Continuing Education Activity

Pilocytic astrocytoma is the most common childhood brain tumor and most often found in the posterior fossa. Complete resection usually cures the patient; however, the patient can present with brainstem compression and hydrocephalus, which are both potentially life-threatening. Therefore, it is essential to achieve early diagnosis and treatment. This activity reviews the evaluation and treatment of pilocytic astrocytoma and highlights the role of the interprofessional team in the care of patients with this condition.

Objectives:

• Identify the etiology of pilocytic astrocytoma.
• Review the appropriate evaluation of pilocytic astrocytoma.
• Outline the management options available for pilocytic astrocytoma.
• Summarize interprofessional team strategies for improving care coordination and communication to advance the care of pilocytic astrocytoma and improve outcomes.

Introduction

Pilocytic astrocytoma (PCA), previously known as cystic cerebellar astrocytoma or juvenile pilocytic astrocytoma, was first described in 1931 by Harvey Cushing, based on a case series of cerebellar astrocytomas; though he never used these terms but rather described a spongioblastoma.[1] They are low-grade, and usually well-circumscribed tumors, which tend to occur in young patients. By the World Health Organization (WHO) classification of central nervous system tumors, they are considered grade I gliomas and have a good prognosis.[2] 

PCA most commonly occurs in the cerebellum but can also occur in the optic pathway, hypothalamus, and brainstem. They can also occur in the cerebral hemispheres, although this tends to be the case in young adults. Presentation and treatment vary for PCA in other locations, and this article will discuss the PCA of the cerebellum only. Glial cells include astrocytes, oligodendrocytes, ependymal cells, and microglia. Astrocytic tumors arise from astrocytes and are the most common tumor of glial origin. The WHO 2016 categorized these tumors as either "diffuse gliomas" or "other astrocytic tumors." Diffuse gliomas include grade II and III diffuse astrocytomas, grade IV glioblastoma, and diffuse gliomas of childhood. The "other astrocytic tumors" group include PCA, pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, and anaplastic pleomorphic xanthoastrocytoma.[2] 

The above-described grading system is histological. It is worth noting that the 2016 WHO classification gives more importance to genetic and molecular markers for categorizing gliomas, however, PCA is essentially a histological diagnosis.

Etiology

There is a strong association between neurofibromatosis type 1 (NF1) and PCA, with up to 20% of patients with NF1 developing a PCA most commonly in the optic pathway.[3][4] However, most PCAs are thought to be sporadic mutations rather than inherited. BRAF gene alterations and MAPK signaling pathway alterations have been found in the majority of PCAs.[5][6][7] BRAF is an intracellular serine/threonine kinase involved in the activation of the mitogen-activated kinase (MAPK) pathway.[8] BRAF is a proto-oncogene, mutations of which have been found to cause human cancers.[9][10]

Epidemiology

Brain tumors are the most common solid cancer in childhood.[11] PCA is the most common childhood brain tumor, with an incidence of 0.8 per 100,000 people.[12][13] PCA most often presents in the second decade of life, with 75% occurring before the age of 20 years.[14] PCA accounts for 15% of all brain tumors in children and comprises 27 to 40% of all pediatric posterior fossa tumors.[15][16] They can occur in adults, though typically in young adults.[17] PCA in adults comprises 5% of all primary brain tumors, still often located in the cerebellar but one case series found them most commonly in the temporal and parietal lobes.[18]

Pathophysiology

PCA tends to occur close to the midline, although, in an adult, it can be more lateral within the cerebellum. PCAs can occur anywhere within the neuroaxis:[16]

• Cerebellum - 42% to 60%
• Optic gliomas & hypothalamic gliomas - 9% to 30% The most common site for PCA related to NF1[5]
• Brainstem - 9%[5][19]
• Spinal cord - 2%
• Cerebral hemispheres (young adults)

Histopathology

PCA is a WHO grade I tumor. There are case series of anaplastic PCA, with uncertain behavior.[20] 

Microscopic features

PCA gets its name from the microscopic appearance of cells with long, thin bipolar processes that resemble hairs (hence pilocytic).[5] There are often Rosenthal fibers, which are elongated eosinophilic bundles that are found on hematoxylin and eosin staining. PCAs have low to moderate cellularity. Multinucleated giant cells with peripheral nuclei can be seen. Tumors that have been present for a more extended period may have hemosiderin-laden macrophages and calcifications.[21] Areas of necrosis may be seen, though exceedingly rare.

Though they are radiologically described as well-circumscribed, nearly two-thirds infiltrate the surrounding brain parenchyma.[22][23] Histological architecture shows that PCA frequently breaks through the pia and breach into the subarachnoid space. They can infiltrate the perivascular spaces. 

Microscopically, it can be challenging to differentiate between PCA and low-grade diffuse astrocytoma.[2] For this reason, the pathology team needs to have demographic and radiographic information available to guide diagnosis. Small biopsy samples also compound this diagnostic issue.

Molecular features

The most common genetic abnormality found in 70% to 75% of PCAs is BRAF gene alterations.[6] BRAF alterations are more common in pediatric PCA than in adult PCA.[24] PCAs have alterations in the MAPK signaling pathway in more than 80% of the cases.[5][7][25] KIAA1549-BRAF fusion is the most common identified mutation in PCA.[8][24] Immunohistochemistry shows positivity for glial fibrillary acidic protein, S100 protein, and oligodendrocyte transcription factor. Importantly, as with other pediatric low-grade gliomas, they are negative for isocitrate dehydrogenase (IDH) and tumor protein p53 (TP53) mutations.[2][15]

History and Physical

PCA can present with symptoms secondary to the posterior fossa mass effect. This may include obstructive hydrocephalus, with resultant headache, nausea and vomiting, and papilledema. If hydrocephalus occurs before the fusion of the cranial sutures (<18-months-of-age), then an increase in head circumference will likely occur.[26] 

Lesions of the cerebellar hemisphere result in peripheral ataxia, dysmetria, intention tremor, nystagmus, and dysarthria. In contrast, lesions of the vermis cause a broad-based gate, truncal ataxia, and titubation. Posterior fossa lesions can also cause cranial nerve palsies. Diplopia may occur due to abducens palsy from the stretching of the nerve. They may also have blurred vision due to papilledema. Seizures are rare with posterior fossa lesions.[26]

Evaluation

The investigation of choice is brain magnetic resonance imaging (MRI) with contrast. This also avoids radiation exposure. However, if the child is neurologically unstable, an urgent head computed tomographic (CT) scan with contrast is indicated. In clinical practice children with posterior fossa tumours tend to get whole neuroaxis imaging as more malignant tumour types can form drop-metastasis. PCAs do not form drop-metastasis like ependymoma and medulloblastoma and theoretically would not require whole neuroaxis imaging. It is important to note, that the variant pilomyxoid astrocytoma is more agressive and can form drop-metastasis. Spinal seeding or leptomeningeal dissemination is extremely rare in PCA; therefore, it is only recommended in suspected or uncertain cases.[27][28][29][30]

PCA can have multiple radiological appearances. In 66%, there is a significant cystic component with an avidly enhancing mural nodule, while in 46%, the cyst wall also enhances.[31] In up to 17% of the cases, the tumor is solid with minimal or no cystic component.[22] Up to 20% may show calcification. PCA is periventricular in 82% of cases.[22] The cyst content is proteinaceous and thus is often denser than the cerebrospinal fluid (CSF).[32] On MRI, the mural nodule is hyperintense on the T2 image and iso or hypointense on the T1 image. The cyst content shows a high signal on the T2 image, similar to the CSF. As described above the nodule is avidly enhancing, which is used to differentiate from low-grade gliomas.

Treatment / Management

Management of the Tumor

The mainstay of treatment is surgical excision with the aim of complete resection margins while achieving minimal neurological injury. Complete resection is considered curative for the disease. However, the involvement of the brainstem or cranial nerves may prevent complete resection. Resection of only the nodule and not the cyst wall is recommended.[31] However, tumors with a thick cyst wall, can be considered part of the nodule and thus removed.[31] 

Conventional radiotherapy is not required; instead, follow up with serial imaging is more appropriate. Radiotherapy, particularly in this region of the brain, carries significant sequelae.[33] If there is a recurrence, further surgical resection is typically adopted. Radiotherapy may be appropriate if surgically unresectable or if malignant histology is present.[34] In some studies stereotactic radiosurgery (SRS) gave excellent results for residual and recurrent tumors. Although, there has been critiscism regarding duration of follow up in these studeis. There is some concern that SRS may encourage anaplastic transformation. [35]

Management of Hydrocephalus

Approaches for Neurologically Well Patients

1. CSF diversion at the time of surgery, followed by immediate tumor resection
2. Surgical resection without CSF diversion. If hydrocephalus persists postoperatively, then perform CSF diversion
3. CSF diversion around two weeks before definitive surgery

If the patient is neurologically unstable due to hydrocephalus or brainstem compression, then urgent intervention is warranted. If the presentation is with hydrocephalus, some authors advocate initial CSF diversion before definitive surgery using an external ventricular drain (EVD), endoscopic third ventriculostomy (ETV), or ventricular-peritoneal shunt (VPS). Some centers will place an EVD or perform an ETV at the time of surgery, followed by immediate definitive tumor resection. However, some advocate that CSF diversion should be around two weeks before resection.[36] 

Disapproval for this approach is that placing a VPS generally commits patients to lifelong shunting and complications. Also, tumor seeding may occur into the peritoneum, although this is rare and can be mitigated by the placement of a tumor filter on the shunt system.[37] Surgical factors to consider with CSF diversion include possible upwards transtentorial herniation and CSF infection due to VPS or EVD contamination. Some criticize that this method causes unnecessary delays to definitive treatment.

Differential Diagnosis

Most Common Pediatric Posterior Fossa Tumors[26][38]

• Medulloblastoma (typically midline, roof of fourth, vermian, <10% have calcification)
• Diffuse pontine glioma (usually multiple cranial nerve palsies)
• Ependymoma (usually arise in the floor of the fourth ventricle, calcification common) 

Other Pediatric Posterior Fossa Lesions (clinical and radiological differentials)

• Hemangioblastoma 
• Atypical teratoid/rhabdoid tumor
• Cerebellar abscess
• Choroid plexus papilloma
• Metastasis: neuroblastoma, rhabdomyosarcoma, Wilm’s tumor

Adults Posterior Fossa Tumors (clinical and radiological differentials)

• Metastasis (by far the most common)[39]
• Hemangioblastoma (7 to 12% of all posterior fossa lesions in adults, vascular, often cystic)[40]
• Brainstem glioma
• Abscess
• Cavernous malformation
• Ischemic stroke
• Cerebellar hemorrhage

Prognosis

PCA is a slow-growing tumor that is often curative on resection. The best prognostic factor is total resection. The survival rate at 10-years is approximately 95% if completely resected.[13][41] Recurrence is rare if complete resection is achieved. Those that do recur tend to do so within a few years.[42] Collins' law states that "the period of risk for tumor recurrence is the age of the child at diagnosis plus nine months".[43] Using this concept, PCA can be considered cured if it does not reoccur within that time. However, there are documented cases of late recurrence.

If there is incomplete resection, recurrence may occur with progression of symptoms. Risk factors for recurrence have been identified, including solid tumor, exophytic component, and tumor invasion.[44]  For PCA in adults, the survival at 5-years is 85%, and progression-free is 70%.[45] Tumor recurrence in adult cases is approximately 20%.[45]

Patients younger than one year have the worst prognosis.[13] However, this is possibly due to the variant pilomyxoid astrocytoma which most commoonly occur in the very young.

For completely removed tumors, a maximum of three-year surveillance imaging is recommended due to the minimal risk of recurrence in pediatric PCA.[46]

Complications

Patients with posterior fossa tumors may develop hydrocephalus requiring a VP-shunt. If so, they will likely be shunt-dependant for life.[36][47] Though recurrence is usually amenable to further resection, some PCAs show malignant degeneration, though this is rare. Most of the cases with malignant degeneration seem to follow radiotherapy.[48][49]

Deterrence and Patient Education

There are no modifiable risk factors for PCA. Some genetic conditions such as NF1 predispose families to PCA, and therefore, genetic testing and counseling may be appropriate. However, most PCAs are due to sporadic mutations.[3][4]

Pearls and Other Issues

• PCA is the most common pediatric brain tumor
• Classified by the WHO as low-grade, grade I
• MRI: Typically cystic with avidly enhancing mural nodule; although can be completely solid
• Microscopy: long, bipolar cellular processes that look "hair-like"
• Excellent prognosis with complete surgical resection; radiotherapy and chemotherapy not routinely used
• 95% 10-year survival with surgery alone if complete resection
• Strong association with NF1, 5% to 20% of patients with NF1 develop PCA mostly in the visual pathway
• Presentation typically with cerebellar signs and features of hydrocephalus
• Patients may require CSF diversion

Enhancing Healthcare Team Outcomes

PCA is the most common pediatric brain tumor and requires urgent assessment and management, though should be considered a chronic disease. These patients will initially present to pediatricians, emergency clinicians, or general practitioners. Therefore, these clinicians must recognize signs and symptoms of masses affecting the cerebellum or brainstem, including the clinical presentation of hydrocephalus.

An interprofessional team will be involved in decision making, which will include neurosurgeons, oncologists, radiologists, neurologists, and primary clinicians. Perioperatively, the team will consist of: neurosurgeons, anesthetists, intensivists, primary clinicians, and nursing teams. During the postoperative and rehabilitation period, physiotherapists will help the patient with activities of daily living.