Clinical manifestations

Presentation and course

The signs and symptoms of children younger than 2 years of age, especially children younger than 1 year of age, differ significantly from those manifestations seen in older patients (05). Many of these tumors are believed to be congenital, and they present during times of maximum brain growth and development (36). They occur at a time when the child's skull is able to expand, resulting in the development of macrocephaly and often masking the signs and symptoms of increased intracranial pressure. Time between onset of symptoms and diagnosis has been noted to be longer for children younger 3 years of age with medulloblastomas, as compared to older children (48). As with central nervous system neoplasms in older patients, presenting signs and symptoms are also partially related to the location of the tumor within the nervous system and the growth rate and growth pattern of the tumor. A presentation unique to infants and young children is a delay or an arrest of attainment of developmental milestones; brain tumors may mimic neurodegenerative processes. Infants and children may also present with unexplained irritability and failure to thrive, with little in the way of localized neurologic deficits. This latter presentation is most common in children with deep-seated infiltrating lesions that affect the hypothalamus or other regions of the diencephalon. Such tumors may cause the "diencephalic syndrome." This syndrome is manifest by failure to thrive, despite an apparent increased appetite and seeming euphoria. Although visual loss or nystagmus may be present, more frequently, children with the diencephalic syndrome present with little in the way of subjective visual symptomatology, except for optic nerve atrophy. Occasionally, congenital brain tumors may be so large as to cause internal dystocia, necessitating cesarean section.

The distribution of tumors arising in the supratentorial and infratentorial spaces has varied among series. In most series, a higher relative incidence of supratentorial tumors is found in infants than in older children (24; 26; 01; 05; 11; 32). This is especially true for children younger than 6 months of age. Children younger than 2 years of age with posterior fossa tumors usually present with vomiting. Incoordination or other evidence of cerebellar dysfunction can be difficult to determine in a young child, and younger children with posterior fossa tumors are as likely, or more likely, to present with delayed milestones and altered sensorium. Most patients will have some evidence of increased intracranial pressure, due to both the bulk of the tumor and obstruction of cerebrospinal fluid flow. The presentation of supratentorial tumors in children younger than 2 years of age is even more variable. A large percentage of these children will have deep-seated diencephalic tumors, which can reach monstrous proportions before a diagnosis. These children present with macrocephaly, delayed milestones, and increased irritability. Although the visual loss is commonly present at the time of diagnosis, it is frequently not appreciated early in the course of illness.

Both supratentorial and infratentorial tumors may result in macrocephaly. Sometimes this is due to obstructive hydrocephalus, and other times it is primarily due to the large bulk of the lesion, especially in children with supratentorial lesions. Although supratentorial tumors in some series constitute well over 50% of all neoplasms arising in children younger than 2 years of age, a surprisingly small proportion of these children have seizures, ranging, in 2 series, from 11% to 33% (05; 50). The seizures may be of any type, and infantile spasms have been related to underlying central nervous system neoplasm.

Due to the ability of the infant's skull to expand, young children with central nervous system neoplasms infrequently have papilledema. More frequently, increased intracranial pressure is manifest by spreading of the sutures and bulging of the anterior fontanelle. Ophthalmologic examination is more likely to show evidence of optic atrophy than papilledema. Dilatation of the third ventricle classically results in loss of upgaze in infants, also known as the "setting sun" sign. Rarely, congenital tumors that arise in the chiasmatic region may alter formation of the optic nerves; both chiasmatic gliomas and craniopharyngiomas may result in optic nerve hypoplasia. Children with chiasmatic and hypothalamic tumors may also present with abnormal eye movement including nystagmus, which may or may not be associated with head nodding. This may cause diagnostic confusion with a benign developmental process termed “spasmus nutans” (02). In the latter condition, the nystagmus more likely is uniocular and has been associated with head nodding, whereas nystagmus due to hypothalamic tumors is more frequently bilateral, rapid, and almost shimmering. Because of the difficulty in clinically separating nystagmus due to chiasmatic lesions from that associated with spasmus nutans, all children with presumed spasmus nutans should be evaluated by either CT or MRI to rule out the possibility of an underlying diencephalic neoplasm.

Prognosis and complications

The prognosis for children younger than 2 years of age with primary central nervous system tumors is highly dependent on the histological and molecular subtype of the tumor, the size, and the location of the tumor. As can be expected, children with malignant tumors generally have a far worse survival rate than those with benign tumors (05). In 1 series, only 9 of 37 patients younger than 2 years of age with malignant tumors survived 5 years following diagnosis, as compared to 30 of 41 patients with benign tumors. The use of more aggressive surgery and the wider use of chemotherapy may alter this prognosis to some degree.

The reasons for the poorer prognosis in children younger than 2 years of age with primary central nervous system tumors, as compared to children diagnosed at an older age, are complex. As stated previously, there may be biological differences between those tumors occurring in younger children and those occurring in older patients (46; 28; 29; 55). Even within a histological subtype, there is some evidence that tumors occurring in younger children are more likely to disseminate through the nervous system early in the course of illness and, possibly because of delay in diagnosis due to the subtlety of presentation, to be larger at the time of diagnosis. Because of the young age of the children and the neurologic deficits that may be present at the time of diagnosis, it is also possible that infants and young children with large brain tumors are treated less aggressively than older patients are. This may include less aggressive attempts at surgical resection and the reluctance of physicians to utilize radiotherapy, a major component of the therapeutic approaches for older children with a variety of different brain tumors.

However, as was previously stated, there has been increasing enthusiasm over the past decade to intensify treatment for young children with brain tumors. This includes the employment of more aggressive surgical resections and the use of multiagent, high-dose chemotherapy in an attempt to delay, if not obviate, the need for radiotherapy (09; 04). Also, with the advent of more focused radiotherapy techniques, it is likely that some of the reluctance over the use of radiotherapy will be lessened. Techniques such as proton radiotherapy may make such focal radiotherapeutic techniques less harmful to surrounding brain (41; 40; 39). In somewhat older children, radiotherapy and chemotherapy may be an option (23). As the biology of tumors is further elucidated, a major hope is that biologically-based precision therapy can provide a survival advantage.

Clinical vignette

A 5-month-old child was brought to the pediatrician by his parents with a complaint of 1 month of poor eating associated with vomiting. The child was somewhat emaciated with a large head. On examination the child was lethargic and difficult to arouse. The child’s head circumference was 49 cm and the anterior fontanelle was bulging. The child’s pupils were reactive. The optic discs were difficult to see, but were slightly pale. Upgaze was limited, and the child had bilaterally in-turned eyes. His facial movements were somewhat decreased. The child’s gag was present, but was somewhat decreased. On motor and coordination testing, there was diffuse hypotonia. When the child was put in a sitting position, there was poor head control and the child seemed to sway from side to side. Reflexes were diffusely increased.

A CT scan showed a large mass in the R frontal lesion extending to thalamus with associated hydrocephalus that was ill-defined. The mass was slightly hyperintense and enhanced readily with contrast. On MRI scanning, the mass was of decreased signal intensity on T1-weighted images and of slightly increased signal intensity on T2-weighted images. The mass homogeneously enhanced with contrast. MRI of the spine showed multiple enhancing lesions along the spinal canal.

The child was taken to surgery where the pathology demonstrated an embryonal tumor with multilayered rosettes. Molecular testing showed fusion between TTYH1 and C19mc miRNA cluster, consistent with an embryonal tumor with multilayered rosettes, with C19mc-altered.

Biological basis

Etiology and pathogenesis

The etiology of most central nervous system neoplasms is unknown, although there is increasing evidence that up to 10% of patients may have underlying germ-line mutations that predispose to the development of cancer (61). Infants with medulloblastoma may have germline mutations in SUFU and PTCH1, as well as TP53 mutations (60). Embryonal tumors of the pineal may have DICER1 mutations (06).

The biologic bases of pediatric embryonal tumors are far from well-delineated. However, detailed molecular genetic studies of large numbers of patients with such tumors have helped clarify embryonal tumors to some degree. Many cortical tumors, previously believed to be embryonal tumors and often classified in the past as supratentorial primitive neuroectodermal tumors, now have molecularly been found to be high-grade gliomas (22). The biology of medulloblastoma, the type of embryonal tumor occurring in the posterior fossa, is discussed in detail in the medulloblastoma summary. Similarly, atypical teratoid/rhabdoid tumors have their own distinct biology and are discussed in the atypical teratoid/rhabdoid statement. However, it is worth noting that atypical teratoid/rhabdoid tumors may occur in very young children less than 1 year of age, can be extremely aggressive in the very young, and are separable into genetic/epigenetic subgroups; younger patients seem to cluster within specific subgroups (58; 25; 15). Molecular analysis has demonstrated that tumors that have been previously separated, such as the embryonal tumor with abundant neuropil rosettes, ependymoblastoma, and medulloepithelioma share similar features. These include chromosome 2 gain and focal amplification in a chromosome 19q13.42. The 19q13.42 chromosome region contains a cluster of microRNA coding genes and its amplification suggests 1 entity. This is even further supported by the overlapping histological features of these tumors, which include multilayered and pseudostratified rosettes forming structures of variable shapes and size. Tumors with these histologic and molecular features are presently considered to be embryonal tumors with multilayered rosettes. Many of these tumors will have cytoplasmic immunopositivity for LIN28A and a fusion between TTYH1 and the C19MC miRNA cluster at 19q13.42, high level amplification of 19q13.42, and frequent trisomy 2 (49). These tumors also display similar copy aberrations and DNA methylation patterns. Despite these fairly characteristic findings, in the most recent WHO classification there is a subcategory of embryonal tumors with multilayered rosettes where the molecular findings cannot be confirmed. In addition, medulloepithelioma has been maintained, as well as a more general waste basket term of embryonal tumor, NOS.

Per the World Health Organization, recognized nonmedulloblastoma embryonal tumors include (35):

Both clarifying and confusing understanding to a greater degree is DNA methylation profiling, which has demonstrated that many of the tumors that were considered embryonal tumors of the supratentorial space in the past are actually high-grade gliomas or ependymomas (22). Other lower grade tumors are also confused with such lesions. Other embryonal molecular entities that have been described include CNS neuroblastoma with FOXR2 activation, CNS Ewing sarcoma family with CIC alteration, CNS high-grade neuroepithelial tumor with MN1 alteration, and CNS high-grade neuroepithelial tumor with BCOR alteration (55). CNS high-grade neuroepithelial tumor with MN1 alteration is the tumor type most commonly containing those tumors that are considered astroblastoma (33). BCOR altered tumors are more frequent than previously thought, and such genetic alterations are found in tumors with variable histologies.

Epidemiology

The ratio between supratentorial and infratentorial tumors in children younger than 2 years of age has varied among series. In general, younger children are more likely to have supratentorial tumors, especially children younger than 6 months of age (13; 05; 11). The percentage of supratentorial tumors in patients younger than 2 years of age has ranged between 40% and over 60%.

Prevention

No method of prevention is known for brain tumors in infants and children younger than 2 years of age.

Differential diagnosis

The differential diagnosis of embryonal infantile brain tumors essentially encompasses all of the processes that can affect the nervous system in young children. The primary distinction is often between such embryonal tumors and low- or high-grade glial or neuronal tumors. Embryonal tumors are difficult to clinically or radiographically separate from the other major forms of embryonal tumor arising in the supratentorial space, such as the atypical teratoid/rhabdoid tumor and malignant gliomas. In children who present with developmental delay, arrest, or apparent neurodegeneration, differential diagnosis includes all of the neurodegenerative processes that can affect the nervous system. Uncontrolled seizures, especially infantile spasms, can cause neurodegeneration and need to be separated from central nervous system tumors that can cause similar neurologic findings. The more common causes of macrocephaly include the congenital or acquired forms of hydrocephalus. Separation of children with intracranial neoplasms and nonprogressive encephalopathies manifest by motor impairments (cerebral palsy) is, at times, clinically difficult. Supratentorial lesions may cause hemiplegic symptoms, and these may mimic cerebral palsy. In children with cerebral palsy, the pattern of neurologic deficit may evolve to some degree over time (such as development of choreoathetosis in children with hypotonia); therefore, diagnostic confusion may occur. A significant change in the quality or degree of the disability should strongly suggest the possibility of an underlining neoplasm.

Diagnostic workup

The diagnostic evaluation for a child with a presumed central nervous system tumor has been greatly simplified by the advent of CT and MRI. The advantages of MRI are well documented; for example, the full extent of the lesion and the relationship of the lesion to other anatomical sites within the central nervous system are better appreciated than on CT. There is usually little need for other diagnostic studies to confirm the presence of the tumor.

Embryonal nervous system tumors tend to disseminate through the neuraxis early in the course of illness (05). This is especially true for infants with such tumors. MRI of the entire brain and spine is usually indicated in all children with embryonal central nervous system tumors to determine the extent of disease. Cerebrospinal fluid cytological examination should also be undertaken, if possible. Extraneural metastases, at diagnosis, may occur. Staging evaluations for extent of disease in children including bone scans and bone marrow aspirates are indicated in those with Ewing tumor family and possibly other embryonal tumors. The yield of such procedures in other tumor types is low.

Management

Surgery remains the first therapeutic option for most infants and young children with embryonal tumor. In general, most investigators favor aggressive surgical intervention for embryonal tumors in young children, in attempts to control the disease and possibly make adjuvant therapy more effective (32).

The long-term detrimental effects of extensive whole-brain radiotherapy on neurocognitive and endocrinologic outcome in young children with brain tumors have been documented (47; 07; 21). Most children receiving such treatments have severe cognitive dysfunction and growth, and other endocrinologic failure. The detrimental effects of more localized radiotherapy on the developing nervous system are less well documented. However, the general approach has been to avoid radiotherapy as much as possible in infants and young children. The use of local radiotherapy, following chemotherapy, statistically improved survival for children with supratentorial primitive neuroectodermal tumors (57), and craniospinal radiotherapy plus chemotherapy during and after radiotherapy may be successful in somewhat older children (23).

Chemotherapy alone has been increasingly utilized as an adjuvant treatment, following surgery, for children with malignant tumors and in those children with low-grade tumors whose tumors cannot be extensively resected. Studies utilizing various chemotherapeutic approaches have reported the potential efficacy of chemotherapy for children with malignant tumors less than 3 years of age (Van Eyes et al 1985; 03; 09; 51). Twenty years ago, the combination of mechlorethamine, vincristine, prednisone, and procarbazine was found to control disease in nearly one half of young children with medulloblastoma who had initially undergone an extensive surgical resection (Van Eyes et al 1985). The drug regimen of cyclophosphamide, cisplatinum, etoposide, and vincristine was employed in 132 children younger than 24 months of age, with a variety of malignant tumors (09). For the subgroup of children who had extensive (total) surgical resections and were treated with chemotherapy, and for those who had complete responses to chemotherapy, a significant number could be maintained on chemotherapy for 2 years before requiring radiotherapy. Progression-free survival was 19% at 5 years for children with primitive neuroectodermal tumors outside the posterior fossa, akin to what is now considered embryonal tumors. In other series, the effectiveness of treatment of young children with central nervous system primitive neuroectodermal tumors was analyzed in 3 biologic subsets (46; 16; 28) grouped as primitive neural, oligoneural, and mesenchymal tumors. Survival varied some between subtypes. Infants with disseminated pineoblastomas and central nervous primitive neuroectodermal tumors do particularly poorly, even with intensive chemotherapy (16). In 1 study of 25 children with supratentorial embryonal tumors, treatment with carboplatin plus procarbazine, etoposide plus cisplatin, and vincristine plus cyclophosphamide demonstrated a median progression-free survival of 5.5 months, and the 2-year survival rate of 30% (37). In another study, younger children with pineoblastoma were also found to have a poorer diagnosis than older children and were more likely to have metastatic disease at diagnosis (44). Extensive surgery at diagnosis seemed to improve survival.

The introduction of peripheral stem cell rescue into treatment regimens to support even higher doses of radiotherapy has shown variable outcomes without clearcut improvement over less intensive chemotherapy (56; 04; 10). A major issue that still needs to be resolved from these studies is whether children who have a complete disappearance of tumor after surgery and chemotherapy require radiotherapy at the end of chemotherapy. This has been investigated by multiple studies (19; 52) without clear resolution. However, it is fairly clear that children with embryonal tumors who fail to go into complete response after surgery and chemotherapy rarely maintain disease control with just maintenance chemotherapy. Also, at recurrence, salvage therapy is usually unsuccessful (14). For these children, the earlier use of radiotherapy or the use of higher doses of chemotherapy, possibly supplemented by autologous bone marrow transplant or peripheral stem cell rescue, has been explored with relatively poor results (12; 20; 38; 43; 53).

The treatment of the rarer subsets of embryonal tumors in young children remains problematic, especially as so few are available for study (27; 46). For those with embryonal tumors with multilayered rosettes (28), treatment with multimodal therapy resulted in 4 survivors out of 11; 3 of the 4 survivors had gross total resections followed by either craniospinal radiotherapy or chemotherapy with autologous blood stem cell rescue (17). Similarly, gross-total resection has been associated with a better likelihood of survival for patients with medulloepitheliomas (42).

It is still unclear how these different approaches have changed the quality of life for children younger than 2 years of age with malignant and benign tumors. Because of the large size of these lesions and their presence at the times of critical development, many of these children are significantly delayed before the initiation of treatment or immediately after surgery (21). Many also have significant focal neurologic sequelae. At this time, there is no clear evidence that the chemotherapy causes progressive neurologic sequelae in these children, although prospective studies still need to be performed (53; 52).

Special considerations

Anesthesia

Precautions similar to those for any patient with increased intracranial pressure should be undertaken.