Cancer and the Central Nervous 133 System System Involvement Sharyu Hanmantgad and Yasmin Khakoo An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.
Children with systemic cancer may develop neurologic symptoms/complications from either metastatic disease or the side effects of treatment. Although primary central nervous system (CNS) tumors are the most common solid tumors of childhood, metastasis of systemic tumors to the CNS is rare. Adults with systemic malignancies develop CNS metastases 20% to 40% of the time, whereas less than 10% of children with systemic malignancies are so affected. In one series of almost 4000 children diagnosed with systemic solid tumors between 1990 and 2012, only 1.4% had brain metastases. In contrast, 3% to 5% of all children with acute lymphoblastic leukemia develop a CNS relapse, and 20% to 40% of children in relapse have CNS disease. Additionally, treatment of systemic malignancy, including surgery, radiation, and chemotherapy, may cause neurologic symptoms. This chapter discusses CNS involvement in systemic childhood cancer (Suki et al., 2014).
Central Nervous System Leukemia CNS leukemia occurs in approximately 4% of children with leukemia. All children with acute lymphocytic leukemia (ALL) receive routine lumbar punctures at the time of diagnosis and, for the majority, such involvement, if present, is asymptomatic. The leukemic cells found in the cerebrospinal fluid (CSF) are cytogenetically identical to those found in the bone marrow. Protein expression profiles may define subsets of leukemic B cells that are more likely to metastasize to the CNS, and signaling of the cytokine CCL19 through its receptor, CCR7, is required for CNS infiltration by leukemic T cells (Jin et al., 2016). Leukemic lymphocytes appear to metastasize to the CNS by hematogenous spread with extravasation that depends in animal models on myosin-IIA, or through the CNS lymphatics near the dural sinuses. Although rare, neurologic symptoms associated with CNS leukemia include headaches (17%), nausea and vomiting (14%), lethargy, and irritability. Symptoms were present in half of patients with greater than or equal to 5 leukocytes/µL with blasts in the CSF or signs of CNS involvement on neurologic examination, and only 20% of patients with less than 5 leukocytes/µL CSF had signs or symptoms whether or not the CSF contained blasts. On examination, there may be nuchal rigidity and papilledema. Cranial nerve involvement is less common but may include seventh, third, fourth, and sixth nerve impairment. Infiltration of the optic nerve can also be seen. Hypothalamic obesity caused by direct infiltration of the hypothalamus is a rare syndrome. Spinal cord involvement has been reported but is quite uncommon. Rarely, patients develop chloromas, distinct masses of leukemic cells, in the CNS. The presence of CNS leukemia has important implications for treatment and prognosis. Before the common understanding of the likelihood of the CNS acting as a sanctuary for leukemic cells, relapse in the CNS was seen frequently. Leukemic relapse
was difficult to eradicate and required aggressive, neurotoxic treatment. To prevent CNS relapse, upfront cranial irradiation was widely employed. Patients experienced neurotoxicities, including cognitive decline, intractable seizures, strokes, and secondary CNS malignancies (e.g., meningiomas). Neurologic sequelae of cranial irradiation, including impaired working memory capacity, inhibition, cognitive flexibility, executive visuomotor control, and attentional fluctuations, may persist into adulthood. Over time, in an effort to reduce the use of prophylactic radiation therapy, intrathecal chemotherapies, such as methotrexate and Ara-C, replaced prophylactic radiation affording similar survival curves but less neurotoxicity. Recent studies of stem cell therapy for childhood ALL suggest that neither additional prophylactic craniospinal irradiation nor intrathecal chemotherapy enhances prognosis beyond that seen in patients treated with a pretransplantation ablative regimen alone. With the use of methotrexate, intravenously at high doses, orally at lower doses, and intrathecally at any dose, 23% of patients developed leukoencephalopathy. Patients with symptomatic leukoencephalopathy may have generalized or partial seizures, stroke-like episodes, and ataxia. Twenty percent of children receiving methotrexate demonstrate MRI changes consistent with leukoencephalopathy regardless of symptoms. A genome-wide association study revealed enrichment in polymorphisms in genes known to play a role in neurodevelopmental pathways, raising the possibility that the products of these genes contribute to propensity of a given patient to develop methotrexate neurotoxicity. Those patients with highrisk leukemia with CNS involvement may require radiation plus chemotherapy. Neurocognitive outcomes, including measures of intelligence and executive function, were negatively correlated with the cumulative dose of craniospinal irradiation and intrathecally administered methotrexate. Another neurologic complication observed in children undergoing treatment for leukemia has been the development of arterial and venous strokes, including dural sinus thrombosis. Dural sinus thrombosis may develop secondary to leukemic infiltration of the dural sinus (Fig. 133-1). Both arterial and venous strokes have been more often related to the use of L-asparaginase, which causes deficiencies of antithrombin, plasminogen, fibrinogen, and factors IX and XI. L-Asparaginase is utilized in the induction therapy of children with leukemia, and is associated with an initial hypocoagulable state, followed by a presumed rebound hypercoagulable state, which may result in thrombosis. L-Asparaginase-associated thrombotic strokes tend to occur at the end of induction, characteristically 7 to 10 days after completion of induction, and may result in seizures, focal neurologic deficit, or, less frequently, coma. Arterial strokes have also been reported with intrathecal administration of cytosine arabinoside. Other factors that can cause strokes in children with leukemia include dehydration with secondary venous thrombosis, CNS infection, and later radiation vasculopathy (Levinsen et al., 2014).
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Figure 133-2. Sagittal T2 spine magnetic resonance imaging demonstrating radiation myelitis.
Figure 133-1. Postcontrast magnetic resonance venography (MRV) demonstrating right transverse sinus filling defect secondary to clot formation from L-asparaginase.
CNS involvement is less frequent in children with acute myelogenous leukemia, but still has been reported to be as high as 20%, and some form of CNS prophylaxis is employed in all patients. Chloromas may occur and may result in focal neurologic deficits, including cranial nerve or spinal cord compression. A rarer form of leukemia—acute promyelocytic leukemia— can be associated with neurologic complications, especially intracranial hemorrhage and stroke, at presentation or early during treatment in children and adults. This is thought to result from acute tumor lysis and release of procoagulants from the large leukemic granular cells. An intracranial disseminated intravenous coagulation picture can be seen. CNS infection, especially with fungal organisms, may complicate the course of leukemia, particularly in patients who are immunosuppressed for long periods and in pa tients from low- and middle-income countries. Similarly, in patients with prolonged immunosuppression, brain abscesses occur because of a variety of organisms. Abscesses are usually associated with pulmonary lesions and may be caused by bacterial involvement with either aerobic or anaerobic bacteria, or by fungal infections, including Aspergillus, Mucor, and Candida. Encephalitis may also occur, especially after hematopoietic stem cell transplantation, and is caused by viruses, including herpes simplex, varicella zoster, and human herpes virus 6. Progressive multifocal leukoencephalopathy is a rare complication of prolonged immunosuppression, especially with agents such as rituximab. Recently, chimeric antigen receptor T cells (CAR T cells) have been used with moderate success in treatment of refractory hematologic malignancies in children and adults. Unfortunately, the toxicities associated with this treatment can be life-threatening, affecting many organ systems. Although the cells target tumor-associated antigens, they may also cross react with normal tissue. The mechanism of action is thought to be a cytokine release syndrome that causes a massive inflammatory response leading to potentially irreversible end-organ damage. Neurologic toxicity includes encephalopathy and intractable seizures. There appears to be no correlation with CNS leukemia. The mainstay of therapy is supportive care with anticonvulsants and correction of metabolic abnormalities as
well as interleukin-6 receptor blockade using tocilizumab. Steroid administration is considered a last resort in some instances because of concern of diminishing efficacy of the CAR T cells. As CAR T-cell therapy gains acceptance for treatment of other malignancies as well as nononcologic disorders, neurologic adverse events may increase in prevalence, requiring the practitioner to become familiar with the treatment of these secondary effects (Brudno and Kochenderfer, 2016).
Lymphoma Primary CNS lymphoma, a subtype of non-Hodgkin lymphoma, is rare in children and is seen primarily in severely immunosuppressed patients, such as those with HIV infection, those who have undergone transplant and require chronic immunosuppression, and those with hemophagocytic disorders. Patients who have undergone bone marrow transplant for other disorders may also develop Epstein-Barr virus (EBV)–associated CNS lymphoma. Cytotoxic T-cell therapy has successfully treated many such patients. Treatment is challenging; because of the rarity of the illness and the immunosuppressed nature of the patients, patients are often treated with B-cell lymphoma protocols with or without the use of focal, more extensive radiation therapy. Systemic lymphoma can metastasize directly to the CNS, to the vertebral bodies with secondary spinal cord compression (Hauser et al., 2005), and to the leptomeninges. Non-Hodgkin lymphoma affects the CNS of children and adolescents in approximately 10% of cases. Mantle radiation therapy, a mainstay of treatment for Hodgkin lymphoma, may cause radiation myelitis in a small subset of patients (Fig. 133-2). Neurologic manifestations include Lhermitte’s sign with upper extremity weakness and sensory changes. Treatments have included steroids and hyperbaric oxygen.
Histiocytosis Langerhans cell histiocytosis (LCH) may involve the CNS in as many as 20% of patients. Diabetes insipidus secondary to posterior pituitary infiltration is the most common presenting symptom. Less commonly, granulomas may develop within the neuroaxis. LCH may be difficult to distinguish clinically from primary CNS tumors (Imashuku and Arceci, 2015). Years after initial, apparently successful treatment of LCH, subtle neurologic deficits, which may be progressive, can occur. Depending on the area of involvement of the CNS, symptoms include ataxia, vertigo, dysarthria, nystagmus, tremor, and
focal motor impairments. Lesions may arise anywhere within the CNS, but they tend to predominate in the hypothalamicpituitary axis, pineal gland, gray matter of the dentate nucleus and basal ganglia, and in the deep white matter of the pons and hippocampus. There may or may not be associated infiltration by histiocytes. Such lesions may be progressive or static over time. It is unclear whether they represent a paraneoplastic syndrome or direct infiltration of histiocytosis into the brain. Treatments have included 2-chlorodeoxyadenosine, retinoic acid, and intravenous immunoglobulins (with or without antineoplastic chemotherapy), and have had variable success.
Neuroblastoma Neuroblastoma is a tumor that originates from the sympathetic ganglia and typically occurs in younger children. Neuroblastoma may invade through neural foramina into the spinal canal (classically with a dumbbell shape) and cause cord compression. In addition, neuroblastoma can spread to other extra- and intracranial sites—most notoriously, to the torcula with resultant dural venous thrombosis that can precipitate severe neurologic compromise, including seizures and coma. Recent advances in therapies include the use of radiolabeled anti-GD2 antibodies that target gangliosides specifically expressed on tumors of neural crest origin. With the widespread use of antibody therapy, the long-term survival rate for patients with stage 4 neuroblastoma has risen significantly. However, these intravenously administered antibodies do not cross the blood-brain barrier, and result in a relative increase in the number of patients with CNS neuroblastoma. Treatment of these patients with CNS metastasis includes surgery followed by low-dose external beam craniospinal radiation with a boost to the primary site followed by administration of intrathecal radiolabeled anti-GD2 antibodies (131I 3F8 or 8H9). A recent report has shown that 17/21 patients were alive at a median of 33 months from diagnosis of CNS neuroblastoma. Future research will involve attempts to identify which patients are at risk for seeding the CNS, followed by targeted attempts to prophylactically treat these individuals. A recent report suggested that traumatic lumbar puncture in patients with active stage 4 neuroblastoma may increase the risk of CNS seeding, but this observation requires further investigation. Neurologic sequelae of intravenous antiGD2 antibodies include Horner syndrome, neuropathic pain, and posterior reversible leukoencephalopathy syndrome (PRES). Spinal cord compression may be acute and cause the rapid onset of motor deficits, including quadriplegia or paraplegia. Conus or cauda equina involvement may result in early bowel and bladder dysfunction. Management of such compression requires immediate commencement of chemotherapy, with surgical decompression generally reserved for benign variants (e.g., ganglioneuroma) (Fawzy et al., 2015). Neuroblastoma also has been associated with a unique para neoplastic syndrome, opsoclonus-myoclonus. (See Chapter 118 for a discussion of this syndrome.) An unusual form of neuroblastoma is esthesioneuro blastoma—neuroblastoma that occurs in the nasopharynx or paranasal sinuses. It accounts for less than 3% of tumors of childhood and adolescence. Radiotherapy is effective in adults with esthesioneuroblastoma, but the scarcity of data in children with this tumor and the significant morbidity of radiation therapy to the head and neck of children have fueled attempts to treat with newer, perhaps safer modalities. One study employing proton beam radiotherapy appeared to demonstrate locoregional control of intracranial and leptomeningeal metastases and tolerable toxicity, but ultimate survival was limited by disease in these sites (Lucas et al., 2015).
System Cancer and the Central Nervous System Involvement
Sarcoma In a study reviewing 12 years of data on pediatric cancer patients, 3950 patients had a solid non-CNS primary cancer. Of those patients, 1.4% had metastases to the brain. Of the primary solid pediatric cancers associated with metastases, sarcomas constituted 54%, whereas melanomas, the next most common tumor, accounted for only 15%. Children between the age of 10 and 15 years are at highest risk. In a postmortem report of 139 pediatric patients with primary solid tumors, 18 patients were found to have CNS metastases. Osteogenic sarcoma and rhabdomyosarcoma were the most frequently reported primary cancers to cause CNS metastases in patients under the age of 15 years. Pulmonary metastases were found in over 90% of patients with CNS involvement, suggesting that the metastases arise hematogenously from the lungs. In general, primary solid tumors with associated CNS metastases are associated with rapid clinical deterioration (Porto et al., 2010). Patients with brain metastases presented with headache, nausea/vomiting, and seizures as the most common chief complaints. The primary tumor and brain metastasis present synchronously in 15% of patients, and in these patients, other extracranial metastases are also present. The remaining 85% of patients are diagnosed with brain metastasis after treatment of the primary disease has been initiated, with a median presentation interval of 17 months after primary cancer diagnosis. Treatment of pediatric sarcoma may also result in neurologic compromise. Intravenous ifosfamide, a commonly used alkylating chemotherapeutic agent, causes encephalopathy, asterixis, and seizures during infusion in 2% to 5% of children without CNS tumors. Symptoms may begin during drug infusion or hours to days later. The encephalopathy results from breakdown of ifosfamide to chloroacetaldehyde and subsequent inhibition of the mitochondrial respiratory chain. Treatment includes longer infusion time of ifosfamide; administration of methylene blue and/or thiamine; or switching from ifosfamide to cyclophosphamide. The neurologic outcome is generally good. Other toxicities include vincristine neuropathy.
OSTEOSARCOMA Osteosarcoma is the most frequently occurring malignant primary bone tumor and most common bone cancer in children. Spread of osteosarcoma is typically hematogenous, primarily reaching the lungs and other bones. Although rare, brain metastases are hypothesized to develop when lung tumor emboli invade the brain; however, there are occasional reports of patients with metastases who have no detectable lung involvement. Dissemination to the brain typically targets the dura and skull and spares the parenchyma (Fig. 133-3). Brain involvement is associated with metastatic disease at diagnosis or with relapse within 12 months of diagnosis.
EWING’S SARCOMA Ewing’s sarcoma comprises about 10% of primary malignant bone tumors and is commonly seen in young adults with a male predominance. Metastases to the lung and other skeletal tissues are common and up to 80% of patients have metastases at the time of diagnosis. In contrast to osteosarcoma, Ewing’s sarcoma is frequently associated with CNS involvement because of direct bony extension, rather than by hematogenous spread. Brain metastases usually occur with lung involvement in over 85% of individuals and as a part of systemic disease involvement. Overall, the presence of brain involvement suggests a poor prognosis in patients with Ewing’s sarcoma;
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adolescents. The relative rarity of CNS metastases of systemic cancer in children has meant that, despite the difference in the primary tumors from which these metastases come, their treatment has been guided by standard clinical practice in adults. Proton beam radiotherapy holds the promise of less toxic radiotherapy for intracranial metastases. In addition, prophylactic cognitive interventions may allow conventional craniospinal radiotherapy to be used without significant deterioration in IQ, memory, or executive function. Acknowledgment The authors would like to thank Joseph Olechnowicz for editorial assistance.
REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. Figure 133-3. Sagittal postcontrast magnetic resonance imaging of brain demonstrating dural-based osteosarcoma metastasis.
however, it is difficult to determine whether this is a function of the systemic disease or the brain involvement.
RHABDOMYOSARCOMA Rhabdomyosarcoma is the most common soft tissue sarcoma in childhood. Twenty percent of cases arise in the parameningeal area, including the middle ear, nasal cavity and paranasal sinuses, nasopharynx, infratemporal fossa/pterygopalatine, and parapharyngeal area, whereas the remaining cases typically occur in the genitourinary system and the extremities. Parameningeal rhabdomyosarcoma requires more aggressive treatment as its proximity to critical anatomic structures allows for more frequent invasion into the CNS. Systemic dissemination of rhabdomyosarcoma occurs hematogenously or through lymphatics with common metastatic sites in the lungs, pancreas, and bone. Although brain metastases are uncommon, there has been an association with pulmonary metastases and history of recurrent metastasis.
Conclusions Both systemic cancer and its therapy contribute to the neurologic morbidity in pediatric cancer patients (Khan et al., 2014). Prevention depends on pretreatment identification of children at risk, and treatment of neurologic sequelae requires development of agents that will not compromise anticancer treatment efficacy. There is no standard therapy for CNS metastases of systemic solid tumors in children and
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