Neuro-Ophthalmologic Manifestations of Pilomyxoid Astrocytoma (PMA)
PMA should be considered in the differential diagnosis of hypothalamic/chiasmal glioma. Cases previously labeled as JPA may be reclassified PMA after histopathology examination and impact treatment and prognosis. PMA is a more aggressive tumor associated with shorter progression-free survival and overall survival compared with JPA. Patients with hypothalamic PMA typically present with DS but develop ophthalmological findings (e.g., optic neuropathy) as the disease progresses. Continued research shows promising results for molecularly targeted therapy compared to conventional chemotherapy or radiation therapy.
Pilomyxoid astrocytoma (PMA) is a rare, aggressive variant of pilocytic astrocytoma (PA) that predominantly occurs in the hypothalamic chiasmatic region and is associated with shorter progression-free-survival and overall survival than PA. Clinicians should be aware of the neuro-ophthalmic presentations of PMA and the differences between PMA and typical juvenile pilocytic astrocytoma (JPA).
JPA is the most common type of glioma in children and adolescents, accounting for approximately 15.6% of all brain tumors and 5.4% of all gliomas. JPA is a relatively benign lesion histopathologically (World Health Organization (WHO) grade I tumor) and clinically with a 90% 10-year survival rate. In the United States, the annual incidence of PAs is approximately 0.35 - 0.37 per 100 persons. The highest incidence is found in children 0-9 years old and decreases with advancing age. Ophthalmologists encounter JPA in gliomas of the optic pathway and hypothalamus.
PMA was introduced in 1999 and was recognized as a grade II tumor by the WHO in 2007. In 2016 the WHO changed the grading of PMA after studies showed histological and genetic similarities between PMA and JPA. Therefore, the current grading of PMA by the WHO continues to evolve.
PMA accounts for only 2.2% of all astrocytomas, but the true prevalence may be underestimated. A retrospective report estimated that 10% of previously labeled PA were actually PMA after histopathology examination. Among the major differences between JPA and PMA is the age of patients and outcomes. PMA tends to affect infants and younger children, with a median age of 10 - 18 months. Although PMA is predominantly found in younger children, cases have been reported in adults as well. PMA has been noted to have a less favorable prognosis and patients are more likely to experience local recurrences and cerebrospinal spread than patients with PA.
PAs can occur in neurofibromatosis type 1 (NF1), and PMAs have also been reported with NF1. PA is the most common glioma in patients found with NF1. The NF1 gene encodes for neurofibromin, which negatively regulates the RAS protein in the mitogen-activated protein kinase (MAPK) pathway. The MAPK pathway mediates cell growth, survival, and differentiation. The loss of the NF1 protein results in increased cell proliferation pathways and decreases cell differentiation through the MAPK pathway or the activation of the mammalian target of rapamycin (mTOR) pathway.
Non-NF1-associated PA and PMA may be the result of an oncogenic tandem duplication at 7q34 that results in a KIAA1549-BRAF fusion gene with constitutive BRAF kinase activity and MAPK pathway activation. Recent studies using capture-based next generation sequencing (NGS) platforms showed that different areas have different copy number alterations, with PMA having trisomy 11 and diploid for chromosome 5 and 7. Pilocytic component showed focal gains in chromosomes 5 and 7, and diploid for chromosome.
Other gene abnormalities have been found in PA and PMA, including a valine to glutamate substitution at position 600 (BRAF V600E mutation). This mutation has been found in approximately 10% of PA cases. Studies have shown gene expression variations between PA and PMA, most notably the overexpression of the developmental genes H19 and DACT2, extracellular matrix collagen (COL2A1; COL1A1), and IGF2BP3 in PMA. The influence of these variations is unclear. Genetic profiles show strong similarities between PMA and PA but further research is needed to clearly differentiate the two diseases.
Ophthalmologic Symptoms, Signs, and Exam Findings
Due to the location of PMA, predominantly found in the hypothalamic-chiasmatic region, ophthalmological symptoms are typically present. Although this Eyewiki will focus on signs for ophthalmology, other manifestations are common including diencephalic syndrome (DS), endocrine syndromes when present in the hypothalamus, and hydrocephalus when blocking the cerebrospinal fluid (CSF) pathway.
Decreased vision, nystagmus, proptosis, strabismus, extraocular muscle palsies, and internuclear ophthalmoplegia (INO) have been reported in PMA and the presentation is dependent on tumor location. The initial presentation of PMA in the hypothalamus or optic pathway may not manifest with ophthalmologic complaints but typically manifest as the tumor progresses. Patients with NF1 may also have additional eye and skin findings including iris Lisch nodules and café au lait spots. The most common ophthalmic presentation of PMA is visual loss and optic atrophy.
Due to the lack of distinct features that PMA presents upon imaging, a definitive diagnosis of PMA requires a biopsy and histopathological examination. One study estimated that 10% of previously labeled PA were PMA after histopathology examination. Previously diagnosed cases of PA may reveal PMA, therefore re-evaluation should be considered for PA’s that are aggressive and found in the hypothalamic-chiasmatic region.
Radiologically, PMA is typically found in the hypothalamic-chiasmatic region but has been reported throughout the neural axis. PMA is usually isointense on T1-weighted magnetic resonance imaging (MRI) and hyperintense on T2-weighted MRI. Radiologically, PMAs are typically more solid rather than cystic; have more prominent enhancing components on T1 post gadolinium MRI; and are more likely to have leptomeningeal dissemination than PAs.
Management & Treatment Options
Although total surgical resection is the preferred treatment for PMA, it is not usually feasible especially in the hypothalamic and chiasmal region. Subtotal resection along with adjuvant therapy is used for tumors at sites where gross total resection is not viable and provides histopathologic confirmation of PMA and also cytogenetic analysis (e.g, BRAF V600E) that might influence the decision for targeted therapy. An effective standard of therapy has not been determined due to the rarity of PMAs. Typically, patients undergo surgery followed by chemotherapy. Since PMA is predominantly found in children, radiation is not typically utilized due to the adverse effects of radiation on children. Research on molecularly targeted therapies including agents that work against BRAF V600E kinase, have shown promising results and is an area of continued research for treatment of low grade gliomas.
PMA has been found to have a less favorable prognosis and are more likely to experience local recurrences and cerebrospinal spread than patients with JPA. Due to rarity of PMA, the clinical data is limited to a small number of cases. Outcomes are improved for patients who underwent complete surgical excision. Age is also a strong prognostic factor for overall survival with infants and younger children (<3 year) having worse outcomes.
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