14 Pediatric Brainstem Tumors
Abstract
Pediatric brainstem tumors include lesions of the midbrain, pons, and medulla. These neoplasms constitute a heterogeneous group with regard to clinical presentation, tumor localization, histopathology, management, and prognosis. The most common and ominous subgroup of pediatric brainstem neoplasms comprises the diffuse intrinsic pontine gliomas, which account for 80% of cases. Less common subgroups affecting the brainstem include focal intrinsic lesions of the midbrain and the cervicomedullary junction and dorsally exophytic neoplasms arising from the floor of the fourth ventricle. Advances in imaging technology have enabled clinicians and surgeons to develop treatment plans, implement image-guided therapies, and determine tumor response to treatment. Comprehensive understanding of these lesions will provide a means to develop new strategies for effective treatment, reduce morbidity, and, most importantly, improve the overall survival and quality of life of affected children.
Introduction
Pediatric brain neoplasms are the second leading cause of malignancy in children. 1 , 2 , 3 Brainstem tumors, defined as lesions located between the diencephalon and the cervicomedullary junction, account for 15 to 20% of primary brain neoplasms in children. 4 These lesions arise in the midbrain, pons, and medulla, and they include tectal tumors, diffuse intrinsic pontine gliomas (DIPGs), and cervicomedullary lesions ( Fig. 14.1 ). 5 , 6 , 7
Advances in imaging technology, histopathologic analysis, and clinical trials have provided clinicians and surgeons with a new understanding of childhood brainstem neoplasms. These tumors comprise a heterogeneous group of lesions, for which the clinical presentation, prognosis, and treatment are dictated by tumor location, configuration, and biological behavior. In this chapter, the authors review the different pediatric brainstem neoplasms and propose strategies for clinical and surgical management.
Epidemiology, Etiology, and Natural History of Disease
Epidemiology
Brain neoplasms and central nervous system (CNS) malignancies are the second most common cause of cancer-related death in children in the United States and Canada. 1 , 8 , 9 Brainstem tumors constitute approximately 11% of all primary brain tumors in persons younger than 19 years of age, with peak incidence occurring between the ages of 5 and 8 years. 10 , 11 Although these lesions affect both boys and girls, boys have a slightly better 5-year survival rate. 10
Primary brain and CNS neoplasms are the most common type of cancer in persons between the ages of 15 and 19 years, and brainstem neoplasms account for approximately 12% of cases. 12 , 13 The most common and aggressive pediatric brainstem tumors are the DIPGs, which represent approximately 80% of neoplasms. These lesions are nonpilocytic astrocytomas, World Health Organization (WHO) grade II or higher. Pediatric low-grade gliomas constitute the remaining 20% of brainstem tumors and follow a more indolent course. 5 , 14 , 15 , 16
Etiology
Established risk factors for pediatric brain tumors include certain cancer syndromes and ionizing radiation. Familial syndromes associated with increased brain tumor susceptibility are neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), tuberous sclerosis (TSC1 and TSC2), Li-Fraumeni (TP53 and CHEK2), nevoid basal cell carcinoma (PTCH), Turcot (APC), Cowden (PTEN), hereditary retinoblastoma (RB1), and Rubinstein-Taybi (CREBBP). 1 , 17 , 18 , 19 , 20 Head and neck radiation is another established risk factor for the development of brain neoplasms.
Other potential risk factors associated with brain tumor predisposition include advanced parental age, birth defects, computed tomography (CT) imaging, maternal diets containing nitrosamine compounds, and pesticide exposure. 21 , 22 , 23 Several studies indicate that children with congenital anomalies have more than a twofold risk of developing CNS lesions. 1 , 24 Contrarily, allergies may protect against childhood brain tumor development. An inverse association has been found between the development of brain neoplasms and allergic conditions, such as allergies, asthma, and elevated levels of serum immunoglobulin E. 1 , 25 , 26
Natural History of Disease
Prognostic factors for children with brainstem tumors include age at presentation, duration of symptoms, pathology, location, surgical resection, and associated adjuvant therapy. 2 Predictors of favorable outcome are long-term duration of symptoms, focal and exophytic neoplasms, and lesions in the dorsal midbrain or medulla oblongata. Tumors affecting the midbrain and medulla are low-grade gliomas in 98% of cases, and pontine lesions are low-grade neoplasms in only 25% of patients. 16
Brain tumors and CNS neoplasms are less responsive to adjuvant therapy than any other type of solid tumor. Several factors contribute to this lack of responsiveness, including the presence of the blood-brain barrier, which restricts drug penetration into the CNS; multiple signaling pathways in high-grade neoplasms; and the development of primary or acquired drug resistance. 27 , 28 Thus, effective approaches to treat brainstem lesions often require combined targeted regimens.
Clinical Presentation
Clinical presentation depends on the affected region of the brainstem. 11 , 29 The most common signs and symptoms include coordination and gait abnormalities (78%), cranial nerve (CN) palsies (52%), pyramidal signs (33%), and headache (23%). 11 , 30 Other clinical manifestations are ophthalmoplegia (19%), focal motor weakness (19%), facial palsy (15%), papilledema (13%), unspecified symptoms of increased intracranial pressure (ICP) (10%), and abnormal eye movements (6%). Signs and symptoms can be nonspecific, and manifestations of behavioral changes or academic difficulties are common. 29
Perioperative Evaluation
Advances in neuroimaging techniques have provided significant information on tumor status at diagnosis and follow-up. 31 Magnetic resonance imaging (MRI) is the most useful study to define infiltration and to assess response to treatment. 32 , 33 Correlation between the MRI findings and brain tumor histology has the potential to predict brain tumor behavior. Craniospinal MRI investigation is essential to assess the neuraxis and to check for tumor spread and drop metastasis at diagnosis. 33
Different studies have described the significant role of diffusion MRI as a prognostic indicator and a potential biomarker of tumor response to treatment. Diffusion-weighted imaging, a technique based on the rate of water mobility in tissue, is described by a variable called the apparent diffusion constant (ADC). Diffusion-weighted imaging has proven sensitivity to cellular status, density, and tissue organization, distinguishing between cytotoxic and vasogenic edema. Increased water tissue in edema will increase the values of ADC, and high cell density zones in tumors will decrease the ADC. 34 , 35
Diffusion tensor imaging (DTI), a technique that detects anisotropic diffusion, provides information on the delineation of the major fiber tracts in the brainstem. 35 Clinical application focuses on using DTI maps and tractography to localize white matter fiber tracts that are crucial for language, motion, and vision. 35 , 36 This imaging modality characterizes tumors and assesses perilesional involvement of white matter tracts using ADC and fractional anisotropy to evaluate treatment response and subsequent disease progression. 35 Reports have described the application of DTI for early detection of DIPG. 37 , 38 Techniques such as DTI facilitate early detection of the tumor extension before it becomes apparent on conventional MRI.
Susceptibility-weighted imaging is the modality of choice to identify tumor bleeding or calcification. 33 Other imagining modalities include perfusion MRI, magnetic resonance spectroscopy (MRS), and positron emission tomography (PET). MRS improves the diagnostic capability of routine MRI studies, providing a means to differentiate between neoplastic and nonneoplastic lesions. 39 Proton MRS provides important information on tumor activity and tissue characteristics. 40 This imaging modality has been used as a reliable indicator of response to treatment and as a predictor of survival.
Differential Diagnosis
Nonneoplastic lesions affecting the brainstem include vascular malformations, hemangioblastomas, epidermoid cysts, granulomas, histiocytic lesions, demyelinating diseases, infectious etiologies, and multiple sclerosis. 39 The differential diagnosis of posterior fossa tumors affecting the brainstem includes embryonal lesions, ependymomas, atypical teratoid-rhabdoid tumors, radiation-induced neoplasms, and gangliogliomas ( Fig. 14.2 ).
Role of Biopsy
The role of biopsy in the diagnosis of brainstem tumors is controversial. A complete patient investigation that includes clinical history, laboratory tests, and MRI studies can provide useful information about brainstem lesions. However, these neoplasms often have various histopathologic entities with heterogeneous clinical, biological, and radiologic features. The sensitivity and specificity of MRI for diagnosing low-grade gliomas have been reported to be as low as 63% and 47%, respectively, whereas for high-grade lesions, sensitivity and specificity have been 58% and 62%, respectively. 41
Stereotactic biopsy provides diagnostic success in approximately 96% of cases. 42 The technique is considered a reliable tool in tumor diagnosis, as it provides a means to perform further molecular and genetic analyses. However, the procedure is not risk-free, as it is associated with overall morbidity and mortality of approximately 7.8% and 0.9%, respectively. There is also a risk of sampling error in brainstem stereotactic biopsy. 42
Classification and Management
Midbrain Tumors
Tumors affecting the midbrain usually arise from the tectum, tegmentum, and periaqueductal regions, and they are rarely located in the ventral region of the midbrain. Midbrain neoplasms are often hamartomas of the tectal plate or focal indolent tumors. Regardless of their histologic features, these lesions are usually accompanied by late-onset aqueductal stenosis and symptoms of increased ICP. 43 , 44 Historically, early deaths were commonly related to uncontrolled hydrocephalus and surgical complications rather than tumor progression. Advances in imaging technology have provided information that enables physicians to diagnose midbrain lesions and manage them promptly.
Tectal plate gliomas are rare dorsal midbrain lesions, accounting for 5% of brainstem tumors and 20% of mid-brain neoplasms. 45 These lesions are often accompanied by noncommunicating hydrocephalus secondary to enlargement of the tectal plate and obstruction of the aqueduct of Sylvius ( Fig. 14.3 ).
Clinical Presentation
Approximately 50 to 70% of children with tectal lesions typically present with symptoms of increased ICP, often without associated brainstem signs. The median age of clinical onset ranges from 9 to 10 years. 43 , 46 Common symptoms include headache, nausea, vomiting, and visual impairment. Bilateral papilledema is present in 25 to 34% of patients. 47 , 48 Some infants may present with macrocephaly as a result of hydrocephalus. Other associated symptoms include pyramidal symptoms, gait ataxia, nystagmus, Parinaud syndrome, abducens nerve (CN VI) palsy, and diplopia. Cognitive symptoms associated with tectal gliomas include memory deficits, decline in academic performance, personality change, and developmental delay. Hydrocephalus can precipitate precocious puberty and slow growth. 45 A clinical history of NF1 has been reported in association with tectal lesions. 48
Tumors in the tegmentum account for 33 to 57% of midbrain neoplasms. 11 , 30 Patients usually present with brainstem symptoms caused by the compression of long fiber tracts or CN nuclei. Such symptoms include hemiparesis, hemihypesthesia, headache, ataxia, and multiple cranial palsies. Signs and symptoms of increased ICP can be present; however, they do not occur as frequently as in tectal tumors.
Periaqueductal lesions, also known as pencil gliomas, constitute 13 to 23% of midbrain neoplasms. 45 Children affected by periaqueductal lesions usually present with symptoms of increased ICP caused by aqueductal obstruction. Other associated clinical presentations include gait ataxia, nystagmus, hemiparesis, and tremors.
Histology
Tectal brainstem tumors are generally low-grade astrocytomas, with fibrillary and pilocytic astrocytomas accounting for 21% and 36% of cases, respectively. 43 Other benign lesions include hamartomas, gangliogliomas, and oligoastrocytomas. High-grade tumors in the tectal plate are rare, but lesions with anaplastic features and poor outcomes can occur.
Tegmental tumors can be low-grade or high-grade gliomas. 4 , 30 Low-grade neoplasms are often nonpilocytic lesions. Neoplasms of the tegmentum are usually more malignant than neoplasms in other regions of the midbrain. High-grade astrocytomas account for 75% of cases. Histologically, fibrillary astrocytomas, which are usually low-grade lesions, are the most commonly reported periaqueductal neoplasm. Other periaqueductal tumors include ependymomas, subependymomas, and oligodendrogliomas.
Imaging
Focal tectal tumors are often well-defined ellipsoid neoplasms without perilesional edema. On CTs, these neoplasms are isodense and calcifications may be observed over time. Tectal gliomas are usually hypointense or isointense on T1-weighted MRI and hyperintense on proton density–weighted and T2-weighted MRI, with little or no contrast enhancement. 45 , 49 Tectal gliomas with atypical behavior or progression often present as large contrast-enhanced lesions with cystic degeneration greater than 10 cm3 in volume.
Tegmental lesions show low signal intensity on T1-weighted MRI, high signal intensity on T2-weighted MRI, and a heterogeneous pattern of contrast enhancement on MRI. 50 These lesions can extend upward to the thalamus and downward to the pons, displacing the adjacent structures rather than infiltrating them. Cystic components are often observed in tegmental lesions. 4
Periaqueductal tumors are usually not identified on CT and are typically isointense on both T1-weighted and T2-weighted MRI. 50 These lesions show homogeneous contrast enhancement of a cord-like structure located in the aqueduct. Therefore, patients presenting with hydrocephalus with aqueduct obstruction should undergo contrast MRI.
Treatment
In most cases, the management of midbrain lesions is conservative and the only required treatment is cerebrospinal fluid diversion by endoscopic third ventriculostomy or ventriculoperitoneal shunt. Several authors recommend endoscopic third ventriculostomy over ventriculoperitoneal shunt for the management of associated hydrocephalus, both initially and at recurrence. 11 , 44 Tumor biopsy is reserved for atypical cases at presentation and for patients with progressive or recurrent disease. Aggressive treatment, such as surgical resection and adjuvant therapy, is reserved for patients presenting with tumor progression or recurrence. However, neurologic deficits are not always reversed by aggressive treatment. 44
Prognosis and Follow-up
Overall, tectal gliomas have a relatively benign and indolent course, and patients have a good long-term prognosis. These lesions often remain stable in size for several years. However, tumor progression has been reported in approximately 25% of cases. 45 Poor prognostic factors include contrast-enhanced lesions, tumor extension to the surrounding structures, and neurologic deficits at presentation. Correlation between size and outcome has been reported for tectal lesions, which can be classified as follows 44 :
Small lesions (2–4 cm3): this group comprises more than 50% of patients, and tumors likely represent hamartomas. Patients should remain under surveillance for a mean period of 3.5 years.
Medium-sized lesions (4–10 cm3): this group constitutes approximately 27% of cases, and patients should remain under surveillance for approximately 7 years.
Large lesions (>10 cm3): tumors larger than 10 cm3 represent 20% of cases, High-grade astrocytomas are usually diagnosed in this population, and aggressive treatment is often required.
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21 Radiotherapy for Pineal, Thalamic, and Brainstem Tumors
20 Stereotactic Radiosurgery for Tumors of the Brainstem, Thalamus, and Pineal Region
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