenchyma or leptomeninges, has been rare. Like primary CNS neuroblastoma, which is even rarer, metastases are often hemorrhagic (Fig. 7). Supratentorial lesions are more common than infratentorial lesions [8]. CNS involvement can be clinically occult and carries with it a poor prognosis. Histologically, secondary forms of cerebral neuroblastoma are similar. They are highly cellular tumors. Grossly, they appear lobulated and well defined but frequently show cystic degeneration and blood staining of cysts and occasionally show extensive hemorrhages (Fig. 8). Hemorrhage is uncommon in most other childhood cerebral neoplasms [2, 4]. Neuroblastoma should be considered in the differential diagnosis of a child with an intracranial mass. Some helpful distinguishing features, including frequent hemorrhage and calcification, have been reported. Oligodendroglioma, astrocytoma, ependymoma, and other primitive neuroectodermal tumors must be included in the differential diagnosis [9]. Most CNS metastases are detected at the time of recurrence rather than diagnosis. The CNS is the sole site of recurrence in 64% of neuroblastoma patients. s the survival of children with metastatic neuroblastoma improves with recent advances in treatment, CNS involvement is being detected more frequently. The CNS can be a sanctuary site for cancer cells because the blood brain barrier impedes penetration of most chemotherapeutic agents [10 12]. The MSKCC experience has confirmed the low but increasing incidence of CNS neuroblastoma as a complication of stage IV metastatic disease (Fig. 9). lthough the overall incidence rate for newly diagnosed patients is approximately 6.3%, among those who have recently been treated with intensive chemotherapy and immunotherapy, the incidence rate is 10% [13]. New regimens for the treatment of neuroblastoma have been developed including bone marrow transplantation and intensive chemotherapy and radiation, which may be changing the metastatic pattern of neuroblastoma. It is also possible that intensive chemotherapy leads to further genetic evolution of the tumors, with a change in metastatic potential [8]. Intraventricular and leptomeningeal metas tases n intraventricular location of metastasis appears to be exceptional: It was observed at diagnosis in only one patient in our series (Fig. 10) and has not been reported previously to our knowledge. Leptomeningeal metastasis is rare except in widely disseminated disease. In children, most leptomeningeal metastases are associated with medulloblastoma, ependymoma, and pineal gland tumors. Leptomeningeal metastases are very sensitive to radiation therapy [14]. The pathogenetic process leading to leptomeningeal involvement by extracranial neuroblastoma is uncertain. Neuroblastoma develops in the embryo from the neural crest, an ectodermal tissue with pluripotential differentiating capability. Investigators have postulated that leptomeningeal tissues, also derived from ectoderm, provide the appropriate soil to support metastasizing neuroectodermal tumors, such as neuroblastoma [15] (Fig. 11). In one exceptional case in our series, progressive leptomeningeal metastases were detected in a 3-year-old girl over several months, with subsequent development of hemorrhagic transformation (Fig. 12). To our knowledge, this is the first case of hemorrhagic leptomeningeal metastases reported in the literature. Discussion CNS involvement in patients with neuroblastoma can be clinically occult and is associated with a poor prognosis. Early detection and aggressive treatment of this complication may allow some patients to live longer than they would have otherwise. MRI and CT are the techniques of choice in the assessment of CNS relapse in children with primary extracerebral neuroblastoma. Metaiodobenzylguanidine scanning is not a reliable predictor of CNS disease [10]. Secondary craniocerebral neuroblastoma manifests most often as osseous metastases involving the calvaria, orbit, or skull base. Metastatic involvement of the skull has been found in up to 25% of cases of neuroblastoma. The reported frequency of CNS metastases (i.e., parenchymal or leptomeningeal) in disseminated neuroblastoma is 2 16%. The 3-year reported risk of CNS metastases in children with stage IV neuroblastoma is 8%. Most CNS metastases are detected at the time of recurrence rather than diagnosis. CNS metastases are usually from tumor infiltration of the mesoderm (dura) and neural crest (leptomeninges) [16]. Direct involvement of the brain parenchyma and of the pia arachnoid and subarachnoid membranes after relapse of classic childhood neuroblastoma is a serious complication that must be recognized and treated early to provide the best opportunity for a favorable outcome [17]. We have assembled representative cases that illustrate many aspects of metastatic neuroblastoma affecting the CNS. Neuroblastoma should be considered in the differential diagnosis of a child with an intracranial mass. Some helpful distinguishing features, including frequent hemorrhage and calcification, have been reported. Neuroblastoma has diverse manifestations including masquerading as primary neurologic disease. This disease must be considered in a child with any unexplained neurologic disorder. Realizing that neuroblastoma may represent the cause of neurologic disease in a child will lead to earlier diagnosis. References 1. Chirathivat S, Post MJ. CT demonstration of dural metastases in neuroblastoma. J Comput ssist Tomogr 1980; 4:316 319 2. Zimmerman R, ilaniuk L. CT of primary and secondary craniocerebral neuroblastoma. JR 1980; 135:1239 1242 3. Healy JF, ishop J, Rosenkrantz H. Cranial computed tomography in the detection of dural, orbital, and skull involvement in metastatic neuroblastoma. J Comput Tomogr 1981; 5:319 323 4. Latchaw RE, L Heureux PR, Young G, Priest JR. Neuroblastoma presenting as central nervous system disease. JNR 1982; 3:623 630 5. Pascual-Castroviejo I, Lopez-Martin V, Rodriguez- Costa T, Pascual-Pascual JI. Radiological and anatomical aspects of the cranial metastases of neuroblastomas. Neuroradiology 1975; 9:33 38 6. Devkota J, El Gammal T, rooks S, Dannawi H. Role of computed tomography in the evaluation of therapy in case of cranial metastatic neuroblastoma. 1224 JR:194, May 2010

Metastatic CNS Neuroblastoma Downloaded from www.ajronline.org by 46.3.204.53 on 12/12/17 from IP address 46.3.204.53. Copyright RRS. For personal use only; all rights reserved J Comput ssist Tomogr 1981; 5:654 659 7. D mbrosio N, Soohoo S, Warshall C, Johnson, Karimi S. Craniofacial and intracranial manifestations of Langerhans cell histiocytosis: report of findings in 100 patients. JR 2008; 191:589 597 8. Matthay K, risse H, Couanet D, et al. Central nervous system metastases in neuroblastoma: radiologic, clinical, and biologic features in 23 patients. Cancer 2003; 98:155 165 9. Polat P, Kantarci M, Eren S, Suma S. Primary cerebral neuroblastoma. JR-TR 2005; 88:148 149 10. Porto L, Keislich M, Yan, Schwabe D, Zanella Fig. 1 1-year-old boy with metastatic neuroblastoma. xial CT image shows large lytic defect, resulting in separation of lambdoid suture, and indistinctness of sutures (arrows). F, Lanfermann H. Isolated CNS relapse in neuroblastoma. Neuropediatrics 2005; 36:112 116 11. Egelhoff JC, Zalles C. Unusual CNS presentation of neuroblastoma. Pediatr Radiol 1996; 26:51 54 12. Gallet L, Egelhoff JC. Unusual CNS and orbital metastases of neuroblastoma. Pediatr Radiol 1989; 19:287 289 13. Kramer K, Kushner, Heller G, Cheung N. Neuroblastoma metastatic to the CNS: the Memorial Sloan Kettering Cancer Center experience and a literature review. Cancer 2001; 91:1510 1519 14. Shaw DW, Weinberger E, rewer DK. Leptomeningeal metastasis from primary extracerebral neuroblastoma: CT demonstration. JNR 1990; 11: 804 15. Palasis S, Egelhoff JC, Morris JD, Koch L, all S. CNS Relapse of treated stage IV neuroblastoma. Pediatr Radiol 1998; 28:990 994 16. latt J, Fitz C, Mirro J Jr. Recognition of central nervous system metastases in children with metastatic extracranial neuroblastoma. Pediatr Hematol Oncol 1997; 14:233 241 17. Kellie SJ, Hayes F, owman L, et al. Primary extracranial neuroblastoma with CNS metastases characterization by clinicopathologic findings and neuroimaging. Cancer 1991; 68:1999 2006 Fig. 2 9-year-old girl with metastatic neuroblastoma. xial CT image shows periosteal response to tumor cells extending from calvarial metastases (arrow), resulting in characteristic hair-on-end appearance, which is often subtle. Fig. 3 7-year-old boy with metastatic neuroblastoma. xial CT image shows scalp softtissue mass in occipital region (arrow). Erosive lytic changes were identified in subjacent occipital bone (not shown). Fig. 4 4-year-old asymptomatic boy with metastatic neuroblastoma. Coronal contrast-enhanced T1 image obtained as part of routine surveillance shows expansile right frontal epidural mass (arrow) compatible with metastasis. JR:194, May 2010 1225

D mbrosio et al. Fig. 5 1-year-old girl with metastatic neuroblastoma., xial contrast-enhanced CT image shows enhancing bilateral dural metastases (arrows)., xial contrast-enhanced CT image 6 months after patient had undergone therapy shows interval resolution of dura-based metastases. Downloaded from www.ajronline.org by 46.3.204.53 on 12/12/17 from IP address 46.3.204.53. Copyright RRS. For personal use only; all rights reserved Fig. 6 3-year-old girl with stage IV neuroblastoma who presented with visual disturbances., Contrast-enhanced CT scan shows large epidural mass (arrow) projecting into suprasellar cistern., Image obtained using bone windows shows underlying osseous metastasis (arrow), characteristically involving area where lateral orbital wall meets greater wing of sphenoid bone. Fig. 7 6-year-old girl who presented with left-sided weakness and headaches. and, Unenhanced () and contrast-enhanced () T1-weighted images show complex, hemorrhagic right parietal lobe mass, with enhancing solid component (arrow, ). C, T2-weighted image shows mild vasogenic edema (arrow) surrounding mass. C 1226 JR:194, May 2010

Metastatic CNS Neuroblastoma Downloaded from www.ajronline.org by 46.3.204.53 on 12/12/17 from IP address 46.3.204.53. Copyright RRS. For personal use only; all rights reserved Fig. 8 4-year-old girl with rapidly progressive neuroblastoma seen over course of 2 months., Initial CT scan obtained during staging is unremarkable., Unenhanced CT scan obtained 2 months after shows acute right frontoparietal lobe hematoma, with surrounding vasogenic edema. C, Contrast-enhanced CT scan obtained at same time as better defines underlying peripherally enhancing lesion (arrow), which was metastatic neuroblastoma, biopsyproven. Fig. 9 and, 4-year-old boy with stage IV neuroblastoma who presented with hemorrhagic left frontal lobe lesion marked by fluid fluid level (arrows) and peripheral rim of enhancement. C JR:194, May 2010 1227

D mbrosio et al. Fig. 10 10-year-old girl with metastatic neuroblastoma., Initial contrast-enhanced MR image shows tiny enhancing intraventricular lesion (arrow) within left lateral ventricle suspicious for metastasis., MR image obtained after patient had undergone 3 months of therapy shows lesion (arrow) is more conspicuous and has nearly doubled in size. Downloaded from www.ajronline.org by 46.3.204.53 on 12/12/17 from IP address 46.3.204.53. Copyright RRS. For personal use only; all rights reserved Fig. 11 6-year-old girl with metastatic neuroblastoma. xial (left) and sagittal (right) contrast-enhanced T1-weighted images show diffuse leptomeningeal enhancement, particularly involving posterior fossa and brainstem, compatible with leptomeningeal metastases. Fig. 12 3-year-old girl with neuroblastoma and leptomeningeal metastases., Initial contrast-enhanced T1-weighted image shows diffuse leptomeningeal enhancement (arrow)., Contrast-enhanced T1 image obtained 2 months after shows leptomeningeal enhancement has progressed over 2-month period. Progression of nodular leptomeningeal metastases (arrows) is also apparent. Two weeks after this image was obtained, patient presented with acute left-sided weakness. C, Contrast-enhanced T1 image shows marked interval progression of leptomeningeal enhancement (arrows) with apparent parenchymal invasion and surrounding vasogenic edema. (Fig. 12 continues on next page) C 1228 JR:194, May 2010

Metastatic CNS Neuroblastoma Downloaded from www.ajronline.org by 46.3.204.53 on 12/12/17 from IP address 46.3.204.53. Copyright RRS. For personal use only; all rights reserved D Fig. 12 (continued) 3-year-old girl with neuroblastoma and leptomeningeal metastases. D and E, xial gradient-echo image (D) and unenhanced CT image (E) obtained shortly after and C show hemorrhagic transformation of leptomeningeal metastases. FOR YOUR INFORMTION Unique customized medical search engine service from RRS! RRS GoldMiner is a keyword- and concept-driven search engine that provides instant access to radiologic images published in peer-reviewed journals. For more information, visit http://goldminer.arrs.org. E JR:194, May 2010 1229