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Pilocytic Astrocytoma
Introduction
Pilocytic astrocytoma, previously referred to as cystic cerebellar astrocytoma or juvenile pilocytic astrocytoma, was first described in 1931 by Harvey Cushing based on a case series of cerebellar astrocytomas.[1] Pilocytic astrocytomas are low-grade, usually benign, slow-growing, well-circumscribed brain tumors that tend to occur in the pediatric population and also young adults. This condition arises from astrocytes—the star-shaped cells that support nerve cells in the brain. According to the World Health Organization (WHO) classification of central nervous system (CNS) tumors, pilocytic astrocytomas are grade I gliomas with a generally good prognosis.[2]
While pilocytic astrocytomas most often occur in the cerebellum, they can also be found along the optic pathways, hypothalamus, and brainstem. These tumors may also occur in the cerebral hemispheres, though this is more common in young adults. The presentation and treatments for pilocytic astrocytomas vary based on their location; however, this article will focus on cerebellar pilocytic astrocytomas. According to the new 2021 WHO classification of CNS tumors, pilocytic astrocytomas are grouped with other circumscribed astrocytic gliomas, such as pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, and choroid gliomas.[2]
Etiology
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Etiology
A strong association exists between neurofibromatosis type 1 (NF1) and pilocytic astrocytomas; up to 20% of patients with NF1 develop a pilocytic astrocytoma, most commonly along the optic pathway.[3][4] However, most pilocytic astrocytomas are believed to be caused by sporadic rather than inherited mutations.
BRAF gene alterations and mitogen-activated protein kinase (MAPK) signaling pathway alterations have been found in the majority of pilocytic astrocytomas.[5][6][7] Roughly 60% of pilocytic astrocytomas found within the cerebellum harbor the KIAA1549-BRAF gene fusion.[8][9] BRAF is an intracellular serine/threonine kinase involved in activating the MAPK pathway.[10] This is a proto-oncogene, mutations of which have been found to cause human cancers.[11][12] Other mutations frequently seen in pilocytic astrocytomas include BRAFV600E point mutations found in 5% to 10% of all cases, although more prevalent in supratentorial tumors.[2]
Epidemiology
Brain tumors are the most prevalent form of solid cancer in childhood.[13] Pilocytic astrocytoma is the most common childhood brain tumor, with an incidence of 0.8 per 100,000 individuals.[14][15] Pilocytic astrocytoma most often presents in the second decade of life, with 75% occurring before the age of 20, and accounts for 15% of all brain tumors in children.[16] This condition comprises 27% to 40% of all pediatric posterior fossa tumors.[17][18]
Pilocytic astrocytoma can also occur in adults, although typically in young adults.[19] This condition comprises 5% of all primary brain tumors in adults and is often located in the cerebellum. However, a case series found them most commonly in the temporal and parietal lobes.[20]
Pathophysiology
Pilocytic astrocytoma can be located anywhere within the neuroaxis and tends to occur close to the midline. In adults, the tumor can be more lateral within the cerebellum.[18] More common locations of pilocytic astrocytoma include:
Histopathology
Pilocytic astrocytoma is a WHO grade I tumor, with a small case series of anaplastic pilocytic astrocytoma displaying uncertain behavior.[22] The tumor's distinct histological features, including its characteristic cell morphology and patterns, provide key insights into its behavior and classification.
Microscopic Features
Pilocytic astrocytoma gets its name from the microscopic appearance of cells with long, thin bipolar processes that resemble hairs, hence the term "pilocytic."[5] Rosenthal fibers, which are elongated eosinophilic bundles, are often found on hematoxylin and eosin (H&E) staining (see Image. Microscopic Features of Pilocytic Astrocytoma). Another pathological characteristic is the presence of eosinophilic granular bodies. Pilocytic astrocytomas typically exhibit low-to-moderate cellularity, and multinucleated giant cells with peripheral nuclei can be observed. Tumors present for an extended period may have hemosiderin-laden macrophages and calcifications.[23] Areas of necrosis may also be seen, albeit rarely. Although pilocytic astrocytomas are radiologically described as well-circumscribed, nearly two-thirds infiltrate the surrounding brain parenchyma.[24][25]
Microscopically, differentiating between pilocytic astrocytoma and low-grade diffuse astrocytoma can be challenging.[26] For this reason, the pathology team should have access to demographic and radiographic information to help guide the diagnosis. Small biopsy samples further compound this diagnostic issue. Pilocytic astrocytomas stain positive for glial fibrillary acidic protein (GFAP), S100, and OLIG2 while being negative for neurofilament, chromogranin, and CD34.[27]
Molecular Features
The most common genetic abnormalities found in 70% to 75% of patients with pilocytic astrocytomas are BRAF alterations.[6] BRAF alterations are more common in pediatric pilocytic astrocytoma than in adult cases.[28] Pilocytic astrocytomas exhibit alterations in the MAPK signaling pathway in more than 80% of cases.[5][7][29] The KIAA1549-BRAF fusion is the most commonly identified mutation in individuals with pilocytic astrocytoma.[10][28] Importantly, as with other pediatric low-grade gliomas, these tumors are negative for IDH (isocitrate dehydrogenase) and TP53 mutations.[26][17]
History and Physical
In patients with pilocytic astrocytoma, findings from the history and physical examinations often reflect the tumor's location and growth pattern. Symptoms typically develop gradually. Patients with pilocytic astrocytomas can present symptoms secondary to a posterior fossa mass effect. This may include obstructive hydrocephalus with resultant headache, nausea, vomiting, and papilledema. Seizures are rare in cases of posterior fossa lesions.[30] If hydrocephalus occurs before the fusion of the cranial sutures, typically before 18 months of age, an increase in head circumference and splaying of cranial sutures will likely occur.[30]
Posterior fossa lesions can also cause cranial nerve palsies. Diplopia may occur due to abducens nerve palsy resulting from nerve stretching. Patients may also have blurred vision due to papilledema. Lesions of the cerebellar hemisphere result in peripheral ataxia, dysmetria, intention tremor, nystagmus, and dysarthria.
In contrast, lesions of the vermis can cause a broad-based gait, truncal ataxia, and titubation. Lesions involving the hypothalamus may result in hormonal imbalances or growth issues. Physical examination often reveals signs of increased intracranial pressure and cerebellar dysfunction. Focal neurological deficits depend on the tumor's specific location and its impact on surrounding structures.
Evaluation
The imaging modality of choice is brain magnetic resonance imaging (MRI) with and without contrast (see Image. MRI of the Brain Showing Pilocytic Astrocytoma). Radiation exposure is minimized, which is crucial for patients with NF1. However, if the patient is neurologically unstable, an urgent head computed tomography (CT) scan may be necessary.
In clinical practice, children with posterior fossa tumors often undergo whole neuroaxis imaging, as more malignant tumors can form drop metastases. Pilocytic astrocytomas typically do not form drop metastases, such as ependymomas and medulloblastomas, and thus may not require whole neuroaxis imaging. However, the variant pilomyxoid astrocytoma is more aggressive and can form drop metastases. While spinal seeding or leptomeningeal dissemination is extremely rare in pilocytic astrocytomas, whole neuroaxis imaging is recommended only in suspected or uncertain cases.[31][32][33][34]
Pilocytic astrocytomas can exhibit various radiological appearances. In 66% of cases, pilocytic astrocytoma presents with a significant cystic component and an avidly enhancing mural nodule; in 46% of cases, the cyst wall also shows enhancement.[35] Up to 17% of tumors are solid with minimal or no cystic component, and up to 20% may show calcification.[24] In addition, pilocytic astrocytomas are periventricular in 82% of cases.[24]
The cyst content in pilocytic astrocytomas is proteinaceous and often denser than cerebrospinal fluid (CSF).[36] On MRI, the cyst content typically shows a hyperintense signal on T2-weighted images, similar to CSF. The mural nodule is usually hyperintense on T2-weighted images and iso- or hypointense on T1-weighted images. As described above, the nodule’s avid enhancement helps differentiate it from other low-grade gliomas.
Treatment / Management
The mainstay of treatment is surgical excision to achieve gross total resection, as this can be considered curative for the disease. However, involvement of the brainstem or cranial nerves may limit complete resection. Resection of the mural nodule rather than the cyst wall is recommended.[35] However, if the cyst wall is thick, it may be considered part of the nodule and thus removed.[35](B3)
Conventional chemoradiation is not typically required upfront; clinical follow-up with serial imaging is preferred. Radiotherapy, especially in this brain region, can have significant adverse effects.[37] If recurrence occurs, additional surgical resection is generally considered if feasible. Radiotherapy may be appropriate if the tumor is unresectable or if malignant histology is present.[38]
Some studies have shown that stereotactic radiosurgery yields excellent results for residual and recurrent tumors, although there is criticism about the duration of patient follow-up. Concerns exist that stereotactic radiosurgery might promote anaplastic transformation.[39] As mentioned previously, radiation is typically avoided in patients with NF1 unless necessary, as these patients are predisposed to further tumor development.
Chemotherapy is generally not used as a first-line treatment for pilocytic astrocytoma; however, several trials have reported 5-year progression-free survival rates between 34% and 45%.[40][41] Given the propensity for these tumors to harbor mutations that affect the MAPK signaling pathway, BRAF- and MEK inhibitors have been studied, with variable response rates.[42][43]
Several approaches are available for managing hydrocephalus in neurologically stable patients. These approaches include:
- CSF diversion at the time of surgery, followed by immediate tumor resection.
- Surgical resection without CSF diversion. If hydrocephalus persists postoperatively, then CSF diversion is performed.
- CSF diversion before imaging studies if patients require anesthesia.
If the patient is neurologically unstable due to hydrocephalus or brainstem compression, urgent intervention is necessary. For patients presenting with hydrocephalus, some experts recommend initial CSF diversion before definitive surgery, using methods such as an external ventricular drain (EVD), endoscopic third ventriculostomy (ETV), or a ventricular-peritoneal shunt (VPS). In certain medical centers, an EVD or ETV may be performed concurrently with surgery, followed by immediate tumor resection. Surgical considerations with CSF diversion include the risk of upward transtentorial herniation and CSF infection from VPS or EVD contamination.
Differential Diagnosis
The differential diagnosis of pilocytic astrocytomas involves distinguishing them from other brain tumors and lesions with similar clinical and radiological features. Accurate diagnosis and appropriate treatment planning depend on identifying key differences. This process includes evaluating imaging characteristics, patient demographics, and histopathological findings to differentiate pilocytic astrocytomas from other low-grade gliomas, high-grade gliomas, and non-neoplastic conditions.
Most Common Pediatric Posterior Fossa Tumors
- Medulloblastoma: Typically located midline, at the roof of the fourth ventricle, or in the vermis of the brain, less than 10% demonstrate calcification.
- Diffuse pontine glioma: Often presents with multiple cranial nerve palsies.
- Ependymoma: Usually arises in the floor of the fourth ventricle; calcification is common.[30][44]
Additional Pediatric Posterior Fossa Lesions: Clinical and Radiological Differentials
- Hemangioblastoma.
- Atypical teratoid or rhabdoid tumor.
- Cerebellar abscess.
- Choroid plexus papilloma.
- Metastasis, which includes neuroblastoma, rhabdomyosarcoma, Wilms tumor.
Adult Posterior Fossa Tumors: Clinical and Radiological Differentials
Prognosis
Pilocytic astrocytoma is a slow-growing tumor that is often curative with gross total resection. Similar to many tumors, the extent of resection is the best prognostic factor. The 10-year survival rate is approximately 95% if the tumor is completely resected.[15][47] Recurrence is rare if a complete resection is achieved.
Tumors that do recur tend to do so within a few years.[48] Collins' law states that "the period of risk for tumor recurrence is the age of the child at diagnosis plus 9 months."[49] Using this concept, pilocytic astrocytoma can be considered cured if it does not recur within that time. However, patients should be monitored for late recurrence. For tumors with gross total resection, some authors recommend a maximum of 3 years of surveillance imaging due to the minimal risk of recurrence in pediatric pilocytic astrocytoma.[50] If there is incomplete resection, recurrence may occur with progression of symptoms. Several risk factors for recurrence have been identified, including a solid tumor, exophytic component, and tumor invasion into the brain parenchyma.[51]
Patients aged 1 or younger generally have the worst prognosis, potentially due to the variant pilomyxoid astrocytoma, which is more common in very young children.[15] In adults, pilocytic astrocytoma has a 5-year survival rate of 85%, with progression-free survival at 70% and a recurrence rate of approximately 20%.[52]
Complications
Patients with pilocytic astrocytoma may experience complications, especially if the tumor is not promptly and effectively treated. Hydrocephalus is common due to obstruction of CSF pathways, leading to increased intracranial pressure. Patients with posterior fossa tumors may develop hydrocephalus and require a VP shunt, potentially making them shunt-dependent for life.[53][54]
Neurological deficits can arise from tumor growth affecting critical brain regions, leading to motor, sensory, or cognitive impairments. Postsurgical complications may include infection, bleeding, or damage to surrounding brain tissue, which can exacerbate neurological issues. Additionally, the risk of tumor recurrence necessitates ongoing monitoring and potential further treatment.
In some cases, radiation or chemotherapy used in treatment can lead to long-term adverse effects, impacting the patient’s quality of life. While recurrence is usually treatable with further resection, some pilocytic astrocytomas can undergo malignant degeneration, although this is rare. Most cases of malignant degeneration seem to follow radiotherapy.[55][56]
Consultations
Patients with pilocytic astrocytoma require consultations with a range of specialists to ensure comprehensive care. Neurosurgical consultation is essential for evaluating the need for surgical resection and planning the procedure. Neuro-oncologists and radiation oncologists may be consulted for adjuvant therapies if complete surgical removal is not feasible. Endocrinologists are often involved if the tumor affects the hypothalamus or other hormone-regulating structures. Ophthalmologists are critical to monitor and manage vision-related issues caused by tumors affecting the optic pathways.
Additionally, consultations with physical therapists, occupational therapists, and rehabilitation specialists are crucial for addressing functional impairments and facilitating recovery. Psychologists or social workers should also be involved to provide emotional support and address the psychosocial aspects of the patient's condition. This multidisciplinary approach ensures that all aspects of the patient's health are addressed, optimizing outcomes and quality of life.
Deterrence and Patient Education
Modifiable risk factors for pilocytic astrocytoma have not been identified. Genetic conditions, such as NF1, predispose families to pilocytic astrocytoma, thereby making genetic testing and counseling potentially appropriate. However, most pilocytic astrocytomas are due to sporadic mutations.[3][4]
Educating patients and their families about the importance of early detection and prompt treatment is crucial for improving outcomes. Regular follow-up appointments are essential for monitoring recurrence and managing the long-term effects of the tumor or its treatment. Patients should be informed about symptoms of increased intracranial pressure and other neurological changes to prompt timely medical consultation when they arise. Providing information on healthy lifestyle choices, supportive therapies, and available resources can further assist patients and families in navigating the challenges associated with pilocytic astrocytoma, thereby enhancing their overall quality of life.
Pearls and Other Issues
Clinicians can benefit from practical insights that enhance patient care when managing pilocytic astrocytoma. These clinical pearls provide valuable guidance on diagnostic approaches, treatment strategies, and patient care. Key clinical pearls to consider include:
- Pilocytic astrocytoma is the most common pediatric brain tumor and is classified as WHO grade 1 glioma.
- Prompt recognition of symptoms such as headaches, ataxia, and visual disturbances can lead to early diagnosis and better outcomes.
- Presentation typically includes cerebellar signs and features of hydrocephalus.
- MRI is the preferred imaging modality for diagnosing pilocytic astrocytoma, providing detailed information on tumor location and characteristics.
- MRI findings are typically cystic with a mural nodule that enhances avidly, although the tumor can also be completely solid.
- Microscopy shows long, bipolar cellular processes that appear "hair-like."
- Gross total resection typically results in an excellent prognosis; radiotherapy and chemotherapy are not routinely used.
- The survival rate is 95% at 10 years with surgery alone if complete resection is achieved.
- Regular monitoring through follow-up imaging is crucial for early detection of potential tumor recurrence.
- A strong association with NF1 exists; 5% to 20% of patients with NF1 develop pilocytic astrocytoma, mostly along the optic pathways.
- Patients may require CSF diversion.
Enhancing Healthcare Team Outcomes
Pilocytic astrocytoma is the most common pediatric brain tumor and necessitates urgent assessment and intervention, while also being managed as a chronic condition. These patients will initially present to pediatricians, emergency room clinicians, or general practitioners. Clinicians must recognize the signs and symptoms of masses affecting the cerebellum or brainstem, including the clinical presentation of hydrocephalus.
Enhancing patient-centered care, outcomes, patient safety, and team performance in the treatment of patients with pilocytic astrocytoma requires a collaborative, interprofessional approach involving various healthcare professionals. Physicians, advanced practitioners, nurses, pharmacists, and other healthcare professionals must possess specialized skills in their respective fields. Physicians and advanced practitioners should be adept at diagnosing and formulating treatment plans, utilizing advanced imaging techniques, and performing surgical interventions when necessary. Nurses require skills for monitoring for complications and providing patient care and emotional support. Pharmacists must be knowledgeable about chemotherapy regimens and potential drug interactions.
Rehabilitation of patients with pilocytic astrocytoma is crucial to address functional impairments and facilitate recovery. Physical therapists focus on improving motor skills and balance, while occupational therapists help patients regain daily living activities and independence. Social workers and counselors address psychosocial aspects and provide support services.
A well-coordinated strategy involves comprehensive treatment planning, where each healthcare team member understands their role and the overall care plan. This includes preoperative assessment, surgical planning, postoperative care, and long-term follow-up. Utilizing clinical guidelines and evidence-based practices ensures the treatment is standardized and effective.
Clear and timely communication between healthcare providers about patient status, treatment progress, and any emerging issues is essential. Regular interdisciplinary meetings and case conferences help ensure everyone is aligned with the treatment plan and any changes. Coordinated care involves seamless transitions between different phases of treatment and care settings, including preoperative care, inpatient surgical care, and postoperative rehabilitation and follow-up. Additionally, care coordination ensures patients receive appropriate referrals to specialists, such as oncologists or endocrinologists, when necessary.
Media
(Click Image to Enlarge)
Microscopic Features of Pilocytic Astrocytoma. Hair-like cell processes can be observed with H&E staining.
Nephron, Public Domain, via Wikimedia Commons
(Click Image to Enlarge)
MRI of the Brain Showing Pilocytic Astrocytoma.
Contributed by S Lange, MD
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