Clinical manifestations

Presentation and course

The classical, or juvenile, pilocytic cerebellar astrocytoma tends to be a slow-growing lesion arising in the lateral cerebellar hemispheres (44). The tumor may cause lateralized appendicular symptoms for weeks to months before extending to the midline and obstructing the fourth ventricle. When cerebrospinal fluid flow is obstructed, the more nonspecific and nonlocalizing signs of increased intracranial pressure, including headache and vomiting, become preeminent. In addition, midline cerebellar deficits, such as truncal unsteadiness, become more frequent. As the tumor enlarges, the child may become apathetic and irritable and develop neck stiffness. Head tilt may occur, secondary to herniation of the cerebellar tonsil ipsilateral to the side of the tumor. Flexion of the neck will cause meningeal signs. Laterally placed cerebellar astrocytoma will infrequently cause cranial nerve palsies, except for abducens involvement due to hydrocephalus. Similarly, corticospinal tract dysfunction usually only occurs late in the course of illness with longstanding hydrocephalus.

Patients with diffuse or nonpilocytic cerebellar astrocytomas tend to be young children and, more commonly, adults. The majority of cerebellar astrocytomas that arise in adults are of the diffuse type. The duration of symptoms prior to diagnosis is usually shorter with diffuse tumors, and patients are more likely to present with midline cerebellar deficits, such as truncal unsteadiness, followed by, or concomitant with, signs of increased intracranial pressure (23). Because the tumor is frequently abutting, or even attached to, the brainstem, cranial nerve palsies are more frequent. Similarly, the cerebellar peduncles may be compressed or infiltrated, and cerebellar outflow abnormalities, including unilateral dysmetria and severe nystagmus, may be present. At times, it may be essentially impossible to distinguish between a diffuse cerebellar astrocytoma invading the brainstem and a large exophytic brainstem glioma extending from the brainstem. In these cases, multiple cranial nerve palsies are frequent, as are cerebellar and long-tract signs and symptoms.

Distinction is primarily between cerebellar astrocytomas and other childhood posterior fossa tumors (44). The other common types of childhood posterior fossa tumors include medulloblastoma or primitive neuroectodermal tumors, brainstem gliomas, and ependymomas. These tumors have different clinical and neuroradiographic features. Medulloblastomas or primitive neuroectodermal tumors tend to have a more explosive presentation. Midline cerebellar deficits and symptoms of increased intracranial pressure occur early in the course of illness. Laterally placed medulloblastomas are even more difficult to clinically distinguish from classical cerebellar astrocytomas. Brainstem gliomas present with the insidious onset of multiple cranial nerve findings, long-tract signs, and cerebellar symptoms. Clinical distinction between an intrinsic brainstem tumor and a laterally placed cerebellar astrocytoma is usually not difficult; however, there may be clinical overlap between exophytic brainstem gliomas and the cerebellar astrocytomas. Similarly, diffuse cerebellar astrocytomas may have associated cranial nerve deficits and can be difficult to distinguish from more exophytic brainstem gliomas. Ependymomas, especially when laterally placed, can be difficult to distinguish from cerebellar astrocytomas. Posterior fossa ependymomas tend to have a somewhat shorter duration of symptoms before diagnosis and result in more cranial nerve deficits.

Other lesions of the posterior fossa may mimic cerebellar astrocytomas. Lhermitte-Duclos or dysplastic gangliocytoma of the cerebellum is a condition wherein there are cerebellar hamartomas that can cause cerebellar deficits (49). This condition is much less likely to cause hydrocephalus and, although considered a nontumorous condition, can apparently cause an increased mass effect over time. In these cases, clinical differentiation of Lhermitte-Duclos and cerebellar astrocytomas is virtually impossible. Other processes that may occur in the cerebellum include acute demyelinating lesions, cerebellar abscesses, and vascular malformations. Cerebellar hemangioblastomas occur with increased frequency in von Hippel-Lindau disease.

Prognosis and complications

The overall prognosis for the majority of patients with cerebellar astrocytomas is excellent. For children with the more common classical juvenile or pilocytic astrocytomas, the 5-year progression-free survival rate after total surgical resection ranges between 90% and 95% (17; 26; 28; 19; 54; 56; 24). The vast majority of such patients can be considered to be cured of their disease. Prognosis for patients subtotally resected is somewhat less favorable in juvenile astrocytomas; however, those patients with subtotally resected pilocytic astrocytomas with a BRAF-KIAA1549 fusion abnormality in their tumors did well (27). The addition of radiotherapy does not improve survival for patients with totally resected pilocytic astrocytomas (36; 17).

In contradistinction, survival rates for patients with diffuse cerebellar astrocytomas are much less favorable. Five-year and 10-year survivals ranging between 7% and 30% have been reported (22; 28). In a series of primarily older patients, a 5- and 10-year survival rate of 7% was documented. In these patients, duration of survival may be somewhat lengthened after the addition of radiotherapy. The rare high-grade cerebellar glioma carries a poor prognosis, possibly worse than those for children with cortical high-grade gliomas (33).

The majority of survivors of low-grade astrocytomas of the cerebellum have good qualities of life. There has been no documentation of deterioration in intelligence over time in such patients treated with surgery alone. They often have minor neurologic abnormalities such as mild residual ataxia, dysmetria, or nystagmus. Postural sway, which relies on vestibular input for equilibrium control, is often present in long-term survivors and has been related to damage of the fastigial and interposed nuclei (34). More subtle findings, such as apraxia and motor neglect, as well as language executive function and memory deficits may be present (01). In addition, more complex neuropsychologic deficits and even epilepsy has been seen after surgery, although there is no clear-cut causation (52; 59; 13). Vermian tumors have been associated with poorer long-term functional outcome (13).

Clinical vignette

A 7-year-old girl was referred to the neurologist because of unsteadiness. Over the previous 3 months, the child had increasing difficulties with balance and, eventually, with the use of her right arm. The week prior to evaluation, she had developed severe morning headaches associated with nausea and vomiting. In retrospect, she may have had some mild headaches over the past 2 months.

On examination, the child was awake and alert. Her pupils were equal and reactive. She had bilateral papilledema. Cranial nerve examination disclosed bilateral mild sixth nerve palsies. Her upgaze was intact and she had good downgaze. Her face moved symmetrically and the remainder of her cranial nerves was normal. On motor and coordination testing, there was marked dysmetria with the right hand; she was a bit unsteady with the left hand. Her gait was wide-based, and she tended to fall to the right.

A CT scan disclosed a cystic mass within the right cerebellum that extended to the midline and caused blockage of the fourth ventricle. There was associated hydrocephalus. After contrast enhancement, a small nodule was found within the cystic-like structure. MRI scan disclosed a similar picture with a large cystic mass. The small nodule (mural nodule) also enhanced readily with contrast on MRI scan.

Biological basis

The etiology in the vast majority of patients with cerebellar astrocytomas is unknown. There is a higher incidence of tumors in children with neurofibromatosis type 1 (10).

Etiology and pathogenesis

The more common classical juvenile pilocytic astrocytoma accounts for 80% to 85% of tumors. The 2021 WHO Classification of Tumors of the Central Nervous System classifies these tumors under the subgroup of circumscribed astrocytic astrocytomas as pilocytic astrocytomas (40). They are composed of fusiform astrocytes loosely interwoven in a fine fibrillary background.

Mitoses are rare in such lesions. The pilocytic tumor frequently has a microcystic component, and Rosenthal fibers, believed to represent the degenerated astrocytes, are commonly seen.

The tumor tends to have a large macrocystic structure, filled with proteinaceous fluid and is often associated with a mural nodule. Nuclear atypia and focal leptomeningeal invasion are often seen, but despite the presence of such more aggressive features, the pilocytic tumor tends to behave in a benign fashion. Rarely, a possibly more virulent variant, the pilomyxoid pilocytic astrocytoma, can occur in the cerebellum (37).

In contradistinction, the diffuse or fibrillary astrocytomas are more histologically similar to low-grade astrocytomas of the cerebral hemisphere. In the newest WHO classification they are considered “pediatric-type diffuse low-grade gliomas” and are then further subclassified based on molecular finding, with the majority being “diffuse low-grade glioma, MAPK pathway-altered” (40).

This tumor is more cellular and infiltrative. Prognosis for the diffuse cerebellar astrocytoma is much less favorable, and these tumors are often either associated with more malignant-appearing glial regions or are more likely to transform into a more aggressive lesion. Molecular features can be useful in separating pilocytic astrocytomas with atypical features from malignant gliomas, as BRAF fusion mutations, as described below, are characteristic of the pilocytic astrocytomas. TP53 mutations suggest a more aggressive clinical course (12).

In Gilles separation, tumors that contain microcysts, leptomeningeal deposits, Rosenthal fibers, or oligodendrial glial features can be grossly grouped into a cluster, or type A classification, which carries a benign prognosis. The Gilles type B tumor contains perivascular pseudorosettes and 1 or more of the following features: high cell density, necrosis, mitosis, or calcification. Gilles and colleagues have outlined a schema to determine the prognostic significance of individual factors in these clusters (22). For example, patients with only 1 factor suggesting poorer prognosis tend to fare better than those patients with more factors. Other investigators have also stressed that histological features, usually related to poorer outcome, such as pleomorphism, endothelial proliferation, and hypervascularity, do not predict poorer outcome for patients with cerebellar astrocytomas (28).

The biological underpinnings of pediatric low-grade gliomas are being increasingly understood. Cytogenetic studies have disclosed that the majority of tumors have no cytogenetic abnormalities (25). BRAF oncogenic activating mutations have been shown to be associated with cerebellar pilocytic astrocytomas (31; 46; 20; 29). The majority of cerebellar pilocytic astrocytomas are fusion protein abnormalities, primarily BRAF-KIAA1549 duplication-fusions, but other activating-fusion protein abnormalities have been noted, as well as much less frequent point mutations (30; 47; 06; 43; 50). In addition, transcriptional profiles of cerebellar astrocytomas demonstrate genes upregulated that are crucial in early brain regionalization, as well as those essential in later stages of cerebellar morphogenesis and differentiation (57).

The diffuse low-grade gliomas MAPK pathway-altered are usually driven by BRAF mutations or FGFR1 alterations (40). Diffuse astrocytoma MYB or MYB1-altered circumscribed astrocytic glioma may also occur (40).

Epidemiology

Cerebellar astrocytomas account for 10% to 20% of all childhood brain tumors (44). They are the second most common tumor of the posterior fossa and comprise 30% to 40% of all posterior fossa tumors in childhood (44). The tumor rarely occurs in adulthood; when such low-grade tumors occur in the adult years, they are more commonly of the nonpilocytic or diffuse type. Diffuse cerebellar astrocytomas also more frequently occur in infants. The peak incidence for cerebellar astrocytomas is in the latter half of the first decade of life, with the second peak in the first half of the second decade.

Prevention

The risk factors for cerebellar astrocytomas are essentially unknown except for the relationship of such tumors and neurofibromatosis type 1.

Diagnostic workup

The diagnostic workup of patients with cerebellar astrocytoma has been remarkably simplified since the advent of CT and MRI (05).

On CT, low-grade cerebellar astrocytomas usually display a homogenous low-density pattern associated with a macrocystic component. Within the macrocystic component, there is frequently a nodule (the mural nodule) that shows marked contrast enhancement. Hydrocephalus is present in the majority of patients at the time of diagnosis. CT findings of the diffuse cerebellar astrocytoma usually disclose an isodense or hypotense lesion, which enhances in a variable fashion after contrast (58). The laterally placed cerebellar astrocytoma most commonly arises in the cerebellar hemisphere and often upwardly displaces the fourth ventricle. The diffuse cerebellar astrocytoma more commonly arises in the midline, compressing the fourth ventricle. On MRI, the tumor's noncystic components are commonly isointense or hypointense in comparison with adjacent normal cerebellum on T1-weighted images, and hypertense compared with normal tissue on T2-weighted images.

The cyst may have intermediate signal intensities depending on the protein content. Hemorrhage within the cyst may occur, but it is uncommon. After gadolinium, the mural nodule of the pilocytic astrocytoma usually enhances. Cyst wall enhancement is infrequent, and enhancement suggests tumor within the wall of the cyst. In patients with diffuse cerebellar astrocytomas, MRI often displays the diffuse infiltrating nature of such lesions, including apparent involvement of the brainstem or cerebellar peduncles.

Usually CT or MRI is all that is needed to confirm the presence of a cerebellar astrocytoma. The classical pilocytic cerebellar astrocytoma rarely, if ever, disseminates the neuraxis, and staging of the tumor with studies such as cerebrospinal fluid cytology and MRI of the spine are not indicated. In contradistinction, dissemination has been more frequently reported in diffuse midline cerebellar astrocytomas, especially in tumors that may display associated anaplastic features (51; 45). In these cases, evaluation of the extent of disease is indicated. Multiple cerebellar astrocytomas have been noted in patients with neurofibromatosis type 1 (14).

The combination of MRI, spectroscopy, and computer-based multifactorial analysis may increase preoperative prediction of tumor type (02).

Management

The treatment of the pilocytic astrocytoma is surgical resection (26; 28; 18). Complete tumor excision is associated with improved long-term survival and cure in the majority of patients. Perioperative cerebrospinal fluid diversion is required in the majority of patients; however, probably less than one third of patients will require internalization of spinal fluid diversion and a ventriculoperitoneal shunt for persistent hydrocephalus. Children less than 3 years old with cerebellar gliomas are somewhat more likely to have higher-grade (malignant) lesions (55).

The management of patients whose tumors are initially partially resected remains unsettled. The short-term survival rate for those patients who undergo partial resections is similar to that for those patients who undergo total resections, but the relapse-free survival rates are much higher in patients undergoing partial resection (36; 17; 28; 21). Ten-year event-free survival rates are lower; those with partially resected tumors have an event-free survival rate of 50% compared to 80% to 90% for total resected lesions (24). In addition, those patients with partially resected V600E mutation tumors likely have a poorer prognosis than those with BRAF-fusion alterations (09; 32). Postoperatively, all patients require a CT scan or an MRI scan with and without contrast, to determine the extent of resection. If there is residual disease after initial tumor resection, patients should either undergo re-resection or be closely observed for tumor progression (08). Because approximately one half of the patients with partially resected tumors will remain free of progressive disease for 5 years, ongoing surveillance with sequential MRIs is required and surveillance neuroimaging will detect recurrence in asymptomatic children (53). Radiation therapy has been utilized for some patients with partially resected tumors (36; 17). Single institution studies have suggested that radiation may improve the duration of progression-free survival for patients with subtotally resected tumors, although the number of patients treated in such studies is small. If radiotherapy is to be used, conformal or other forms of more focused radiotherapy, such as gamma knife treatment, should be considered. At the present time, the consensus is to re-resect such lesions prior to making a decision to begin radiotherapy.

Patients with diffuse cerebellar astrocytomas have a worse prognosis. The tumors in such patients are often less amenable to total resection, and the tumors have a greater tendency to disseminate the neuraxis and possibly transform into more histologically malignant lesions (45). In patients with subtotally resected, diffuse cerebellar astrocytomas, postsurgical adjuvant therapy is frequently recommended.

Chemotherapy with carboplatin and vincristine or with vinblastine has been shown to be of benefit in children with progressive pilocytic astrocytomas (24; 41; 35). Biological therapy with bevacizumab and irinotecan or MEK inhibitors (04; 43; 16) has been shown to be beneficial in children with low-grade astrocytomas, and will have a future role in the management of diffuse subtotally resected cerebellar astrocytomas (42; 07; 16). For those tumors that have BRAF mutations, studies using BRAF-inhibitors, some in combination with MEK inhibitors, are nearing completions, including prospective trials comparing molecular-targeted therapy to chemotherapy for those with newly-diagnosed partially-resected disease. Focal radiotherapy can also be used. However, in many situations, a period of observation is indicated, and treatment is only started if there is progression.

Outcomes

The overall prognosis for the majority of patients with cerebellar astrocytomas is excellent. For children with the more common classical juvenile or pilocytic astrocytomas, the 5-year progression-free survival rate after total surgical resection ranges between 90% and 95% (17; 26; 28; 19; 54; 56; 24). The vast majority of such patients can be considered to be cured of their disease. Prognosis for patients subtotally resected is somewhat less favorable in juvenile astrocytomas; however, those patients with subtotally resected pilocytic astrocytomas with a BRAF-KIAA1549 fusion abnormality in their tumors did well (27).

In contradistinction, those with subtotally resected cerebellar low-grade gliomas with V600E BRAF mutations have a poorer prognosis (09; 32). In one retrospective study, low-grade diffuse gliomas, except for those with BRAF-fusion alterations, had a small, but real chance of malignant transformation (15). The addition of radiotherapy does not improve survival for patients with totally resected pilocytic astrocytomas (36; 17).

The majority of survivors of low-grade astrocytomas of the cerebellum have good qualities of life. There has been no documentation of deterioration in intelligence over time in such patients treated with surgery alone. They often have minor neurologic abnormalities such as mild residual ataxia, dysmetria, or nystagmus. Postural sway, which relies on vestibular input for equilibrium control, is often present in long-term survivors and has been related to damage of the fastigial and interposed nuclei (34). More subtle findings, such as apraxia and motor neglect, as well as language executive function and memory deficits may be present (01). In addition, more complex neuropsychologic deficits and even epilepsy has been seen after surgery, although there is no clear-cut causation (52; 59; 13). Vermian tumors have been associated with poorer long-term functional outcome (13).

Special considerations

Anesthesia

Because the majority of patients with cerebellar astrocytomas have increased intracranial pressure at the time of diagnosis, anesthesia techniques for patients with increased intracranial pressure must be utilized.