Chapter 85
Wilms Tumor
John A. Kalapurakal and Patrick R.M. Thomas
Wilms tumor (WT, nephroblastoma) is a highly curable childhood neoplasm. The prognosis of children with WT has improved considerably from a very high mortality rate at the beginning of the 20th century to the current cure rate of >90%.1 The management of WT is a paradigm for successful interdisciplinary treatment of solid tumors of childhood to maximize cure rates and minimize treatment-related complications.

EPIDEMIOLOGY
WT is the most common malignant renal tumor of childhood. It occurs with an annual incidence of 7 cases per million children <15 years of age. Approximately 500 new cases are diagnosed each year in North America. The peak incidence is between 3 and 4 years of age. WT may arise as sporadic or hereditary tumors or in the setting of specific genetic disorders.2 Most WTs are solitary lesions, multifocal within a single kidney in 12% and bilateral in 7%.3 The clinical syndromes associated with WT include WAGR syndrome (WT, Aniridia, Genitourinary malformations, mental Retardation), Denys-Drash syndrome (pseudohermaphroditism, mesangial sclerosis, renal failure, and WT), and overgrowth syndromes like Beckwith-Wiedemann syndrome (somatic gigantism, omphalocele, macroglossia, genitourinary abnormalities, ear creases, hypoglycemia, hemihypertrophy, and a predisposition to WT and other malignancies) and Simpson-Golabi-Behmel syndrome.4,5

BIOLOGY
Among the various genetic changes implicated in the development of WT, the most widely studied involves WT1, which is a tumor suppressor gene at chromosome 11p13 that was isolated from a child with WAGR syndrome.6 WT1 is likely to play a specific role in glomerular and gonadal development.7 WT1 can also act as a dominant negative oncogene resulting in abnormal cell growth such as in Denys-Drash syndrome.8 Germline WT1 mutations are observed in approximately 82% of WT patients who have genitourinary anomalies or renal failure. The frequency of WT1 mutations in sporadic and familial WT is much lower at ∼20% and ∼4%, respectively.9 Beckwith-Wiedemann syndrome maps to chromosome 11p15.5; this locus is also referred to as WT2.10
Patients with loss of heterozygosity (LOH) at 16q and 1p have higher relapse and mortality rates.11 The National Wilms Tumor Study-5 (NWTS-5) prospectively evaluated the prognostic significance of LOH on 16q and 1p. Analysis of these data revealed that the relative risks (RR) for relapse for patients with stages I to IV favorable histology (FH) tumors with LOH stratified by stage were 1.8 for LOH 1p (P <.01) and 1.4 for LOH 16q (P = .05). When the effects of LOH for both 1p and 16q were considered jointly, the RR for relapse in stages I and II FH disease was 2.9 (P = .001) and for stages III and IV FH disease was 2.4 (P = .01). The RR for death for patients with stages I and II FH disease with LOH for both regions was 4.3 (P = .01) and for stages III and IV was 2.7 (P = .04). Based on these results, it was proposed that in future WT trials, the therapy for children with LOH at both 1p and 16q be augmented by the addition of doxorubicin to regimen EE4A (discussed below) for early-stage (stages I and II) tumors and cyclophosphamide/etoposide to regimen DD4A (discussed below) for advanced-stage tumors (stages III and IV).12
A novel Wilms tumor suppressor gene on the X chromosome, WTX, was recently discovered. This gene is inactivated in approximately one-third of sporadic WT cases.13 Anaplastic tumors have shown changes on 17p consistent with TP53 deletion and specific genomic loss or underexpression on 4q and 14q and focal gain of MYCN.14 Rhabdoid tumors are characterized by the genetic loss of the SMARCB1/hSNF5/INI-1 gene located at chromosome 22q11. Global gene expression studies have shown that loss of SMARCB1 results in repression of neural crest development and loss of cyclin-dependent kinase inhibition.15 In children with very low-risk WT treated with just surgery alone, the presence of WT1 mutation and 11p15 loss have been prospectively validated to be an important predictor of relapse. These biomarkers may be used to stratify patients to receive reduced chemotherapy in the future.16

PATHOLOGIC CLASSIFICATION
Although histopathologists had attempted to relate appearance to prognosis, no generally acceptable classification was available until the report of Beckwith and Palmer17 from the National Wilms Tumor Study-1 (NWTS-1). The NWTS classifies all tumors as having either FH or unfavorable histology (UH). The UH tumors include anaplastic tumors, clear cell sarcoma, and rhabdoid tumor of kidney. Of 1,465 patients randomly assigned on NWTS-3, 163 (11.1%) had UH.18 WTs are usually sharply demarcated, spherical masses with a “pushing” border and a surrounding distinct intrarenal pseudocapsule. Histologically, WT reflects the development of the normal kidney, consisting of three components: blastemal, epithelial (tubules), and stromal elements, in varying proportions.17 The proportion of the different components has prognostic significance.19 Nephrogenic rests consist of embryonal nephroblastic tissue and are found in 35% of kidneys with unilateral WT and in nearly 100% of kidneys with bilateral WT.20 Nephrogenic rests may be intralobar or perilobar based on their location within the kidney.21 Most nephrogenic rests undergo spontaneous regression and only a small proportion (1% to 5%) transform into WT.22 The histologic feature of greatest clinical significance in WT is anaplasia.23 Anaplasia may be focal (FA) or diffuse (DA). The definitions of FA and DA have been revised to reflect the distribution of anaplastic cells in the tumor rather than their quantitative density. These revised definitions are of prognostic significance. The 4-year survival rates for patients with stages II, III, and IV FA were 90%, 100%, and 100%, compared with 55%, 45%, and 4%, respectively, for patients with similar stage DA WT.24
Clear cell sarcoma of kidney (CCSK) and malignant rhabdoid tumor of kidney (RTK) are no longer considered true WT, but they have been included in NWTS protocols.17 CCSK has a propensity to metastasize to bone, and a skeletal survey and bone scan should be performed. RTK is the most lethal renal neoplasm in children. Primitive neuroepithelial tumors of the cerebellum or pineal region may be seen in 10% to 15% of patients with RTK.25

CLINICAL PRESENTATION
The classic presentation for WT is that of a healthy child in whom abdominal swelling is discovered by the child’s mother or by a physician during a routine physical examination. A smooth, firm, nontender mass on one side of the abdomen is felt. Gross hematuria occurs in as many as 25% of these cases.26 The child may be hypertensive or have nonspecific symptoms such as malaise or fever.27 Only rarely does a patient present with symptomatic metastases.

DIAGNOSTIC WORK-UP

Figure 85.1  Computed tomography scan of a 4-year-old girl with a large right…
The differential diagnosis of WT includes other malignant ­childhood lesions of the kidney, neuroblastoma, and benign conditions such as hydronephrosis, polycystic disease, and splenomegaly in left-sided tumors. Plain films of the abdomen may demonstrate calcifications, which occur in 60% to 70% of neuroblastomas but in only 5% to 10% of WT. Excretory urography (intravenous pyelography) was once the mainstay of imaging in WT and now has largely been replaced by ultrasonography and computed tomography (CT) scanning. Ultrasonography is very useful because it is readily available and is cost-effective.28 A specific advantage of ultrasonography is its ability to assess vessels for flow and tumor thrombus with duplex and color Doppler.29 Routine use of Doppler sonography after abdominal CT scans was not found to be useful in detecting cavoatrial thrombus in a Children’s Oncology Group (COG) study.30 Abdominal CT scans can demonstrate gross extrarenal spread, lymph node involvement, liver metastases, and the status of the opposite kidney (Fig. 85.1).31 Magnetic resonance imaging (MRI) has several advantages over CT scans, especially in identifying renal origin and vascular extension of the tumor.32 CT and MRI are useful in the detection and follow-up of patients with nephrogenic rests.33 Clinical and imaging impressions do not, however, obviate the need for inspection at laparotomy.34 Plain chest radiography and chest CT are also essential because asymptomatic pulmonary metastases are common.35 A complete blood cell count and urinalysis should be performed. Patients with WT can be anemic from hematuria. Serum blood urea nitrogen and creatinine levels and liver function tests are routine. If neuroblastoma is not ruled out, a test for urinary catecholamines should be performed. Table 85.1 outlines the pretreatment investigations recommended by the COG.

NATURAL HISTORY
The disease is often localized at diagnosis, as evidenced by the fact that surgery and radiation therapy is curative in almost 50% of cases.36 The first signs of local tumor spread beyond the pseudocapsule are invasion into the renal sinus or the intrarenal blood and lymphatic vessels. Spread throughout the peritoneal cavity may also occur, especially if there has been preoperative rupture or the disease has been spilled at surgery.37,38 The most common sites of metastases of WT are in the lungs, lymph nodes, and liver. Among patients with stage IV disease, lungs were the only metastatic site in approximately 80% and 15% have liver metastases.39 The NWTS-2 study demonstrated the prognostic importance of lymph node involvement. The 2-year relapse-free survival (RFS) with and without lymph node involvement was 54% and 82%, respectively.37

STAGING
Tumor staging is performed after examining the radiologic, operative, and histopathologic findings.38,39 In NWTS-1 and NWTS-2, a tumor grouping system was used for staging and treatment stratification. After analyzing the prognostic significance of several clinicopathologic factors in NWTS-1 and NWTS-2, a new staging system was adopted in NWTS-3. The presence of lymph node involvement was upstaged to stage III instead of group II, and local tumor spill was downstaged from group III to stage II.38 In NWTS-5, the most significant change was the distinction between stages I and II. The criteria for stage I was revised to accommodate an important subset of WT that is being managed by nephrectomy alone. Before NWTS-5, the distinction between stages I and II in the renal sinus was established by the hilar plane, which was an imaginary plane connecting the most medial aspects of the upper and lower poles of the kidney. This criterion was difficult to apply because of tumor distortion, and thus the hilar plane criterion has been replaced with renal sinus vascular or lymphatic invasion. This definition includes not only the involvement of vessels within the hilar soft tissue, but also the vessels located in the radial extensions of the renal sinus into the renal parenchyma.40,41 The COG staging guidelines for WT are shown in Table 85.2. The major change from NWTS-5 is that children with tumor spillage are upstaged from stage II to stage III because of the higher risk for relapse with two-drug chemotherapy alone.42 The COG risk group classification for treatment assignment in the new generation of WT protocols is shown in Table 85.3. In addition to tumor stage, this classification will also consider the patient’s age, tumor weight, presence or absence of LOH at 1p and 16q, and response to chemotherapy in children with FH tumors and lung metastases.

GENERAL MANAGEMENT
The diagnosis of WT is usually made before surgery and confirmed at surgery. A transverse transabdominal, transperitoneal incision is recommended for adequate exposure and thorough abdominal exploration.43 The surgeon must excise all tumors without spillage, if possible. Lymph node sampling from the para-aortic, celiac, and iliac areas must be performed. The use of titanium clips to identify residual tumor and margins of resection is also recommended. Routine exploration of the contralateral kidney was mandated in the past, but it is no longer recommended due to better imaging of the contralateral kidney with CT and MRI scans.
The chemotherapy and radiation therapy (RT) regimens for WT in the COG protocols are outlined in Tables 85.4 and 85.5.

RADIATION THERAPY TECHNIQUES
RT guidelines used for primary and recurrent WT in the COG protocols are shown in Table 85.5.
Timing of Radiation Therapy
The NWTS has shown that although RT does not need to be given immediately after surgery,36 a delay of ≥10 days after surgery was associated with a significantly higher abdominal relapse rate, particularly among patients with UH tumors.44,45,46,47 Because the pathologist cannot always rule out UH quickly, all patients with WT should be scheduled to start RT no later than day 9, the day of surgery being day 0. Although most patients may not be irradiated, it is easier to cancel than to make arrangements to start RT for a small child on short notice. The influence of RT delay on abdominal tumor recurrence in patients with FH tumors treated on NWTS-3 and NWTS-4 has been reported. The mean RT delay was 10.9 days. Although univariate and multivariate analysis did not reveal RT delay of ≥10 days to adversely influence flank and abdominal recurrence, it is important to note that in 59% of children the RT delay ranged from 8 to 12 days.48 For the COG protocols, it is recommended that RT be given preferably by day 9 but no later than day 14 after surgery.
Radiation Therapy Dose
In NWTS-1 and NWTS-2 RT dosages to the operative bed were given according to the age of the patient, however, no significant dose–response association was detected.45,47 In NWTS-3, there was a randomization for patients with FH tumors that resulted in elimination of RT for stage II FH, and a reduction of dose to 10 Gy for stage III patients.46 NWTS-3 and NWTS-4 data showed no RT dose response for CCSK and anaplastic tumors.49 Therefore, it was decided to treat all abdominal disease with 10 Gy. In the COG protocols, the dose is 10 Gy for most indications except for stage III DA and stages I to III RTK, where a higher dose of 19.8 Gy is recommended (Table 85.5).50,51
Radiation Therapy Volume

Figure 85.2 Anteroposterior flank irradiation portal in a 2…
Parallel-opposed fields using 4 or 6 MV photons are preferred. The flank RT field is determined by the CT or MRI scan performed at diagnosis before any chemotherapy is administered. The planning target volume is the tumor bed (outline of the kidney and associated tumor on the initial CT or MRI) with a 1-cm margin. The medial border must cross the midline to include the entire width of the vertebrae so as to minimize growth disturbances. An example of a flank RT portal is shown in Figure 85.2.44 When whole-abdomen RT is administered, the femoral heads and acetabulum must be shielded (Fig. 85.3). Whole-lung Irradiation (WLI) portals are shown in Figure 85.4. If the lungs and either the flank or whole abdomen have to be treated simultaneously, it is preferable to include them in one treatment portal.

SUMMARY OF CLINICAL TRIALS
No tumor has been studied by clinical trials as thoroughly and effectively as WT. The NWTS has been active in North America since 1969. There have also been successful studies run by the International Society for Pediatric Oncology (SIOP). The long-term results of NWTS-3 and NWTS-4 are shown in Table 85.6.

First National Wilms Tumor Study (1969–1974)
NWTS-1 showed that postoperative RT was not necessary for children younger than 2 years of age with group I tumors, and that combined dactinomycin and vincristine for irradiated patients with group II and III tumors was better than therapy with either agent alone. The RFS with and without RT among patients with group I tumors younger than 2 years of age was 90% and 88%, respectively.44
Second National Wilms Tumor Study (1974–1979)
NWTS-2 showed that in patients with group I tumors there was no survival difference between 6 months or 15 months of dactinomycin plus vincristine. Patients with groups II to IV tumors had a superior 2-year RFS of 77% with doxorubicin, dactinomycin, and vincristine compared with 63% with dactinomycin and vincristine alone.37
Third National Wilms Tumor Study (1979–1985)
The overall objective of NWTS-3 was to reduce therapy for low-risk patients (stages I to III FH) and to intensify treatment by adding a fourth drug, cyclophosphamide, for stage IV tumors with FH and all UH tumors. The results of this study demonstrated that RT and doxorubicin could be eliminated in children with stage II FH tumors. Patients with stage III FH tumors who received doxorubicin or 20 Gy had fewer abdominal relapses than those receiving 10 Gy without doxorubicin.46 The addition of cyclophosphamide in high-risk patients did not improve outcomes.49

Fourth National Wilms Tumor Study (1986–1994)
By the conclusion of NWTS-3, it was clear that the treatment of WT had been refined for the majority of patients; 62% of patients with WT have stage I or II FH disease and therefore require neither flank RT nor the potentially cardiotoxic doxorubicin. NWTS-4 was designed with cost containment in mind. The results proved that the survival was similar among patients who received standard-course (5 days) or single-dose, pulse-intensive dactinomycin chemotherapy. Further, pulse-intensive therapy was associated with less hematologic toxicity and marked reduction of treatment costs.52,53

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Chapter 84

Central Nervous System Tumors in Children

Carolyn R. Freeman, Jean-Pierre Farmer, and Roger E. Taylor

Central nervous system (CNS) tumors account for 20% to 25% of all malignancies that occur in childhood. According to the North American Association of Central Cancer Registries (NAACCR), the age-standardized incidence rate was 48.47 per million in the 0- to 19-year age group for the period 2004–2007.1 The incidence was highest among children 1 to 4 years of age and lowest among 10- to 14-year-olds.

The etiology of pediatric CNS tumors remains largely unknown. Only 2% to 5% can be ascribed to a known genetic predisposition. Included in this category are those seen in patients with neurofibromatosis types 1 (NF-1) and 2 (NF-2), tuberous sclerosis, nevoid basal cell (Gorlin’s) syndrome, familial adenomatous polyposis, and Li-Fraumeni syndrome. An even smaller percentage can be attributed to ionizing radiation used for diagnostic or therapeutic purposes. For the majority of patients, no predisposing factors can be identified.

The management of children with CNS tumors has changed substantially over the past three decades. Routine use of magnetic resonance imaging (MRI), and now frequently also functional imaging, and improved neuropathologic examination and molecular diagnostics have contributed to better characterization of the different tumor types. Improved neurosurgical techniques and perioperative care permit greater degrees of surgical resection even for tumors previously considered inoperable because of their location in eloquent areas of the brain. All of these, as well as improved radiotherapy techniques, newer chemotherapy agents and regimens, and national and international clinical trials, have contributed to improved outcomes for children and adolescents with CNS tumors. According to the NAACCR, 5-year survival has increased from 62.9% for patients diagnosed in 1980–1989 to 75.3% for those diagnosed in 2000–2006.1

RADIOTHERAPY FOR PEDIATRIC CNS TUMORS: GENERAL ISSUES

Radiotherapy is an essential component of treatment for many children with CNS tumors. However, survivors are at significant risk for the development of long-term sequelae,2,3 many of which, while usually multifactorial, are in large part due to radiotherapy; many of the strategies used in the management of children with CNS tumors over the past three decades have been designed to reduce the risks associated with treatment. Recent developments in radiotherapy including improved targeting and new technologies and techniques for treatment, as well as new treatment modalities such as protons, all offer important opportunities for therapeutic gain that will be discussed below and in each section of this chapter.

Long-Term Effects of Radiotherapy

The quality of survival of children with brain tumors may be compromised by long-term sequelae. While some patients (e.g., patients with NF-1) may be at particular risk and while some sequelae (e.g., neurologic deficits) are more often due to the tumor and/or surgery, it is clear that radiotherapy is directly, alone or modulated by other factors, responsible for many late effects. A review by Kortmann et al.4 gives an excellent account of radiation-related sequelae in children treated for low-grade glioma including effects on brain parenchyma, neurologic deficits, neurocognitive and behavioral effects, endocrine dysfunction, vasculopathy, and the development of second tumors.

The neurocognitive sequelae of radiotherapy have become much better characterized over recent years. It is now known that myelinization and functional maturation of the CNS continue until well into adolescence and even into young adulthood. Through its effect on the microvasculature as well as on the oligodendrocyte precursor cells that produce myelin, radiotherapy causes disrupted neurogenesis and cortical atrophy. Patients fail to acquire new knowledge and skills at an age-appropriate rate and show a progressive decline in IQ over time.5 The magnitude of the deficit depends most importantly on age at treatment, but many other host (e.g., NF-1 or not), tumor (e.g., location, hydrocephalus or not), and treatment factors (e.g., radiotherapy volume and dose,6,7,8 use of chemotherapy9,10) play a role. Moreover, the development of other deficits such as behavioral difficulties related to the location of the tumor and/or surgery or hearing impairment due to cisplatinum may have a modulating effect. The end result for many patients is impaired school and social performance that deteriorates over time. There is increasing evidence that intervention using cognitive or behavioral therapy or pharmacotherapy and even exercise may be useful and that this should start soon after treatment for best results.5,11,12

Endocrine deficits are very common after radiotherapy.13Even though a substantial proportion of patients may have had deficits prior to radiotherapy due to the tumor or to surgery,14,15and even though there may be modulating factors such as chemotherapy that affect the frequency of deficits, radiotherapy is primarily responsible for the growth hormone deficiency that correlates with the dose of radiotherapy to the hypothalamic–pituitary axis16,17,18, and the primary hypothyroidism seen after craniospinal radiotherapy. There may be direct and indirect effects on musculoskeletal development. Osteopenia is a rather common finding that may put patients, particularly those with residual neurologic deficits, at significant risk for fracture.

Radiotherapy has been implicated as well in the development of cardiovascular complications including cerebrovascular events and coronary heart disease.15,19 Although again the etiology is likely multifactorial, it is important to be cognizant of the risks and to minimize the dose to vascular structures and the heart.

Strategies that have been used to avoid or minimize the long-term effects of treatment for pediatric brain tumors include the following:

Avoidance of radiotherapy altogether (e.g., in patients with low-grade astrocytoma for whom surgery alone may be a good option)

Delay of radiotherapy for young children (i.e., those younger than age 3 to 8) by the use of chemotherapy

Use of daily anesthesia, improved immobilization techniques (e.g., rigid casts or a stereotactic frame), and/or daily pretreatment image verification, all of which allow the use of reduced safety margins

Use of image-based treatment planning using computed tomography (CT)–MRI or CT–MRI–functional imaging coregistration and better treatment-planning and delivery techniques that result in greater sparing of normal brain and organs at risk

Use of new radiation modalities (e.g., proton therapy that provides even greater sparing of the surrounding normal brain and organs at risk)

Use of reduced radiotherapy target volumes when it is shown safe to do so (e.g., tumor bed rather than whole posterior fossa for the boost in standard-risk medulloblastoma)

Reduction of radiotherapy dose (e.g., in young patients with standard-risk medulloblastoma for whom in the North American studies the dose for craniospinal irradiation has been reduced progressively from 35 to 36 Gy to 23.4 Gy and, in current studies, to 18 Gy for children younger than 8)

Use of smaller fraction sizes where appropriate (e.g., 1.5 Gy/day for patients with radiosensitive tumors such as germinoma)

Use of hyperfractionated radiotherapy (HFRT) (e.g., as in the current European studies for standard-risk medulloblastoma)

These will be discussed later in each relevant clinical situation.

Preparation for Radiotherapy

The planning and delivery of radiotherapy for children with CNS tumors are technically challenging and labor intensive for the entire interprofessional team. The expertise of specialist personnel such as pediatric nurses and play therapists can be pivotal in encouraging a young child to lie still for the making of an immobilization device, for radiotherapy-planning procedures, and for treatment itself. For children younger than age 4 or 5 years, daily anesthesia will almost always be necessary, and this will require a skilled pediatric anesthetist because anesthesia will be administered in an environment without all of the support available in an operating room.

Radiotherapy Target Volumes and Treatment Techniques

Focal, Tumor or Tumor Bed Radiotherapy

For most tumor types, target volume definition is best accomplished using CT simulation with CT–MRI image coregistration. For patients who have undergone cerebrospinal fluid (CSF) diversion or surgical resection or in whom tumor shrinkage has occurred with chemotherapy, it will be important to take into account any anatomic shifts that may have taken place. This will be more of an issue for tumors arising in some areas than others and often adds significantly to the time required for contouring. The clinical target volume (CTV) will be tumor type specific, while the planning target volume (PTV) will be technique specific, ranging from 1 to 5 mm depending on the type of immobilization device used and whether daily pretreatment image verification is to be performed.

Modern radiotherapy treatment-planning and delivery techniques make it easier to achieve conformity of the treated volume to the target and sparing of uninvolved normal structures than in the past. The choice of technique in an individual patient will require careful analysis of the dosimetry in the context of the available options. A recent article by Beltran et al.20 provides an excellent example of the issues to be considered now when weighing alternatives.

Other options for focal treatment include brachytherapy and intracystic injection of radioactive colloids. These will be discussed in the context of the relevant clinical situation.

Whole-Ventricle Radiotherapy

Whole-ventricular irradiation is used most frequently in patients with CNS germ cell tumors. Because subependymal spread is common, the target volume logically would include the lateral, third, and fourth ventricles with a margin of 1 to 1.5 cm. If lateral opposed fields are used, the volume of brain spared will be small. Better sparing can be achieved using intensity-modulated image-guided radiotherapy.21,22,23

 Craniospinal Radiotherapy

The CTV for craniospinal radiotherapy has an irregular shape that consists of the whole brain and spinal cord and their overlying meninges. In standard techniques, the lower borders of lateral whole-brain fields are matched to the cephalad border of a posterior spine field, usually with a moving junction between the brain and spine fields to minimize the risk of underdose or overdose in the cervical spinal cord. Compensators may be needed to achieve dose homogeneity throughout the target volume.

Patients have traditionally received craniospinal irradiation (CSI) in the prone position, but modern technology allows safe treatment in the supine position that in general is more comfortable and, if anesthesia is required, allows better control of the airway. In either case, immobilization is essential and involves the use of a head shell or full-body immobilization. Careful attention to positioning at the time of simulation is critical to minimize or even eliminate the risk of certain long-term effects. For example, using neck extension together with careful selection of the level for the junction of the brain and spine fields, it is possible to avoid including the dentition in the exit from the superior aspect of the spinal field and thus damage to developing teeth.

Figure84.1 The use of computed tomography simulation is superior to…

CT simulation is necessary to ensure adequate coverage of the CTV in the subfrontal region at the cribriform plate. Traditionally, blocks have been used in the lateral fields to shield not only the facial structures but also the lenses. However, in most children it is impossible to adequately irradiate the cribriform plate and shield the lenses (Fig. 84.1), and adequate PTV coverage should take precedence.

Figure84.2 The use of computed tomography simulation with contouring…

CT simulation is helpful, too, in identifying the lateral aspect of CTV for the spine field that includes the extensions of the meninges along the nerve roots to the lateral aspects of the spinal ganglia (Fig. 84.2). The field will be narrower in the dorsal region to avoid unnecessary irradiation of the heart and lungs and wider in the lumbar region, although here it is important to avoid an excessively wide field that will result in unnecessary irradiation of the bone marrow and gonads. The lower limit of the CTV for the spine field is best determined by MRI. Traditionally, the lower border of the spine field was placed at the lower border of the second sacral foramen, but it is well documented that the lower border of the thecal sac can be as high as L5 or as low as S3. In the interest of both CTV coverage and normal tissue sparing, it is important that the lower border be individualized according to the MRI findings.

There are many issues that need to be addressed in designing a CSI technique (Table 84.1). Many of the different solutions24add further complexity. Using modern tools for treatment planning and delivery, it is possible to greatly simplify the technique and substantially reduce planning and delivery times. One such technique is shown in Figure 84.3.25 In general, photons in the 6- to 10-MV range provide satisfactory coverage of the PTV. A variation of dose along the spinal axis of >10% will require the use of dose compensation that can be achieved using multileaf collimation.

Table84.1 Technical Considerations for Craniospinal…

Figure84.3 To cover the clinical target volume for…

Electrons are used in some centers to treat the spinal axis and in fact may be of greater interest now than in the past because of improved dose calculation algorithms and even electron dose modulation techniques. However, at the same time newer treatment-planning and delivery methods such as intensity-modulated radiation therapy (IMRT) together with daily image verification allow for improved dosimetry with photons with clinically relevant dose reductions to structures anterior to the target volume such as the heart, gastrointestinal (GI) tract, and gonads.26 The use of IMRT and smaller PTV margins raises new issues that are not as relevant when lateral opposed fields are used, such as the need to ensure adequate coverage of all CSF extensions including those along the optic nerves and into the internal auditory canals (Fig. 84.4).

Figure84.4 Postoperative axial T2-weighted magnetic…

Protons provide a dose distribution for CSI that cannot be achieved by even the most sophisticated photon beam treatment planning, with significant reduction in low-dose exposure outside the target volume.27 For now, however, access to proton therapy is limited and the cost prohibitive.

Radiation Dose and Dose-Fractionation Regimens

The conventional daily fraction size for the treatment of most pediatric CNS tumors is 1.8 Gy and the total dose typically on the order of 54 to 55.8 Gy. When treating a primary tumor of the spinal cord, it is conventional to use a lower total dose (e.g., 50.4 Gy). It is also usual to use lower doses for children younger than age 3 years to reduce the risk of neurocognitive deficits. When treating radiosensitive tumors such as intracranial germinoma, radiotherapy may be delivered using a lower dose per fraction (e.g., 1.5 Gy) and lower total doses of 30 to 45 Gy.

Many pediatric brain tumors exhibit a dose–response relationship for tumor control and in some cases local progression is not prevented by the use of a conventional “CNS tolerance” radiation dose. When the target contains only a small volume of normal brain tissue, dose escalation may be possible using newer treatment-planning and delivery techniques. HFRT may be a useful strategy in situations where dose escalation cannot be achieved safely using conventional fractionation.

Follow-Up During and After Radiotherapy

An excellent review by Donahue28 describes the acute reactions seen during treatment with radiotherapy and provides guidelines for their management. These days nausea and vomiting almost always can be prevented by the use of the 5HT-3 antagonists. Headache is not an expected side effect and should be investigated by physical examination for signs of raised intracranial pressure and by imaging as appropriate. Steroids, if used, usually can be tapered by the second or third week of treatment. Fatigue is a rather common symptom and is cumulative. The neurologic status of the patient, especially coordination and gait, may appear to worsen during the last weeks of treatment because of this. Children usually recover relatively quickly and often can get back to their usual routine quite soon after completion of treatment.

Predictable effects of treatment include hormonal deficits, especially primary hypothyroidism when CSI is delivered using photons and growth hormone deficit secondary to inclusion of the hypothalamic–pituitary axis. Patients should be monitored closely in follow-up and treatment instituted as appropriate. Many will also need regular follow-up in ophthalmology and audiology.

Extra pedagogic support may be necessary. Patients should have ready access to a neuropsychologist for evaluation of any special needs and in the longer term to vocational assessment and counseling.

RADIOTHERAPY FOR SPECIFIC TUMOR TYPES

The World Health Organization (WHO) classification of tumors of the nervous system29 is given in Table 84.2 and the distribution by tumor type and location in Figure 84.5. There are important differences between tumors seen in childhood and those occurring in adults. In children, almost half of all tumors arise in the infratentorial compartment. Low-grade astrocytic tumors as a group account for approximately one-third to half of all CNS tumors, but medulloblastoma is the most common distinct entity. High-grade gliomas, which account for the majority of primary brain tumors seen in adults, are much less common in children.

Table84.2 World Health Organization Classification of…

Figure84.5 Distribution of central nervous system tumors by…

This chapter will follow the order of the WHO classification. Although in the past tumors arising in infants and very young children were grouped together and all managed similarly with chemotherapy in order to delay or if possible avoid radiotherapy, they are now managed according to the specific tumor type and so will be discussed here in each relevant section.

ASTROCYTIC TUMORS

According to the WHO classification, astrocytic tumors comprise the following clinicopathologic entities:

Pilocytic astrocytoma (WHO grade I)

–Pilomyxoid astrocytoma

Subependymal giant cell astrocytoma

Pleomorphic xanthoastrocytoma

Diffuse astrocytoma (WHO grade II)

–Fibrillary astrocytoma

–Gemistocytic astrocytoma

–Protoplasmic astrocytoma

Anaplastic astrocytoma (WHO grade III)

Glioblastoma multiforme (WHO grade IV)

–Giant cell glioblastoma

–Gliosarcoma

Gliomatosis cerebri

These tumors are heterogeneous with respect to clinical presentation (age, gender, location in the CNS, imaging findings) as well as to growth potential and rate of progression. Two, pleomorphic xanthoastrocytoma and subependymal giant cell astrocytoma, are rare tumors. Their clinical presentation and imaging findings are quite characteristic and surgery is usually curative. They will not be discussed further here.

Low-Grade Astrocytoma (WHO Grades I and II)

So-called benign or low-grade astrocytomas (LGAs) comprise a heterogeneous group of tumors with behavior patterns that are fairly typical according to location and pathologic type. In general, in children, they follow an indolent clinical course with overall survival rates at 10 and 15 years as high as 80% to 100%. LGAs can be grouped according to their anatomic location:

Cerebellar astrocytomas (15% to 20% of all CNS tumors)

Hemispheric astrocytomas (10% to 15% of all CNS tumors)

Midline supratentorial tumors, including the corpus callosum, lateral and third ventricles, and hypothalamus and thalamus (10% to 15% of all CNS tumors)

Optic pathway tumors (approximately 5% of all CNS tumors)

Brainstem LGAs (brainstem tumors account for 10% to 15% of all CNS tumors; 20% to 30% of these are LGAs)

LGAs of the spinal cord (spinal cord tumors account for 3% to 6% of all CNS tumors; approximately 60% of these are LGAs)

Pilocytic astrocytomas are the most common type in the pediatric age group, accounting for almost all of the LGAs at certain sites (e.g., the cerebellum and the anterior optic pathway). They account for a smaller proportion of LGAs arising in the deep midline structures and in the cerebral hemispheres. Macroscopically, pilocytic astrocytomas appear well circumscribed and frequently have an associated cystic component. Pilocytic astrocytomas are characterized histologically by a biphasic pattern with a varying proportion of compacted bipolar cells with Rosenthal fibers and loose-textured multipolar cells with microcysts and granular bodies. Rare mitoses, occasional hyperchromatic nuclei, microvascular proliferation, and even infiltration of the meninges are compatible with a diagnosis of pilocytic astrocytoma and not a sign of malignancy. A variant, pilomyxoid astrocytoma, first described in infants and young children with chiasmatic/hypothalamic tumors, appears to be associated with more aggressive behavior that may include leptomeningeal seeding.30

Diffuse astrocytomas account for only approximately 10% to 15% of all LGAs in children but for a relatively higher proportion of those seen in infants and adolescents. Most intrinsic pontine tumors and a large proportion of astrocytomas arising in the cerebral hemispheres are diffuse astrocytomas. Diffuse astrocytomas grow by infiltration rather than destruction of anatomic structures and usually are not well circumscribed. Microscopically, they are composed of well-differentiated fibrillary or gemistocytic neoplastic astrocytes on a background of loosely structured, often microcystic, tumor matrix. Cellularity is moderately increased. The presence of nuclear atypia is a diagnostic criterion, but mitotic activity, necrosis, and microvascular proliferation are absent. The growth fraction as determined by Ki-67 and MIB-1 labeling indices is usually low. Diffuse astrocytomas may undergo malignant progression, although this is not common in the pediatric age group with the notable exception of tumors arising in the pons.

Patients with LGAs typically present with a long history of nonspecific and nonlocalizing symptoms. Symptoms and signs of raised intracranial pressure may be seen in patients with midline and cerebellar tumors. Patients with posterior fossa tumors may present with neck stiffness and a head tilt as a manifestation of raised intracranial pressure causing tonsillar herniation, altitudinal diplopia, or spinal accessory nerve irritation. Seizures are present in as many as three-quarters of patients with hemispheric lesions. Other symptoms relatively less frequent and usually of more recent onset relate to the location of the tumor. These may include, for example, focal motor deficits with hemispheric tumors, visual field deficits with tumors compressing or involving the optic pathway, neuroendocrine deficits with hypothalamic tumors, and the diencephalic syndrome (consisting of emaciation with loss of subcutaneous fat despite normal or increased appetite, alert appearance, increased vigor and euphoria, pallor without anemia, and nystagmoid movements of the eyes) in young children with chiasmatic/hypothalamic tumors.

Neuroimaging findings are usually quite characteristic. Pilocytic astrocytomas are well circumscribed, often with a cystic component that may be large relative to the size of the solid component. There is usually little edema or mass effect. The solid component enhances brightly and uniformly with contrast material. Diffuse or fibrillary astrocytomas are usually not well seen on nonenhanced CT or MRI and usually show little enhancement with contrast material. T2-weighted or fluid-attenuated inversion recovery (FLAIR) MRI sequences usually best demonstrate the extent of disease.

Management of Low-Grade Astrocytomas: General Principles

Some children with LGAs may not require any tumor-specific treatment. These include, for example, patients with NF-1, as many as 15% of whom have optic pathway tumors.31 NF-1 patients also may have astrocytic tumors in other parts of the CNS as well as hamartomatous lesions, typically in the brainstem. These lesions may be detected on routine imaging, but even tumors that are symptomatic may remain stable over long periods so that surveillance is appropriate initial management.32,33,34 A number of clinical and imaging characteristics have been correlated with a more aggressive course, but even for these patients active intervention will usually be undertaken only at time of progressive disease that is symptomatic.

Progression-free survival without treatment may be very good as well for patients with tectal lesions who present with hydrocephalus without localizing brainstem signs. LGA in this region may be very indolent, showing either no progression (the majority) or only very slow progression over the course of many years following CSF diversion alone. The common characteristics of these very indolent tumors are their small size (<1.5 or 2 cm) and the fact that on imaging they are hypodense/hypointense and nonenhancing. Follow-up with MRI is essential to identify patients with progressive lesions as manifested by increasing size and/or enhancement with gadolinium. Treatment (usually radiotherapy but sometimes now surgery) at time of progression is associated with a high probability of long-term tumor control.

These special situations underscore the need for careful evaluation and individualization of management of patients with LGAs depending on the specific clinical situation and tumor type. If in doubt, a period of surveillance generally will be an acceptable initial approach.

Figure84.6 Surgical planning for a dysembryoplastic…

Surgery is the mainstay of treatment for LGAs. Complete resection is more likely to be accomplished in patients with smaller tumors and those arising in noneloquent parts of the brain as well as in patients with the generally well-circumscribed pilocytic tumors. Modern surgical techniques that include, for example, computer-assisted resections (“neuronavigation”) aided by preoperative functional MRI, MR tractography, and intraoperative mapping of eloquent areas (Fig. 84.6) together with intraoperative MRI permit greater degrees of resection in larger proportions of patients, including many who in the past would have been considered to have inoperable lesions. Complete resection is now achieved in >80% of cerebral, cerebellar, and spinal cord tumors and about 50% of diencephalic tumors.

Children with LGAs who undergo complete resection fare very well, with long-term disease-free and overall survival rates of 80% to 100%.35,36,37,38,39,40 In most series, results are better (close to 100%) for patients with pilocytic astrocytomas than for those with diffuse or fibrillary LGAs, although some have disputed this, showing equally satisfactory results for both. In either type, postoperative adjuvant therapy is not indicated.

For children who undergo less than complete resection, the progression-free survival rate after surgery alone is less satisfactory. In a joint Children’s Cancer Group (CCG)–Pediatric Oncology Group (POG) study in which such patients were observed without adjuvant treatment, any residual tumor was associated with an inferior progression-free survival rate: the 8-year progression-free survival rate was 56% for patients with <1.5 cm3 residual tumor and 45% for those with >1.5 cm3. However, the majority of patients can be salvaged with a second surgical resection and/or radiotherapy. In the CCG–POG study, overall survival at 8 years was 95% and 90%, respectively.41

Figure84.7 An algorithm for the management of patients with low…

The role of postoperative radiotherapy following less than complete resection remains unclear. In most series, the use of radiotherapy in this situation results in improved disease-free survival without any benefit in terms of overall survival. Because only approximately half of all patients will develop progressive disease, the usual recommendation for a patient who is neurologically stable will be surveillance, with MRI performed at least every 6 months for the first 3 years, the period during which risk of progression is greatest.42 A second surgical procedure would usually be considered at time of progression, and other treatment, either radiotherapy or chemotherapy, reserved for patients with progressive, inoperable disease (Fig. 84.7).

In the past, patients with deep midline and other tumors considered surgically inaccessible were treated with radiotherapy, often even without histologic confirmation of diagnosis. However, using modern neurosurgical techniques, it is feasible to resect surgically about half of these lesions (Fig. 84.8), and the overall strategy for these patients should now be as for patients with LGAs at other locations, albeit with the understanding that outcome is not as satisfactory. The 8-year progression-free and overall survival rates in the CCG–POG study for patients with midline chiasmatic tumors were 25% and 84%, respectively.41

Figure84.8 A 12-year-old boy referred to the radiation…

When adjuvant therapy is indicated, the options include chemotherapy, particularly for infants and young children and for patients of all ages with NF-1 who are at greatest risk of developing neurocognitive, vaso-occlusive, and neuroendocrine sequelae of treatment. Complete responses to chemotherapy are not common, but overall response rates that include stable disease range from 70% to 100% and the use of chemotherapy has been shown to permit delay of radiotherapy by 2 to as many as 4+ years.43,44,45,46 The age limit below which chemotherapy should be used is controversial. It is likely that delaying radiotherapy for 2 to 3 years will be of benefit for a child younger than age 5 to 8. However, the benefit from a similar delay for an older child is less clear, particularly when any benefit may be offset by neurologic compromise from further tumor progression as well as the need for a larger radiotherapy target volume. Moreover, recent advances in radiotherapy practice that have the potential to reduce the risks of radiotherapy have led to a reassessment of the role of radiotherapy in LGAs and better acceptance of its earlier use even in very young children.

Radiotherapy in LGAs

Due largely to improvements in surgery and to a lesser extent to successful treatment of younger children with chemotherapy, there has been a substantial decrease in the use of radiotherapy over recent years. Currently only approximately 10% of all children with LGAs receive radiotherapy.

Radiotherapy is not indicated after complete resection

Radiotherapy may be indicated following incomplete resection in situations when tumor progression would compromise neurologic function (e.g., “threat to vision”)

The clearest indication for radiotherapy is in patients with progressive and/or symptomatic disease that is unresectable

The radiotherapy target volume (the gross tumor volume or GTV) consists of all disease seen on MRI performed just prior to treatment (Fig. 84.9). The resulting treatment volume usually will be considerably smaller than one based on preoperative imaging, which until recently would have constituted standard practice. Similarly, margins that were considered standard (and still are in adult practice) are unnecessary, particularly for the well-circumscribed pilocytic tumor for which a CTV margin of 1 cm40 or even 0 cm (i.e., CTV = GTV)47 around the GTV as seen on T1-weighted gadolinium-enhanced images has been shown to result in excellent local control. More generous margins of 1 to 1.5 cm around the GTV as seen on T2-weighted or FLAIR images may be more appropriate for the more infiltrative diffuse fibrillary tumors.

Figure84.9 This patient underwent subtotal resection of a…

Evidence for a dose–response correlation in LGAs in children is scant. Although the European and North American studies that randomized adult patients with LGAs between low-dose (45 and 50.4 Gy, respectively) and high-dose (59.4 and 64.8 Gy, respectively) radiotherapy failed to demonstrate any advantage for the higher dose, it may be unwise to extrapolate that in children doses of 45 to 50 Gy are as effective as the higher doses of 54 to 55 Gy that until now have constituted standard practice. There are biologic differences between LGAs in children and in adults. As well, children who have progressed on chemotherapy may have tumors that are less sensitive. For now, the recommendation for children with LGAs would be a “standard” dose of 50 to 54 Gy depending on the age of the child and the location of the tumor and its relationship to critical normal structures such as the optic chiasm.

External-beam radiotherapy using a conventional dose-fractionation schedule should be considered the standard of care in LGAs and the technique to be used that which provides homogeneous irradiation of the CTV and best spares surrounding normal tissues.

Other approaches that have been used in LGAs include radiosurgery using the Gamma knife or linear accelerator–based techniques.48 While the use of a single fraction, typically of 10 to 20 Gy, to the periphery of the lesion or a small number of large fractions may not be optimal for diffuse or fibrillary LGAs with tumor cells embedded in rather than displacing normal brain, such treatment may be of interest for part or even all of the treatment for the less invasive pilocytic astrocytomas that are often small at time of progression.

Another option for treatment is brachytherapy, which has been used with some success particularly in European centers.49,50,51,52,53 As for radiosurgery, the principal limitation with respect to the use of brachytherapy is the size of the target volume. Brachytherapy series necessarily select for smaller tumors, and there is no evidence that brachytherapy is a better treatment option than external-beam radiotherapy. Radioactive solutions such as 32P, 90Y, 198Au, and 186Re may be useful in cystic LGAs, particularly for patients with recurrent disease after radiotherapy in whom symptoms not infrequently relate more to the cyst than to the solid component of tumor. Simple aspiration with or without placement of an internal shunt usually will alleviate symptoms for protracted periods, but in some cases, particularly those in which the cyst wall enhances and is felt to be biologically active, control of the cyst may be difficult, and the use of radioactive solutions could be considered. However, this is not a procedure without risks and care has to be taken to avoid leakage.

Tumor regression after radiotherapy typically is slow and patients and their families need to be warned that the tumor may remain stable or sometimes even increase in size in the first months after completion of treatment. It is important not to assume that changes seen on MRI represent progressive disease. Close follow-up with early repeat imaging usually will be the best approach in this situation.

High-Grade Astrocytoma (WHO Grades III and IV)

Anaplastic astrocytoma (AA) is a diffusely infiltrating malignant astrocytoma characterized by nuclear atypia, increased cellularity, and significant proliferative activity. Glioblastoma multiforme (GBM) is the most malignant astrocytic tumor. Histopathologic features include nuclear atypia, cellular pleomorphism, mitotic activity, vascular thrombosis, microvascular proliferation, and necrosis. Both AA and GBM may develop from WHO grade II astrocytomas. However, with the exception of tumors that arise in the pons, they arise almost always in the pediatric age group de novo without evidence of a less malignant precursor lesion.

High-grade astrocytomas (HGAs) account for 5% of all CNS tumors in the pediatric age group. They are the most common tumor type in older adolescents. Two-thirds of HGAs are located in the cerebral hemispheres and the remainder approximately equally divided between the deep midline structures (thalamus and basal ganglia) and cerebellum. Patients with HGAs usually present with symptoms of short duration that relate to the location of the lesion.

Surgery is an important component of treatment. Because most studies show a survival advantage for patients who have undergone complete resection,54,55,56,57,58 maximal surgical resection compatible with a good neurologic outcome should be the goal for all patients and a second surgical procedure should be considered if there is significant residual tumor after the first. Postoperative radiotherapy always is indicated. Although leptomeningeal seeding is seen in a substantial minority (10% to 30%) of patients, the predominant failure pattern is local and the radiotherapy target volume is local, with a GTV that consists of the tumor bed and any residual enhancing or nonenhancing residual tumor plus any abnormality seen on T2-weighted MRI with a margin for the CTV of 1.5 cm. Because these are often large tumors and doses beyond tolerance levels for structures such as the optic chiasm are required, it is usual to consider a volume reduction at 50 to 54 Gy to a CTV that consists of the tumor bed and any residual tumor plus a reduced margin of 1 cm. The dose to the CTV should be at least 54 Gy given over 6 weeks, but a dose of 59 to 60 Gy is more usual if feasible. There is no evidence that higher doses delivered using radiosurgery or stereotactic boosts, boosts with brachytherapy, or HFRT result in improved outcome, but IMRT delivering accelerated treatment to a component of the target volume (such as the GTV) may be of interest, if only to decrease the overall treatment duration.

The role of chemotherapy remains to be defined. Although responses are seen to many different agents and regimens, results have often been difficult to interpret because of small patient numbers, inconsistent inclusion criteria with respect to pathology, and confounding variables such as tumor location and extent of surgical resection. The cooperative groups in North America and Europe are investigating a number of approaches that include newer chemotherapeutic and biologic agents, some of which have radiosensitizing properties. Whenever possible, patients should be treated on such protocols. Off study it may be difficult to make a recommendation with respect to adjuvant chemotherapy, although the poor prognosis, particularly for patients with macroscopic residual disease following surgery, usually is given as an argument for the use of the “current best” regimen, most often now temozolomide as in adults.

The prognosis for children with HGAs is poor, with a median time to progression of 10 to 11 months and an overall survival at 5 years of only approximately 20%. Several factors correlate with outcome. Patients with lesions in the cerebral hemispheres fare better than those with tumors in other locations, apparently independent of extent of surgical resection. The prognosis for children with thalamic lesions appears to be particularly poor.59Age also may be an important factor. In contrast to most other tumor types, children younger than age 3 with HGAs fare better than older children, with overall survival at 3 to 5 years in the 33% to 50% range in the North American and United Kingdom Children’s Cancer Study Group/International Paediatric Oncology Society (UKCCSG/SIOP) baby studies.60,61,62,63 The prognosis may be even better for children younger than age 1.64Histologic grade (AA vs. GBM) has not been shown consistently to affect outcome, but p53 overexpression and a high MIB-1 labeling index appear to identify patients with a particularly adverse prognosis.65

Management of Astrocytic Tumors in Specific Locations

Optic Pathway Gliomas

Optic pathway gliomas collectively account for approximately 5% of all CNS tumors in the pediatric age group. These are tumors of young children: the peak age incidence is between 2 and 6 years and 75% of all patients are younger than 10. One-third of patients have NF-1. They may be divided into three clinicopathologic entities: tumors confined to the optic nerve(s), tumors of the optic chiasm with or without optic nerve involvement (collectively “anterior” tumors), and tumors that involve the hypothalamus or adjacent structures (“chiasmatic/hypothalamic” or “posterior” tumors). Management of patients with optic pathway gliomas is often said to be controversial but is really not when differences in behavior between the different tumor types and between patients with and without NF-1 are taken into consideration.

Optic nerve gliomas may involve one or both optic nerves. Bilateral involvement is pathognomonic of NF-1. In a substantial proportion of cases, the optic nerve tumors are incidental findings on routine imaging and patients may remain asymptomatic with nonprogressive lesions over long periods; even spontaneous regression is well documented. The frequency of progression is difficult to establish, ranging from lows of <10% among patients followed in NF-1 clinics to 40% to 50% in series reported by oncology centers. Even in patients with symptomatic tumors, the course can be quite variable: only 30% to 60% of such patients will develop progressive disease that requires treatment.34,66 Thus, management of patients with optic nerve tumors will usually consist initially of close follow-up with regular ophthalmologic examinations and MRI, with active intervention, usually chemotherapy, reserved for patients with clear evidence of progression that is symptomatic.66,67,68

Patients with unilateral optic nerve involvement may not have NF-1. They present most frequently with proptosis that may be relatively long-standing. Findings on examination may include optic atrophy and impaired visual acuity. On MRI, optic nerve tumors are usually relatively small and well circumscribed, with bright enhancement typical for pilocytic astrocytoma. Biopsy is not necessary to make a diagnosis. Treatment usually, although not always, will be necessary and the approach will depend on whether there is useful vision. If not, then surgical resection will be the treatment of choice. If useful vision is preserved, chemotherapy would be the preferred option for infants and very young children up to age 5 and for patients of all ages with NF-1. Radiotherapy could be considered for older children. Overall, the prognosis is very good. Visual acuity remains stable or improves in the majority of cases following chemotherapy or radiotherapy. Long-term tumor control approaches 100% with either modality.69

Chiasmatic gliomas are tumors that involve the optic chiasm and sometimes one or both optic nerves as well. Patients typically present with loss of visual acuity and temporal field defects. On imaging, the tumors are usually relatively small and well circumscribed and enhance uniformly and brightly with contrast material, suggestive of pilocytic histology. Biopsy is usually not necessary.

A period of surveillance is appropriate initial management, particularly for patients with NF-1. For patients without NF-1, especially those who present before age 5, there is a high probability of early progression and the majority of patients will require treatment within a few months following diagnosis. Surgery is rarely an option for tumors in this location. As for optic nerve tumors, chemotherapy usually will be the treatment of choice for infants and young children and for patients with NF-1. Radiotherapy is reserved for salvage after chemotherapy and for definitive treatment of older children without NF-1, providing a reasonable expectation that vision will not deteriorate further and a probability of long-term progression-free survival in the 60% to 90% range.68,70,71,72,73 Overall survival for patients with chiasmatic tumors is in the 90% to 100% range.

Posterior, or chiasmatic/hypothalamic, gliomas account for approximately 70% of all optic pathway gliomas in children. They are typically rather large lesions that probably arise in the optic chiasm and extend to involve the hypothalamus. They may extend posteriorly along the optic tracts as well. They often fill the third ventricle, eventually causing hydrocephalus. Early findings consist of nystagmus, impaired visual acuity, and visual field deficits; only later do patients present increasing head circumference and/or symptoms and signs of raised intracranial pressure.

Treatment consists of CSF diversion, if necessary, and surgical resection, particularly if tumor is growing exophytically into the basal cistern because this may provide rapid relief of symptoms. In most patients, however, resection will be incomplete. As for LGAs at other locations, a period of surveillance following surgery is reasonable, although most patients will require adjuvant therapy.44,69 The treatment of choice for children younger than 5 and those with NF-1 usually will be chemotherapy. Progression-free survival at 3 to 5 years is rather low at 20% to at best 60%.44,45,46,74 However, some patients will never need further treatment, and for those who do, the use of chemotherapy allows radiotherapy to be deferred by a median of 2 to 4+ years without jeopardizing overall survival.

The indications for radiotherapy are (a) progressive disease on chemotherapy for children younger than 10 and (b) progressive disease at diagnosis or after surgery for older patients. Radiotherapy in this situation, given to local fields to a dose of 45 to 50 Gy for younger children and of 50 to 54 Gy for those older than 5, results in local tumor control in 70% to 80% of cases.44,69,73,75,76 Overall, however, outcomes are less satisfactory for this group of patients than for those with anterior tumors. Long-term survival is in the 50% to 80% range, and many patients will be left with significant neuroendocrine and neuropsychologic sequelae. Patients with NF-1 are particularly at risk. They may have subnormal IQ even without chemotherapy and/or radiotherapy.77 They are also at greater risk for moyamoya syndrome, a progressive vaso-occlusive process involving the circle of Willis. This may be seen without radiotherapy, but when radiotherapy is used in patients with NF-1 it is important to include MR angiography as part of the regular follow-up imaging protocol and intervene surgically if necessary to avoid a cerebrovascular accident.

Brainstem Gliomas

Tumors arising in the midbrain, pons, and medulla oblongata account for 10% to 15% of all CNS tumors in the pediatric age group. They are of several distinct types that can be broadly grouped as the more favorable low-grade focal, dorsal exophytic, and cervicomedullary tumors and the much more aggressive diffuse intrinsic pontine tumors.78,79

Focal tumors by definition are tumors of limited size (<2 cm) that on MRI are well circumscribed, without evidence of infiltration, and without edema. They may be cystic, and, as with cystic tumors at other sites, the cystic component may be large relative to the solid, biologically active, component. Focal tumors may occur at any level in the brainstem but most frequently are seen in the midbrain and medulla. They usually present with a long history of localizing findings such as an isolated cranial nerve deficit and a contralateral hemiparesis. Signs and symptoms of raised intracranial pressure are uncommon except in patients with tumors arising in the tectal region that may cause aqueduct stenosis while still small.

The management depends on the location of the tumor in the brainstem and the specific imaging characteristics of the tumor. As noted previously, patients with nonenhancing focal tumors in the tectal region who present with only hydrocephalus may do well without any treatment other than CSF diversionary procedures, usually endoscopic third ventriculostomy. Active intervention, including biopsy, is reserved for patients with clinical and radiologic evidence of progressive tumor. This is important because surgery for tumors in this location is associated with a substantial risk of morbidity even with modern techniques.

Surgery is the treatment of choice for focal tumors at other locations that are surgically accessible (meaning that they extend either toward the surface of the brainstem laterally or at the floor of the fourth ventricle) and have imaging characteristics suggestive of low-grade histology. In this regard, uniform bright enhancement with contrast material, which correlates with pilocytic histology, and the absence of peritumoral hypodensity are of particular importance. In experienced hands, the risk of morbidity for well-selected patients is low and, as with completely or subtotally resected LGAs at other sites, results may be excellent with freedom from progression in a majority of cases.81,82 Outcomes are less satisfactory for patients with bulky tumors and for patients with tumors in the medulla with lower cranial nerve deficits who are at risk of developing postoperative feeding and/or breathing difficulties.

There are several treatment options for patients with surgically inaccessible focal lesions. By extrapolation from series reporting results of treatment using conventional radiotherapy in brainstem tumors in which outcome correlates with location (pons vs. other), imaging appearance (tumor volume, density on CT, enhancement pattern), and histology (malignant vs. benign), it is reasonable to assume that 50% to 70% of focal lesions may be permanently controlled with such treatment. Similar results have been obtained in small numbers of patients treated with HFRT and with interstitial irradiation using 125I.49,51,53 There is also some experience with the use of radiosurgery. However, standard treatment is as for LGAs at other locations, that is, external-beam radiotherapy using a margin for the CTV of 0.5 cm, to a total dose on the order of 54 Gy given over 6 weeks. The risks of HFRT, radiosurgery, or stereotactic irradiation with large fraction sizes, or interstitial irradiation in inexperienced hands cannot be justified in the absence of any established superiority.

Dorsal exophytic tumors arise from the floor of the fourth ventricle. They are usually large, filling the fourth ventricle, but do not invade the brainstem to any significant extent. They present insidiously with failure to thrive in younger children and symptoms and signs of raised intracranial pressure in older patients. Cranial nerve deficits are seen in about half of the patients. On MRI, they are sharply delineated from surrounding structures. They are hypointense on T1-weighted images, are hyperintense on T2-weighted images, and enhance uniformly and brightly after gadolinium injection. Most are pilocytic astrocytomas.

Surgery is the treatment of choice for dorsal exophytic tumors. Intraoperative image guidance is essential to achieve a maximal degree of tumor resection. However, because there is usually no definite tumor–brainstem interface, even an optimal resection will leave a thin layer of tumor on the floor of the fourth ventricle. Nonetheless, the majority of children do well following surgery and routine postoperative adjuvant therapy is not indicated. Radiotherapy should be considered for the rare patient who is found to have a high-grade lesion or for patients with low-grade tumors who develop progressive disease in the early (<9 months) postoperative period. For patients whose tumors recur later, further surgery should be considered and radiotherapy reserved for those with inoperable disease. The radiotherapy volume and dose should be similar to those used for LGAs in other locations. The literature suggests that salvage is possible in the majority of cases and overall the prognosis for patients with dorsal exophytic tumors is excellent.83,84,85

Cervicomedullary tumors arise in the upper cervical cord and grow rostrally beyond the foramen magnum. Most are low-grade lesions whose axial growth is limited by the pyramidal decussations located ventrally at the junction of the cervical cord and medulla. At this point, the tumor grows posteriorly, causing a bulge in the dorsal aspect of the medulla, toward the fourth ventricle.78 These tumors typically present with lower cranial nerve deficits, sleep apnea and feeding difficulties in younger children, long tract signs, and sometimes torticollis. Hydrocephalus is unusual.

Surgery is the treatment of choice. Gross total resection may be achieved in 70% to 80% of cases and subtotal removal in most of the remainder. The probability of long-term tumor control after such treatment appears to be excellent for the typical low-grade lesion. There is, therefore, no indication for routine postoperative radiotherapy for these patients.

Diffuse intrinsic pontine tumors (DIPGs) account for 70% to 80% of all brainstem tumors. They arise in the pons and cause diffuse enlargement of the brainstem. Extension to the midbrain and medulla and/or exophytic growth is seen in at least two-thirds of cases. In contrast to the other types of brainstem tumors, the majority of DIPGs are fibrillary astrocytomas with a propensity for malignant change and a very poor prognosis.

DIPGs typically present with a short duration of symptoms consisting of multiple, bilateral, cranial nerve deficits (especially VI and VII) as well as long tract signs and ataxia. About 10% of patients have hydrocephalus at diagnosis. On CT, DIPGs are isodense or hypodense, with little enhancement after contrast injection, similar to diffuse fibrillary astrocytomas at other sites. They are best seen on T2-weighted or FLAIR MRI. The presence of ring enhancement is suggestive of high-grade histology.

Surgery has no role in the management of patients with DIPGs. Outside a clinical trial, even biopsy, a relatively nonmorbid procedure now, is considered unnecessary because in the context of a typical clinical presentation, the MRI findings are characteristic and histology does not influence treatment.86,87Treated with conventional radiotherapy, the majority (70% or more) of patients with DIPGs will improve clinically. However, the progression-free interval is short (median <6 months) and survival is poor, with a median survival of <1 year and survival rates at 2 years <20%.

So far all attempts to improve the outcome for children with DIPGs have proved futile. HFRT was tested in a series of phase I/II studies using doses ranging from 64.8 to 78 Gy. Time to progression and overall survival were not improved in comparison with conventional radiotherapy.88,89 Moreover, at the higher doses of HFRT of 75.6 Gy and 78 Gy, morbidity was considerable. This included steroid dependency, vascular events, and white matter changes outside the radiation field, as well as hearing loss, hormone deficiencies, and late-developing seizure disorders in the small number of long-term survivors.88,90,91,92

Accelerated and hypofractionated radiotherapy regimens have also been tested in single-institution studies using, respectively, a total dose of 50.4 Gy given in 28 twice-daily fractions of 1.8 Gy over 3 weeks

Accelerated and hypofractionated radiotherapy regimens have also been tested in single-institution studies using, respectively, a total dose of 50.4 Gy given in 28 twice-daily fractions of 1.8 Gy over 3 weeks93 and 39 Gy in 13 daily fractions and 45 Gy in 15 daily fractions.94,95 Progression-free and overall survival rates were similar to those seen in the HFRT studies.

Alternative approaches that use chemotherapy in combination with radiotherapy also have been disappointing. None of the many single-agent and multiagent regimens that have been tested in this patient population have been shown to provide a survival advantage compared with radiotherapy alone. New agents and novel chemotherapy–radiotherapy combinations are under investigation by the pediatric cooperative groups in North America and Europe.

Currently, standard treatment for DIPGs consists of radiotherapy given to the GTV as usually best demonstrated on T2-weighted or FLAIR MRI with a margin for the CTV of 1 to 1.5 cm to a dose of 54 Gy given in 30 daily fractions over 6 weeks that because of the initial rapid progression of neurologic deficit treatment often needs to be started on a semi-urgent basis. Because no unexpected toxicity was seen with the hypofractionated regimens, these in some cases could be considered an alternative to conventional radiotherapy that reduces the burden of treatment for the child and family.

Improvement in clinical status is usually evident as early as 2 to 3 weeks into treatment and steroids, if used, usually can be discontinued at that point. This improvement is often impressive and well appreciated by the family, despite being of only short duration. Treatment at time of progression may include experimental chemotherapy regimens or supportive care, or even retreatment with radiotherapy in selected cases.96,97

Astrocytoma of the Spinal Cord

Intramedullary spinal cord tumors account for 3% to 6% of all CNS tumors in the pediatric age group. About 60% are astrocytomas, the majority of which are LGAs; 30% are ependymomas; and the remainder, gangliogliomas and developmental tumors such as teratomas, lipomas, and dermoid and epidermoid cysts.

Patients typically present with pain and motor deficits, often of long duration. Rapid progression of symptoms and signs is suggestive of high-grade histology. On imaging, astrocytomas most often are seen to comprise a solid component and one or more cysts that may be intratumoral and/or extend rostrally and caudally beyond the solid component. Most enhance heterogeneously with the use of contrast material. Ependymomas, in contrast, only rarely harbor intratumoral cysts (although they may have an associated syrinx) and usually enhance homogeneously.

The management of spinal cord tumors has changed over recent years.98 In the past, patients typically were treated with biopsy followed by radiotherapy, and there is evidence to suggest that this is effective treatment in more than half of children with LGAs.99 However, improvements in surgery and the routine use of surgical adjuncts such as ultrasonic aspiration and support systems such as intraoperative ultrasonography and sensory and more recently motor evoked potential monitoring improve the safety and completeness of resection so that complete or subtotal resection is now possible in approximately 80% of children with pilocytic astrocytoma (the majority), especially those with a syrinx. Resection is more difficult and less likely to be complete in patients with grade II astrocytoma because of the more infiltrative nature of these tumors and the absence of a clear interface.98 Because outcome following complete or subtotal resection for LGAs is very good, with long-term progression-free survival in the 70% to 90% range,100,101,102routine postoperative adjuvant therapy is not indicated. For children in whom complete or subtotal resection is not possible, the options will be as for patients with LGAs in other locations, that is, early second surgery if feasible, or close follow-up with second surgery and/or radiotherapy at the time of progression. As for LGAs in other locations, chemotherapy may be an alternative to radiotherapy for young children.103,104 The benefit of surgical resection in HGAs is less clear and the more usual approach is biopsy followed by postoperative radiotherapy.105

The radiotherapy target volume for LGAs consists of the solid portion of the tumor (including intratumoral cysts) with a margin for the CTV of 1 to 1.5 cm. The usual dose is 50.4 Gy given in 28 daily fractions over approximately 6 weeks. The CTV should be larger for patients with HGAs for whom a margin beyond the entire lesion of at least 1.5 cm (or one vertebral body) would be more appropriate. The dose usually will be as for LGA because of the substantial risk of morbidity at higher doses but often chemotherapy will be given as well. While older studies99,100 and data from the Surveillance, Epidemiology, and End Results (SEER) registry106 and from the German cooperative group107 all suggest that 20% to 35% of children with high-grade gliomas will survive following such treatment, a recent study from St. Jude Children’s Research Hospital presents an even bleaker picture with a very high rate of both local progression and leptomeningeal spread and no long-term survivors among patients with GBM.105

EPENDYMAL TUMORS

The following types are seen in children:

Myxopapillary ependymoma (WHO grade I)

Ependymoma (WHO grade II)

Anaplastic ependymoma (WHO grade III)

Myxopapillary Ependymoma

Myxopapillary ependymomas are slowly growing lesions almost always located in the conus filum terminale region of the spinal cord. They are the most common spinal cord tumor in this location. They usually present with back pain. On imaging, myxopapillary ependymomas are well circumscribed and usually enhance brightly after contrast injection. Despite their low-grade histology, leptomeningeal spread is not uncommon even at diagnosis and all patients should have an MRI of the whole spine and brain as part of their initial workup.

Surgical resection is the treatment of choice. If the tumor is contained within the filum, complete resection may be possible after mobilization of the filum. Whether postoperative radiotherapy is necessary after complete resection is unclear. A significant proportion of tumors recur locally and/or with leptomeningeal metastases, but salvage with further surgery and/or with radiotherapy seems to be possible in most.108,109,110If the tumor is in continuity with the conus, resection is more difficult and more likely to result in significant sequelae so that there frequently will be residual tumor. If the tumor is not resected en bloc or if there is macroscopic residual tumor, the risk of recurrence is high. Postoperative radiotherapy in this situation results in improved local control.101,111,112,113 The radiotherapy target volume is local (macroscopic disease plus a margin cephalad and caudad of 1.5 cm [or one vertebral body]) for the CTV and the dose, 50.4 Gy.113 Patients with leptomeningeal seeding at diagnosis or at relapse after surgery alone should be treated with curative intent with CSI followed by a boost to the primary site with a reasonable expectation of long-term tumor control.101,109,112,114

Ependymoma

Figure84.10 Typical appearance of an ependymoma that fills the…

Ependymoma is the third most common CNS tumor in children. About half of all cases arise in children younger than 5. Ependymoma can occur at any site in the ventricular system or in the spinal canal, but in children approximately two-thirds arise in the ependymal lining of the fourth ventricle. Tumors in this location typically present with symptoms and signs of raised intracranial pressure. On imaging the tumor is usually large but relatively well circumscribed, with displacement rather than invasion of adjacent structures. Extension through the foramen magnum into the upper cervical region is not uncommon (Fig. 84.10). Tumors that arise in the supratentorial compartment, some of which arise outside the ventricular system, present with focal neurologic deficits. Intramedullary ependymomas, which account for approximately 30% of all spinal cord tumors arising in childhood, usually present initially with dysesthesia and sensory deficits due to their central location in the cord and only later with pain and motor deficits.

Spread of ependymoma is primarily local. However, 5% to 10% of patients have leptomeningeal seeding at diagnosis, and gadolinium-enhanced MRI of the whole CNS and CSF cytology are essential components of the workup for all patients.

Management of Ependymoma

The completeness of the surgical resection is the factor that has the greatest impact on the outcome of patients with ependymoma.115,116,117,118,119,120,121,122,123,124 Currently, it is estimated that complete resection is achieved in 70% to 90% of supratentorial ependymomas and in a similar percentage of spinal ependymomas. Complete resection is less frequently possible in patients with infratentorial ependymomas. Most commonly, residual tumor is left behind on the floor of the fourth ventricle or laterally at the cerebellopontine angle where tumor protruding through the foramen of Luschka encircles lower cranial nerves and vessels. “Second-look” surgery may be considered, if feasible, either after the realignment of structures that takes place following resection of an initially bulky tumor in an often unstable young child or after chemotherapy.

Postoperative radiotherapy is the standard of care for all children with ependymoma. Some have questioned the need for such treatment for patients who have undergone complete resection.121,125,126 However, a number of studies including studies in young children in which the goal was to delay or avoid altogether radiotherapy suggest that such a strategy results in worse disease-free and overall survival and in the long term greater morbidity122,127,128,129,130 and therefore can be considered acceptable only for (a) patients with ependymoma of the spinal cord who have undergone complete resection for whom disease-free survival in contemporary series approaches 100%131,132,133,134 and (b) selected patients with supratentorial ependymoma, such as those with intraventricular tumors or with extraventricular tumors that are solid and located in noneloquent areas and can be resected with a wider margin.126

In the past, CSI was recommended for treatment of infratentorial ependymoma. However, there is no evidence that the use of CSI affects outcome, and local radiotherapy is now accepted as the standard of care.135,136 The GTV is a composite of the tumor bed, including any extension caudal to the foramen magnum and taking into account any anatomic shifts due to surgery plus any residual tumor. In the St. Jude prospective study of conformal radiotherapy that included both ependymoma and anaplastic ependymoma, the margin for the CTV was 1 cm.124 In the subset of 107 patients in that study that received immediate postoperative radiotherapy, local control was excellent (cumulative incidence of local failure 7.8%) for patients who had undergone gross total resection, while patients who had undergone near-total or subtotal resection fared less well. All failures were reported to be within the 95% isodose. The current Children’s Oncology Group (COG) study uses an even smaller margin for the CTV of 0.5 cm.

Figure84.11 Care is necessary to ensure that the inferior extent of disease is…

There is evidence for a dose–response in ependymoma, with improved tumor control with doses >45 to 50 and even 54 Gy.135 Although the lower doses may be the maximum possible for spinal ependymomas, the current standard is a dose of at least 54 Gy for children older than 18 months with infra- or supratentorial tumors. Moreover, because failure most often occurs at the site of macroscopic residual disease, even higher doses may be desirable and most would reduce the CTV at 54 Gy to respect the tolerance of the spinal cord and/or other structures and continue to a total dose of 59.4 Gy (Fig. 84.11).

HFRT has been explored in ependymoma as a strategy to more safely deliver these higher radiotherapy doses. Studies from the Children’s Hospital of Philadelphia in which the majority of patients received HFRT to a mean dose of 70.7 Gy,137from the Italian pediatric oncology group that used a dose of 70.4 Gy,138 and from the French pediatric oncology group that used a lower total dose of 60 Gy in 60 fractions139 all reported HFRT to be feasible. However, in none of these studies was there any clear evidence of benefit, particularly in the context of improved surgery and modern radiotherapy.

The role of chemotherapy in ependymoma remains to be defined. There is some evidence of efficacy, but even in the more recent infant studies in which chemotherapy was used because of the desire to delay or even avoid altogether radiotherapy, more than half of the patients progressed on chemotherapy,63,128,130,140,141 and in the COG baby study, prolonged use of chemotherapy and a delay to radiotherapy of more than 1 year was associated with a worse survival.127 Consequently, most would now use radiotherapy for all children older than 12 months following complete resection. In patients with residual disease, chemotherapy has been justified because of the poor prognosis. As well, it may facilitate complete resection of residual disease at second-look surgery, and current North American and European trials are testing chemotherapy in this setting.

For patients who fail standard treatment with either local recurrence or, less frequently, leptomeningeal dissemination, retreatment with radiotherapy is an option that may result in durable control in a proportion of patients.142,143

Anaplastic Ependymoma

By definition, an anaplastic ependymoma is a malignant glioma of ependymal differentiation that is characterized by high mitotic activity, often accompanied by microvascular proliferation and pseudopalisading necrosis. There are no histopathologic features that can reliably differentiate anaplastic ependymomas from the more slowly growing and more favorable ependymomas, which probably explains the controversy in the literature with respect to the prognostic significance of tumor grade. Proliferation markers may be more useful in this regard, but several groups also are investigating genetic and expression profiles based on preliminary data that suggest that a molecular classification system can be built that will prove useful for risk stratification.

Management of anaplastic ependymoma begins with maximum surgical resection consistent with a good neurologic outcome and a workup consisting of a gadolinium-enhanced MRI of the spinal axis and CSF cytology to rule out leptomeningeal seeding, which is only slightly more frequent than in ependymoma. Postoperatively all patients receive radiotherapy. As for ependymoma, the role of chemotherapy remains to be defined but may be an option in very young children to delay the use of radiotherapy.

CSI was previously the standard of care for anaplastic ependymoma, but several institutional studies, a careful retrospective review, and prospective studies by the POG all suggest that there is no survival advantage for CSI.116,144,145,146,147,148 Thus, a target volume consisting of the tumor bed and any macroscopic residual disease with a margin for the CTV of 1 cm is used for patients with localized disease and only patients with leptomeningeal seeding at diagnosis receive CSI. As for ependymoma, the dose should be at least 54 to 55 Gy and, if feasible, 59 to 60 Gy.

In contemporary series, disease-free survival for patients with anaplastic ependymoma is typically still only in the 30% to 45% range at 3 to 5 years,138,148 although results were better in the St. Jude series, with event-free survival at 7 years of 61.3% and overall survival, 71.8%.124 This may be in part at least due to the high rate of gross total resection in that series because, as others have shown, the prognosis is better for patients in whom complete resection has been achieved than for those with residual disease.147,148 Patients with leptomeningeal dissemination at diagnosis fare poorly despite intensive treatment that includes CSI and chemotherapy.

CHOROID PLEXUS TUMORS

Choroid plexus tumors arise from the epithelium of the choroid plexus of the cerebral ventricles. They include:

Choroid plexus papilloma (WHO grade I)

Atypical choroid plexus papilloma (WHO grade II)

Choroid plexus carcinoma (WHO grade III)

Choroid plexus tumors account for only 2% to 4% of all brain tumors that occur in children but as many as 10% to 20% of those seen in the first year of life. Choroid plexus papillomas (CPPs), which account for more than half of choroid plexus tumors in children, are composed of delicate fibrovascular connective tissue fronds covered by a single layer of uniform cuboidal columnar epithelial cells with round or oval basally situated monomorphic nuclei. Mitotic activity is low and increased mitotic activity in a CPP defines an atypical choroid plexus papilloma. In contrast to both, choroid plexus carcinomas (CPCs) are solid tumors that tend to transgress the ventricular wall and invade the brain. Histologically CPCs show frank evidence of malignancy including frequent mitoses (>5%/10 HPF), increased cellular density, nuclear pleomorphism, blurring of the papillary pattern with poorly structured sheets of tumor cells, and necrotic areas.

In children, most choroid plexus tumors arise in the lateral ventricles causing obstruction to CSF flow. Infants commonly present with increasing head circumference and older children with symptoms and signs of raised intracranial pressure. On neuroimaging, choroid plexus tumors are usually hyperdense, contrast-enhancing masses. Even papillomas seed into the CSF space and workup for both benign and malignant lesions should include a gadolinium-enhanced MRI of the spinal axis and CSF cytology.

Management of Choroid Plexus Tumors

Surgery is the treatment of choice for CPPs both for the primary lesion and for metastatic deposits, if feasible. Complete resection is achieved in a high percentage of cases now and outcome in this situation is excellent. Less than 10% of tumors recur and overall survival is close to 100%.149,150,151,152, The role of radiotherapy following incomplete resection is unclear, but because not all patients will progress, follow-up without adjuvant treatment would be the usual strategy, with consideration of further surgery, if feasible, and/or radiotherapy only at the time of progression.

Results are less satisfactory for patients with CPCs. Surgery is an important component of treatment but often difficult. Blood loss may be considerable and staged procedures may be necessary to obtain maximal resection. In most series, results are better for patients who have undergone complete resection149,153,154,155,156,157,158,159,160,161,162 and the need for adjuvant therapy in this situation is not clearly established. In one series of pooled data, survival was significantly better when radiotherapy had been given postoperatively despite a probable bias toward the use of radiotherapy in patients considered to have more unfavorable disease.156,159

Others have reported excellent results following complete resection, in some cases with chemotherapy but without radiotherapy.153,154,157,158 In contrast, patients who have residual disease fare very poorly. Postoperative radiotherapy appears to be useful,162 but the desire to avoid radiotherapy in infants and very young children may mean that chemotherapy is used instead despite less convincing evidence of efficacy. When both are used, radiotherapy is usually delivered early (following two cycles of chemotherapy) with the exception of infants and very young children in whom radiotherapy is delayed until age 3 years. Genetic and genomic analyses may in the future help guide therapy. A substantial percentage of patients with CPCs have TP53 mutations, and patients without such mutations are reported to have a more favorable prognosis and be successfully treated without radiotherapy.163

The radiotherapy target volume is also controversial. CSI was traditionally used in patients with CPCs, and a recent literature review showed that the use of CSI was associated with improved progression-free survival as compared with radiotherapy to the whole brain or tumor bed only.162Importantly, more than half of all failures occurred outside the treatment field. This is problematic given the young age of the patients, and a pragmatic approach in which local fields are used for patients with CPPs with postoperative residual (including metastatic sites) as well as for patients with atypical CPPs or CPCs without evidence of leptomeningeal seeding and only patients with atypical CPPs or CPCs with leptomeningeal seeding receive CSI would seem reasonable for now.

NEURONAL AND MIXED NEURONAL-GLIAL TUMORS

These are uncommon tumors that are characterized by the presence of both neuronal and glial elements in variable amounts. They include entities such as desmoplastic infantile astrocytoma and dysembryoplastic neuroepithelial tumor. Most will be cured by surgery, but radiotherapy may be indicated in two tumor types:

Ganglioglioma and anaplastic ganglioglioma

Central neurocytoma

Ganglioglioma and Anaplastic Ganglioglioma

Gangliogliomas are well-differentiated slowly growing tumors composed of mature ganglion cells in combination with neoplastic glial cells (WHO grade I or II). Tumors in which the glial component shows anaplastic features (WHO grade III) are called anaplastic gangliogliomas.

Although these tumors can arise anywhere within the CNS, most in children arise in the temporal region and typically present with seizures. Surgery is the treatment of choice. When resection is complete, the probability of long-term tumor control in patients with ganglioglioma is excellent.164,165,166 The indications for radiotherapy are as for patients with LGAs, that is, for patients with progressive or recurrent disease that is not resectable, and the radiotherapy target volume and dose likewise. The significance of a high proliferation index or of the presence of anaplasia in patients with ganglioglioma is controversial. Although it seems clear that the risk of recurrence is higher in patients with these features,164,165,167 the indications for postoperative radiotherapy remain undefined except for patients with anaplastic gangliogliomas who have undergone less than complete resection in whom the use of radiotherapy has been shown to result in improved progression-free survival.166,168

Central Neurocytoma

This is a neoplasm composed of uniform round cells with neuronal differentiation that arises in the lateral or third ventricles, typically the former, that is seen predominantly in adolescents and young adults. Patients usually present with symptoms and signs of raised intracranial pressure. Surgery is the treatment of choice, and when complete resection is achieved long-term tumor control is excellent without adjuvant treatment.169 Patients in whom complete resection cannot be achieved as well as those with tumors with atypical histology or a high mitotic rate fare less well,169,170 and postoperative radiotherapy should be considered in these situations. While a dose of 50 Gy appears adequate for patients with typical neurocytomas,171there is evidence of improved tumor control at doses of at least 54 Gy in patients with atypical neurocytoma.172

PINEAL PARENCHYMAL TUMORS

Pineal region tumors account for 2% to 8% of intracranial tumors in children. Approximately half are germ cell tumors, one-fourth to one-third are pineal parenchymal tumors, and most of the remainder are astrocytic tumors. Pineal parenchymal tumors are derived from pineocytoma, which are cells with photosensory and neuroendocrine functions, or their embryonal precursors. According to the WHO classification, the following entities can be distinguished:

Pineocytoma (WHO grade I)

Pineal parenchymal tumor of intermediate differentiation

Pineoblastoma (WHO grade IV)

Pineocytoma

Pineocytoma is a slow-growing tumor composed of small uniform mature cells resembling pineocytes, with occasional large pineocytomatous rosettes, that accounts for approximately half of pineal parenchymal tumors and in childhood most commonly occurs in the teenage years. Patients typically present with symptoms and signs of raised intracranial pressure. Some will have symptoms of upper mesencephalic tegmental dysfunction (Parinaud’s syndrome), consisting of limitation of upward gaze, lid retraction, retraction nystagmus, and pupils that react more poorly to light than to accommodation. On MRI, pineocytomas are usually spherical, well-circumscribed masses, hypointense on T1- and hyperintense on T2-weighted images, with homogeneous contrast enhancement. Leptomeningeal spread has been described in pineocytoma,173 but it is probable that the explanation for this lies in sampling error. With better imaging and more extensive surgery with more complete histologic evaluation of the tumor, it seems that leptomeningeal spread can be considered to be an uncommon event.174

Treatment consists of surgical resection via an occipital transtentorial or an infratentorial supracerebellar approach using modern operative adjuncts such as functional MRI and MR tractography in relation to the location of the primary visual cortex and deep MR venography. If complete or subtotal resection is accomplished, progression-free survival is in the 90% to 100% range.175,176 Patients who undergo lesser degrees of resection or only biopsy fare less well and, although some have questioned its usefulness based on the results of a systematic review,176 postoperative radiotherapy usually is recommended.177 The target volume is local, consisting of macroscopic residual disease with a margin for the CTV of 1 cm, and the dose, 50 to 55 Gy over 6 weeks.

Pineal Parenchymal Tumor of Intermediate Differentiation

Pineal parenchymal tumors of intermediate differentiation are composed of diffuse sheets or large lobules of uniform cells with mild to moderate nuclear atypia and low to moderate mitotic activity. They are rare tumors, accounting for only 10% of pineal parenchymal tumors, and optimal management remains to be defined. In one series, three patients treated with surgery alone survived free of disease.175 At the other extreme, another group considers these to be tumors “with seeding potential” and recommends postoperative treatment with CSI as for pineoblastoma.174

Pineoblastoma

Pineoblastoma is a highly malignant tumor composed of patternless sheets of densely packed small cells with round to irregular nuclei and scant cytoplasm.

Pineoblastomas most frequently affect infants and very young children, who typically present with an enlarged head circumference or symptoms and signs of short duration of raised intracranial pressure. On MRI, pineoblastomas are usually multilobulated and often enhance heterogeneously, with areas of necrosis and/or hemorrhage. Infiltration of surrounding structures is common. Leptomeningeal spread is seen in as many as 50% of patients at diagnosis.

Surgery for lesions in the pineal region is difficult and complete resection is often not possible. Postoperatively, children older than 3 are treated with CSI and chemotherapy, as for high-risk medulloblastoma and supratentorial PNETs (see later). Five-year survival in this age group is in the 50% to 70% range.174,178,179 However, infants treated with chemotherapy without radiotherapy fare extremely poorly: in prospective studies of the POG and CCG, all tumors recurred within the first 11 months (POG) and 1.2 years (CCG) and all patients died of disease.180,181 Thus, more aggressive treatment that includes chemotherapy dose intensification is necessary. Patients with familial bilateral retinoblastoma with pineoblastoma (“trilateral retinoblastoma”) also have an extremely poor prognosis, most dying within a year following diagnosis.

EMBRYONAL TUMORS

Embryonal tumors as a group are the second most common type of CNS tumor in the pediatric age group. They include:

Medulloblastoma

–Desmoplastic/nodular medulloblastoma

–Medulloblastoma with extensive nodularity

–Anaplastic medulloblastoma

–Large cell medulloblastoma

Supratentorial PNET

–CNS neuroblastoma

–Medulloepithelioma

–Ependymoblastoma

Atypical teratoid/rhabdoid tumor

Medulloblastoma

Medulloblastoma accounts for 15% to 20% of all CNS tumors in children with a median age at presentation of 6 years. It is a malignant invasive embryonal tumor of the cerebellum with predominantly neuronal differentiation and an inherent tendency to metastasize via CSF pathways. In the majority of cases the tumor arises in the cerebellar vermis and projects into the fourth ventricle. Patients typically present with symptoms and signs of raised intracranial pressure (i.e., headache and morning vomiting). On MRI medulloblastomas appear as solid masses that enhance usually fairly homogeneously with contrast material (Fig. 84.12). The frequency of leptomeningeal seeding at diagnosis is approximately 30% to 35% and investigation at diagnosis must include a gadolinium-enhanced MRI of the spinal axis and CSF cytology. The former should be obtained whenever possible preoperatively or else at least 2 weeks postoperatively because of the artifactual changes that may be seen in the early postoperative period. CSF cytology, which should be obtained by lumbar puncture, usually cannot be obtained safely preoperatively because of the presence of raised intracranial pressure and more commonly is obtained at least 2 weeks postoperatively to avoid false positives that may be seen in the early postoperative period. Medulloblastoma is one of the few CNS tumors to spread outside the CNS (to lymph nodes, bone), but this is a very uncommon event at diagnosis and other studies such as a bone scan or bone marrow aspiration or biopsy are not justified as a routine.

Factors that correlate with outcome include age at diagnosis, the presence or absence of leptomeningeal spread at diagnosis, and the completeness of the surgical resection. Patients are allocated to one of two risk categories: standard and high risk. Those who have undergone complete or subtotal resection with <1.5 cm2 of residual tumor on postoperative MRI performed within 48 to 72 hours of surgery and no evidence of CSF dissemination (M0) are considered to have standard-risk disease, whereas patients who have larger-volume residual tumor and those with evidence of CSF dissemination at diagnosis are characterized as high risk. With contemporary neurosurgical techniques, complete or near-total resection is accomplished in approximately 80% of cases. Overall, approximately two-thirds of patients will be standard risk and one-third will be high risk.

Management of Standard-Risk Medulloblastoma

Until the 1990s, the standard of care for patients older than 3 years with standard-risk disease consisted of postoperative radiotherapy to the craniospinal axis to a dose of 35 to 36 Gy followed by a boost to the whole posterior fossa to a total dose of 54 to 55.8 Gy. In multi-institution studies, such treatment results in long-term event-free survival in 60% to 65% of patients.10,182,183 Sequelae of treatment include hormonal deficits, decreased bone growth, and neurocognitive deficits that correlate with the age of the child and the radiation dose.7

Several treatment strategies designed to reduce the morbidity associated with the use of radiotherapy have been tested. An attempt by the French Cooperative Group (SFOP) to reduce the radiotherapy target volume to avoid supratentorial radiation produced disastrous results,184 and CSI remains the standard of care. The use of reduced-dose CSI (23.4 Gy) alone (without chemotherapy) in the North American intergroup study (CCG-923/POG#8631) resulted in a significantly increased risk of isolated neuraxis failure and an event-free survival at 5 and 8 years of only 52%.183 HFRT may be a more promising strategy. In an SFOP pilot study that tested HFRT to a CSI dose of 36 Gy without chemotherapy, early toxicity was reduced and progression-free survival at 3 years was 81%.185 The results of the European SIOP PNET-4 study in which patients were randomized to HFRT or conventional radiotherapy are pending.

An alternative strategy consists of reduced-dose CSI followed by a boost to the posterior fossa to a total dose of 55.8 Gy in combination with systemic chemotherapy. Progression-free survival was 79% at 5 years in a CCG pilot study that used CSI to a dose of 23.4 Gy in combination with weekly vincristine followed by adjuvant systemic chemotherapy consisting of vincristine 1.5 mg/m2, CCNU 75 mg/m2, and cisplatinum 75 mg/m2.186 In the joint CCG/POG phase III randomized study (A9961) that followed, this regimen was compared to a regimen in which the CCNU was replaced by cyclophosphamide. Event-free survival at 4 years was approximately 85% in both arms,187and such an approach is now considered to be the standard of care for children with standard-risk medulloblastoma in North America. The current COG study is testing the safety of an even lower dose of CSI (18 Gy) in children aged 3 to 8 years and of a reduced-volume posterior fossa boost in children of all ages.

In the next generation of studies in medulloblastoma, risk stratification will be based on biologic parameters in addition to clinical and pathologic features. Already, patients with anaplastic large cell histology are no longer included in the standard-risk group given their poorer outcome. As well, evidence now suggests that β-catenin nucleo-positivity is associated with a better prognosis and MYC gene amplification with a worse one, opening up the possibility of reduced-intensity treatment, even perhaps elimination of radiotherapy, in the former group, while maintaining or even increasing the intensity of treatment in the latter.188

Management of High-Risk Medulloblastoma

Patients with residual disease >1.5 cm2 and/or those with leptomeningeal seeding are considered to have high-risk disease. This is the group of patients in which the use of chemotherapy was shown in the prospective randomized phase III studies conducted in the 1970s to result in significant improvement in disease-free survival. Research since then has largely focused on the chemotherapy regimens, including changes in scheduling in relation to radiotherapy and in doses and routes of delivery of chemotherapy. Some have used higher-dose CSI or altered radiotherapy fractionation schedules. An overview of studies performed by the North American and European cooperative groups up until the early 2000s is given in Freeman et al.189

It is important to note that the definition of risk factors has evolved considerably over the past two decades, making comparison of published data quite problematic. Better postoperative imaging and more complete staging as well as identification of unfavorable pathologic features (e.g., large cell and anaplastic histology) have led to transfer of patients from the standard-risk to the high-risk category, which may partly explain the improving results for both standard-risk and high-risk disease. The category of high-risk disease is heterogeneous and includes more favorable subsets such as patients with postoperative residual disease without leptomeningeal spread, and even those with M1 (cytology-positive) disease, for whom it may be appropriate to consider a treatment approach different from that for patients with M2/3 disease with nodular seeding. For example, for patients with residual disease, M0, it would be logical to consider using a boost to residual disease in the posterior fossa to a dose higher than the standard 55.8 Gy. Management of patients with M1 disease remains controversial, but the weight of evidence suggests that they should be treated similarly to those with M2/3 disease.190 Results for patients with M2/3 disease remain quite poor, although an impressive 81% 4-year overall survival was reported for patients treated on a COG pilot study using carboplatin daily during radiotherapy as a radiosensitizer. This forms the backbone of the current COG study for high-risk medulloblastoma, while the standard of care in many centers in Europe is now a hyperfractionated accelerated radiotherapy (HART) regimen given in combination with pre- and postradiotherapy chemotherapy.191

Management of Medulloblastoma in Infants

Medulloblastoma accounts for 20% to 40% of all CNS tumors in infants. While up to half of infants have more favorable histologic types (desmoplastic/nodular or medulloblastoma with extensive nodularity), the prognosis overall is worse than in older children. The explanation for this is likely multifactorial. In addition to biology, the rate of complete resection is lower in this age group and the frequency of leptomeningeal seeding at diagnosis higher (as much as 50%), but also, many patients do not receive optimal treatment.192 Because of the significant risks with respect to neurocognitive function associated with the use of radiotherapy in infants and very young children, chemotherapy has been used in an attempt to either delay or avoid radiotherapy altogether. Infants with M0 disease who have undergone total resection may do well with chemotherapy alone, with a 5-year overall survival of 69% in the first POG infant study193 and of 93% in the German study,194 although it is noteworthy that treatment in the latter included intraventricular methotrexate for which there are also concerns about the risk of neurocognitive sequelae. In other studies results were less satisfactory, in some because of the need for aggressive salvage regimens that were associated with significant long-term sequelae.195 In fact, with the possible exception of very young children with desmoplastic/nodular medulloblastoma without residual disease, evidence suggests that radiotherapy is an important component of treatment,62 and because recurrences are generally early (6 to 12 months) and local,62,193,196 the recently completed North American study used early radiotherapy to a limited treatment volume consisting of the tumor bed plus an anatomically confined margin for the CTV of 1 cm for patients without leptomeningeal seeding. Infants with M2/3 disease generally are treated with intensive chemotherapy regimens. While patients with desmoplastic/nodular histology may do quite well, with an overall survival at 5 years of 52.9% in the UKCCSG/SIOP baby study, for example,63 the prognosis for those with other subtypes is much less satisfactory. Despite this, the goal of treatment generally will still be to avoid radiotherapy (especially CSI) and the decision to use it highly individualized based on the clinical situation and the wishes of the parents.

Radiotherapy for Medulloblastoma

CSI is the standard of care, and careful attention to coverage of the entire target volume that includes the meninges overlying the brain and spine including extensions along nerve roots is critical. In the SFOP M - 7 protocol, 50% of relapses could be correlated with targeting deviations. In the subsequent studies (MSFOP - 93 and MSFOP - 98) the relapse rate was 1.7% in patients who had inadequate coverage of only one part of the CTV (a typical example being the cribriform plate), 28% for patients who had inadequate coverage at two sites, and 67% for patients who had inadequate coverage at three or more sites. 197,198  In an SFOP pilot study that tested reduced - dose CSI for standard - risk disease, overall survival at 5 years was significantly worse for patients with inadequate coverage at two or more sites as compared with no or only one major deviation (54% vs 79.3%). 199

CSI is followed by a boost to the posterior fossa.  Traditionally, the entire posterior fossa has been treated to a total dose of 54 to 55.8 Gy. Using conformal treatment techniques, it is possible to reduce the dose to the inner ear, which is important in children who will also be receiving chemotherapy with cisplatinum, but there will be little sparing of other structures such as, and most especially, supratentorial brain. Better sparing of the cochlea, 200  pituitary and hypothalamus, and the temporal lobes can be achieved using a reduced target volumen for the boost (Fig. 84.13) . Fukunaga - Johnson et al.  201 found a low risk of isolated failure outside the tumor bed in the posterior fossa in a cohort of 114 patients, and data from several other centers as well as an SFOP pilot study that used a conformal boost limited to the tumor bed similarly support such an approach. 185,202,203,204,205  The optimal CTV for a reduced - volume posterior fossa boost remains to be defined, although an anatomically confined expansion of 1.5 cm around the CTV (any macroscopic residual tumor and surgical bed) seems to be reasonable and this is the volume under investigation in the current COG study for standard - risk disease.

Delay to radiotherapy may be associated with poorer outcomes, and CSI should ideally start within 28 to 30 days following surgery. There is evidence, too, that it is important to deliver radiotherapy in a timely fashion, avoiding unnecessary gaps in treatment resulting from a machine servicing, holidays, and the like. In the SIOP PNET - 3 study event - free and overall survival were significantly worse when the duration of treatment exceeded 50 days as compared with the results fro children treated as planned over 45 to 47 days. 206  When CSI has to be interrupted, for example, because of hmatologic toxicity, treatment should continue to the posterior fossa boost volume while waiting for the blood counts to recover. Granulocyte colony - stimulating factor may be used to hasten recovery of the counts.

Supratentorial Primitive Neuroectodermal Tumor

By definition, supratentorial primitive neuroectodermal tumor (stPNET) is an embryonal tumor composed of undifferentiated or poorly differenntiated neuroepithelial cells. Tumors with only neuronal differentiation are termed cerebral neuroblastoma or ganglioneuroblastoma. Tumors that re - create features of neural tube formation are called medulloepithelioma. Tumors with ependymoblastic rosettes are called ependymoblastoma. All are highly malignant tumors that show aggressive behavior. 

stPNETs account for less than 5% of all CNS tumors in the pediatric age group. Patients are typically young, with a median age at presentation of 3 years, and usually present with symptoms and signs of raised intracranial pressure. Tumors arising in the cerebral hemispheres in particular may be very large. On imaging they are often quite heterogeneous, with cystic or necrotic areas and areas of hemorrage. Leptomeningeal seeding is present at diagnosis in up to 40% of patients and MRI of the spinal axis and lumbar puncture for CSF cytology are mandatory prior to treatment.

Over the past two decades, patients with stPNETs have been treated using an approach similar to that used for patients with high - risk medulloblastoma, that is, with postoperative radiotherapy (standard - dose CSI plus a boost) and chemotherapy. Overall survival is at best only 30% to 50%.  Factors that have been associated with a better outcome include smaller size (less than 5 cm), 207 location in the pineal region, and complete resection, 193,208,209,210 while younger patients 62,63,193,211 and patients  M+ at diagnosis 179,207,209,212,213,214 fare significantly worse, with survival in the 0% to 30% range. Radiotherapy appears to be an importnat component of treatment that is associated with improved progression - free and overall survival. 179,210,211 However, the benefit of chemotherapy reamins rather unclear despite its widespread use and the high risk of recurrence despite chemotherpay and the short time to progression, together with poor salvage rates, has led to recommendations for early radiotherapy particularly in patients  with macroscopic residual tumor. 210

Radiotherapy treatment factors including timing of radiotherapy (i.e., its use immediately postoperatively rather than following completion of chemotherapy212), the use of CSI rather than reduced (whole-brain or local) volumes,212,214,215 and dose (CSI dose >35 Gy and dose to the primary site >54 Gy)212have all been shown to be associated with improved outcomes. Even in contemporary series, however, failure at both the primary site and in the leptomeninges is a significant problem: local failure was seen in 42% of patients with M0 disease treated on the CCG 921 protocol, and failure in the leptomeninges as a first site of failure was seen in 43% of M+ patients.213 Both HFRT and HART have been tested as a means to more safely deliver the higher radiotherapy doses that seem to be needed in patients with stPNETs. Of five patients treated with HFRT at Duke University, four survived without evidence of disease 4.3 to 8 years following diagnosis.216 Preliminary results from the Italian cooperative group using HART were interpreted as promising, with progression-free survival at 3 years of 54%.217

For now, the usual approach for a child older than 3 with a stPNET without leptomeningeal spread consists of maximal surgical resection followed by postoperative radiotherapy (CSI followed by a boost) and chemotherapy. Experimental regimens such as high-dose chemotherapy with stem cell rescue are used in infants and young children and in patients with M+ disease. The use in more favorable patients of a lower CSI dose or even local radiotherapy rather than CSI, while certainly of interest as a strategy to reduce the risk of long-term sequelae of treatment, should be considered experimental for lack of evidence to support such an approach at this time.

Atypical Teratoid/Rhabdoid Tumor

Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant embryonal tumor seen in very young children with a peak incidence in the birth to 2-year age group, at which age in one population-based study ATRT was as common as PNET and medulloblastoma.218 Composed of rhabdoid cells with or without fields resembling a classical PNET, ATRT is diagnosed on the basis of the characteristic molecular findings, namely, deletion and/or mutation of the INI1 locus on chromosome 22. ATRT can arise at any location within the CNS, including the spine. Leptomeningeal seeding is seen at diagnosis in a quarter to a third of patients.

Since recognition of ATRT as a separate entity with a high frequency of early relapse and a very poor prognosis, patients have been treated with increasingly intensive chemotherapy regimens. Radiotherapy appears to be an important component of treatment.219,220,221,222,223,224,225 In a series of 37 patients treated at St. Jude, early use of radiotherapy and the use of CSI were found to be associated with improved outcomes,223 and it has been suggested that the worse survival reported for children younger than age 3 may be due in part to the less frequent use of radiotherapy and, when used, to the use of local radiotherapy rather than CSI in this age group. However, in a recent update limited to patients who received age- and risk-stratified radiotherapy, delay to radiotherapy was found to be the important factor.226 In the current COG study, the treatment plan calls for early radiotherapy (after completion of two cycles of induction chemotherapy), although in practice the use and timing of radiotherapy depend on the age of the child, the location (infra- or supratentorial), and the extent of disease at diagnosis (M0 or M+). Thus, children younger than 6 months at completion of chemotherapy with an infratentorial tumor and those younger than 12 months with a supratentorial tumor receive radiotherapy later, upon completion of both induction and consolidation chemotherapy. The radiotherapy target volume is local (tumor bed and any macroscopic residual disease plus a margin for the CTV of 1 cm) for children with localized disease and CSI followed by a boost for those with leptomeningeal spread. Doses are age dependent for both local radiotherapy and CSI (50.4 Gy vs. 54 Gy and 23.4 Gy vs. 36 Gy for children younger and older than 3 years, respectively). In Europe, patients with nonmetastatic ATRT receive doxorubicin-based chemotherapy and local radiotherapy to a dose of 54 Gy, while those with metastatic disease receive CSI. An ATRT registry (EURHAB) has been established to collect multi-institutional and multinational data on patient management and outcome.

GERM CELL TUMORS

Germ cell tumors of the CNS constitute a group of rare tumors that are morphologic homologs of germinal neoplasms arising in the gonads and at other extragonadal sites. They include the following entities although in many cases more than one tumor type is present:

Germinoma

Embryonal carcinoma

Yolk-sac tumor (endodermal sinus tumor)

Choriocarcinoma

Teratoma

–Mature

–Immature

–Teratoma with malignant transformation

Mixed germ cell tumor

A teratoma is a tumor composed of an admixture of different tissue types representative of ectoderm, endoderm, and mesoderm. A mature teratoma is composed exclusively of fully differentiated tissues, sometimes arranged in such a manner as to resemble normal tissue relationships. Mitoses are absent or rare. An immature teratoma is composed of incompletely differentiated tissues resembling those of the fetus. Mitoses typically are present.

In the West, CNS germ cell tumors are relatively rare, accounting for 3% to 5% of all CNS tumors in the pediatric age group. They are more common in Asia, where they account for as many as 15% to 18% of all CNS tumors occurring in childhood. The peak age incidence is 10 to 12 years. Boys are affected more frequently than girls, with a ratio of approximately 3:1. CNS germ cell tumors arise from primordial germ cells in structures about the third ventricle, with the region of the pineal gland being the most common site of origin followed by the suprasellar region. Nongerminomatous germ cell tumors (NGGCTs) are the most common tumor type in the former area and germinomas in the latter.

The presenting symptoms and signs depend on the tumor type and the location of the tumor. Tumors in the pineal region cause obstruction to CSF flow at the aqueduct of Sylvius resulting in hydrocephalus, and most patients with tumors in this region present with a relatively short history with symptoms and signs of raised intracranial pressure. Another characteristic presentation of tumors in this region is Parinaud’s syndrome as a result of dorsal midbrain compression. In contrast, patients with tumors in the suprasellar region usually present with a longer history initially of neuroendocrine deficits, especially diabetes insipidus, growth failure, and precocious puberty, and only later of visual field deficits and, later still, of symptoms and signs of raised intracranial pressure. On imaging, most germ cell tumors appear as solid masses. Teratomas are more heterogeneous with cysts, areas of calcification, and sometimes fat, whereas choriocarcinomas often contain areas of hemorrhage. Bi- or multifocal disease around the third ventricle is seen in approximately 10% of patients with germinomas. Gadolinium-enhanced MRI of the spinal axis is an essential part of the workup to exclude leptomeningeal dissemination, which is found at diagnosis in approximately 10% of patients with germinomas and 10% to 15% of patients with NGGCTs. Measurement of serum and CSF tumor markers is another essential part of the initial workup. Modest elevation of β-human chorionic gonadotropin (β-hCG) (<100 IU/mL) may be seen with pure germinomas that may contain syncytiotrophoblastic cells. Higher levels of β-hCG are more suggestive of a choriocarcinoma. An elevated α-fetoprotein (α-FP) is diagnostic of a yolk-sac tumor.

In the past, many lesions arising in or about the third ventricle were treated without histologic confirmation of diagnosis. This is no longer considered acceptable practice because the differential diagnosis includes many disparate entities (such as Langerhans cell histiocytosis, astrocytoma, and ependymoma) and all patients should undergo biopsy unless CSF and/or serum markers confirm the presence of an NGGCT (elevated α-FP and/or β-hCG >100 IU/mL) or unless a histologic diagnosis is made by other means (e.g., CSF cytology). For tumors in the pineal region with hydrocephalus, the usual surgical approach is an endoscopic third ventriculostomy, which allows access to the lesion for biopsy purposes. Intraventricular lesions have to be biopsied with care because hemorrhage, which is not infrequent, may be difficult to manage endoscopically. A stereotactic approach is also possible, but this may be quite challenging because of the proximity of deep cerebral veins and, moreover, may be suboptimal for diagnosis because of the potential for sampling error. Occasionally complete resection will be possible; this would be a reasonable strategy for patients with NGGCTs if it can be accomplished without major morbidity because it would ensure complete characterization of the pathology and may even obviate the need for further therapy.

Germinoma

In the past, standard treatment for patients with germinoma, whether localized or disseminated, was radiotherapy alone. Results of treatment using CSI followed by a boost to the primary site are excellent, with long-term disease-free survival rates of 100% in some series.227,228,229,230,231 For patients with unifocal disease without leptomeningeal spread, radiotherapy alone to limited volumes, that is, whole brain232,233 or whole ventricle,227,229,234 results in a high probability of local control and a low (0% to 5%) risk of failure in the spinal axis. Experience with local radiotherapy (tumor plus a margin) alone generally has been less satisfactory,232,233,234,235,236 although some have reported excellent results.237 To reduce the risk of morbidity associated with radiotherapy, chemotherapy has been considered another option, either alone or in combination with reduced-volume and/or reduced-dose radiotherapy. Several studies have shown clearly that the former, that is, the use of chemotherapy alone, is not acceptable: only 40% to 50% of patients remain disease free, and although salvage using further chemotherapy together with radiotherapy is possible in most cases and overall survival is high, this is achieved at the cost of considerable toxicity.238,239,240,241

In contrast, a combined approach using platinum-based chemotherapy followed by reduced-volume, reduced-dose radiotherapy is an attractive option that results in disease-free survival rates in the 90% to 96% range.239,242,243,244 The optimal radiotherapy target volume using such an approach remains to be defined. Local failures were seen in 10 of 60 patients treated in the SFOP TGM-TC-90 study with chemotherapy followed by local radiotherapy245 and with even greater frequency in some single-institution studies, which, although with a patient population with a median age in adolescence, included adult patients.236,246 Local failure appears to be less frequent after whole ventricular radiotherapy246 and this is becoming generally accepted as the appropriate volume in this context (Fig. 84.14), but prospective data are lacking for now.

Figure84.14 Target volume definition for whole ventricular…

For patients with leptomeningeal spread at diagnosis, radiotherapy alone using CSI with boosts to macroscopic disease is certainly an option, although in North America chemotherapy followed by CSI followed by a boost to all sites of involvement would be the more usual approach. Management of patients with bi- or multifocal midline tumors is controversial. In the past these patients were treated as having disseminated disease, but at least some, that is, those with bifocal disease by imaging or by inference (e.g., in a patient with a pineal region primary who has diabetes insipidus), are now more usually treated with chemotherapy and whole ventricular radiotherapy.

There is less controversy now with regard to the radiotherapy dose and dose-fractionation schedule for germinoma. Results are excellent with a CSI dose as low as 21 Gy even in patients with leptomeningeal spread. The total dose to the primary site has typically been 40 to 45 Gy but probably can be safely reduced to 30 Gy or even to 24 Gy239,244 in patients treated with a combined chemotherapy–radiotherapy regimen who have had a complete response to chemotherapy. Finally, because germinoma is a very radiosensitive tumor, a fraction size of 1.5 Gy can be used, which, in theory, further reduces the risk of injury to normal structures.

Nongerminomatous Germ Cell Tumors

For NGGCTs the diagnosis can be made in as many as one-third of all patients on the basis of imaging findings (location and appearance) plus tumor markers. NGGCTs are of several different histopathologic types that carry different prognoses (Table 84.3). Patients with mature teratomas without any associated malignant elements can be managed with surgery alone, while those with mature teratoma with germinomatous elements will be treated as germinomas. All other patients with intermediate- and poor-prognosis tumor types247 require more aggressive treatment. The results of treatment using radiotherapy alone are very poor, with overall survival in the 10% to 30% range. Results are better with chemotherapy alone, although 40% to 60% of patients relapse following chemotherapy and will be subjected to aggressive salvage regimens.238,248,249 A multimodality approach that includes both chemotherapy and radiotherapy appears to be associated with the best outcome. Event-free survival was 81% in the German/Italian pilot study that led to the most recent SIOP CNS GCT study.250 The current standard of care therefore consists of platinum-based chemotherapy followed by radiotherapy.

Table84.3 Classification of Nongerminomatous Germ Cell…

There is controversy with respect to the radiotherapy target volume for NGGCT. Although good results have been reported by some groups using chemotherapy followed by local radiotherapy,177 others show a high rate of failure outside the primary site.249,251,252,253,254,255 Thus, as for germinoma, a whole-ventricle volume may be a better option for more favorable patients (e.g., the intermediate-risk group, α-FP <1,000 ng/mL), while CSI would be used for those with less favorable or disseminated disease. The usual dose to the whole-ventricle volume or CSI is 30 to 36 Gy and to the primary site, 54 Gy.

Patients who have less than a complete response to chemotherapy fare poorly. Second-look surgery may be useful to both exclude the possibility that the residual imaging abnormality represents mature teratoma and/or resect residual viable tumor. This would be followed by CSI and more intensive chemotherapy such as high-dose chemotherapy with stem cell rescue.

TUMORS OF THE SELLAR REGION

Tumors arising in the sellar region in children include the following:

Craniopharyngioma

–Adamantinomatous

–Papillary

Pituitary adenomas

Craniopharyngioma

By definition, craniopharyngiomas are benign partly cystic epithelial tumors that arise in the sellar region from remnants of Rathke’s pouch. In children, almost all are of the adamantinomatous type. They account for approximately 5% of intracranial tumors in the pediatric age group with a peak incidence between the ages of 5 and 14 years.

In the majority of patients, craniopharyngiomas have both suprasellar and intrasellar components. Children typically present with neuroendocrine deficits, especially diabetes insipidus and growth failure. Visual field deficits often go unnoticed initially. Cognitive and behavioral changes are not uncommon. Compression of or tumor growth within the third ventricle may lead to hydrocephalus and symptoms and signs of raised intracranial pressure. On neuroimaging, the findings are very typical, with solid and cystic areas in varying proportions. Calcification is seen in the majority of cases. The solid portion(s) and the cyst capsule usually enhance with the use of contrast material.

Treatment of craniopharyngiomas, although long considered a controversial issue,256 in practice depends on the characteristics of the tumor and the availability of the surgical expertise required. The argument for surgical resection is based on single-institution (mostly specialist center) reports of long-term tumor control after complete resection as confirmed on postoperative imaging in 85% to 100% of patients.257 However, in a three-nation prospective study event-free survival at 3 years was only 64%.258 Moreover, while visual deficits, if present, improve after surgery in the majority of cases, new neuroendocrine deficits are very common and hypothalamic damage is a major concern particularly in patients with tumors that have grown retro-chiasmatically into the floor of the third ventricle.259,260,261 Devastating sequelae that include rage, aggressivity, and hyperphagia permanently compromise the quality of life of the patient and his or her family. The transsphenoidal approach that has been used more frequently in recent years, even in younger children and even in patients with tumors with a supradiaphragmatic component, is associated with fewer complications. In general, therefore, tumors that are smaller and/or subdiaphragmatic in location and without hypothalamic involvement would be managed surgically. Patients who have residual tumor following surgery are at high risk for progressive disease within the first 2 to 3 years following surgery,258,262,263,264,265 mandating close follow-up with MRI performed at 3-month intervals during that time period. Patients at greater risk for complications secondary to surgery would be managed with biopsy, cyst decompression, if necessary, and radiotherapy.266,267,268,269,270,271

Radiotherapy may, therefore, be given as the sole therapy after biopsy, after incomplete surgery, or at time of progression/recurrence after surgery, and the heterogeneity of tumor types and situations means that one of several approaches may be used. For example, a lesion with a small solid component and a simple cyst may be well treated with intracavitary injection of liquid radioactive material. Most contemporary experience is with β emitters such as 32P and 90Y delivering a high dose (i.e., 200 Gy) to the cyst wall. Intracavitary injection of radioactive material is not always easy.272 Sometimes the cyst fluid is very thick in consistency and there may be little or no communication between multiple cysts. It is essential to use contrast material to ensure that the catheter is well placed in the cavity and that there is no leakage of material outside the cyst before injecting radioactive material. This could be combined with radiosurgery or fractionated stereotactic irradiation to the associated solid component, although it may be reasonable to do so only later and only if there is evidence of progressive disease. Special care is needed if, as is usually the case, the tumor is in close proximity to the optic chiasm or optic nerves.273 Tumor control rates using this approach are good for carefully selected patients.274However, conventionally fractionated external-beam radiotherapy may be a better option for all except very small tumors, with a lower risk of morbidity.256,275

The target volume for external-beam radiotherapy consists of the entire lesion (i.e., both the solid and cystic components) as demonstrated on MRI performed just prior to treatment. While some have used a margin for the CTV of 1 cm,276 a smaller margin of 0.5 cm or even 0 cm (i.e., CTV = GTV) can be justified on the basis of excellent tumor control using such margins.277,278,279 A dose of 54 to 55 Gy given in 30 daily fractions over 6 weeks appears to be necessary to achieve a high probability of tumor control. Cyst enlargement during treatment or within the first 2 to 3 months after completion of radiotherapy is not uncommon. Early recognition and appropriate management consisting usually of cyst decompression is essential to avoid further neurologic compromise or even death.280 The long-term prognosis is good, with event-free survival of 80% to 100% in most series.258,276,279,281,282

Pituitary Adenomas

Pituitary adenomas are rare in childhood. Almost all cases arise in adolescence. Most are functioning adenomas that present with endocrine dysfunction, most often menstrual irregularities and galactorrhea in girls and delayed puberty in boys. They may be quite large, with extrasellar extension, and appear to be more invasive than those seen in adults.283,284,285 Visual loss, when present, may be more severe and more likely to be associated with optic atrophy.284

Management will, in general, parallel that for adult patients. Prolactin- and growth hormone–secreting adenomas are managed medically as in adults. When surgery is necessary, a transsphenoidal approach using neuronavigation appears to be feasible and safe in children, even in those with poor pneumatization of the sphenoid sinus.283,285 Radiotherapy is indicated if surgical resection is not possible or if hormone levels remain elevated following surgery. Highly conformal treatment with a margin for the CTV of 0.5 cm beyond macroscopic disease is appropriate in most cases, the technique used being that which optimally spares adjacent critical structures including major vessels. The usual dose, as in adults, will be 45 to 50 Gy over 5 to 6 weeks. Close follow-up by an endocrinologist is essential to ensure appropriate management of hormone deficits