This case was originally published in 2017. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.
Clinical History
A 21-year-old man with no significant past medical history presented to his primary care doctor with a complaint of severe headaches, balance problems, dizziness, and nausea over the past several months. An MRI showed a 5 x 3 x 3 cm enhancing heterogeneous mass centered in the superior cerebellar vermis and extending into the cerebellar hemispheres with mild local mass effect. The lesion was hyperintense on T2- and FLAIR-sequences. A small cystic component was also noted. A surgical resection was performed.
Tissue Site
Cerebellum
Whole Slide Image
The whole slide image provided is an H&E stain from a brain resection.
Questions
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Which of the following histopathological feature is associated with the CORRECT diagnosis?
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Eosinophilic granular bodies and Rosenthal fibers
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High mitotic count and proliferative index
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Marked pleomorphism of tumor cells
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Palisading necrosis
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Verocay bodies
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Which of the following is TRUE regarding pilocytic astrocytoma?
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Can be WHO grade I, II, or III depending on histologic features
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Occur primarily in infants and children, but can be seen in adults
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Predominantly found in the spinal cord
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Usually exhibit an aggressive, diffusely infiltrating pattern of growth
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Usually recur as high-grade astrocytomas after gross total resection
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Which of the following is a genetic/molecular feature of this diagnosis?
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BRAFV600E mutation is the most common sporadic molecular change in this disease.
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Cytogenetic and comparative genomic hybridization studies usually show no large chromosomal alterations in this neoplasm.
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KIAA1549-BRAF gene fusion causes an inactivation of the BRAF kinase activity.
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Patients with neurofibromatosis type 2 (NF2) often have these neoplasms.
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The KIAA1549-BRAF gene fusion is a rarely found molecular alteration in this neoplasm.
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Discussion and Diagnosis
Pilocytic astrocytoma (PA) is the most common CNS neoplasm in the pediatric population. PAs most often occur in patients under 14 years old but can be found in young adults and rarely in older adults. A WHO grade I neoplasm with non-infiltrating growth, PA is most often encountered in the posterior fossa growing in the cerebellar vermis or hemispheres, usually with a cystic component and a solid mural nodule. However, PAs can be found anywhere in the CNS - including brainstem and spinal cord. In infants, the optic pathway/hypothalamic region is a prevalent site.
Clinical and radiographic correlation is helpful in developing the differential diagnosis in pediatric CNS neoplasms, and this is especially true for the pathologist providing intraoperative consultation. Establishing an intraoperative diagnosis of PA is important, as the surgeon so informed will likely attempt a complete resection which will usually be curative. Radiographically, these tumors are often well-circumscribed masses with the solid component often isointense or hypointense to gray matter on T1-weighted images and hyperintense on T2-weighted images. However, PAs can have variable appearance and are challenging to interpret on MRI. Seventy percent of optic pathway/hypothalamic gliomas occur in patients with neurofibromatosis type 1 (NF1) - and the majority of these are PAs.
PAs can display variable histopathological features. While often described with a cystic component when occurring in the posterior fossa, a true cyst wall is not seen on histology. The solid component shows variable cellularity often with a biphasic pattern of loose, microcystic areas and more dense areas of elongated astrocytic cells exhibiting long bipolar or unipolar piloid processes (Image A). Rosenthal fibers and eosinophilic granular bodies (Image B) are often seen and greatly assist with establishing the diagnosis, but are not required elements. Some nuclear pleomorphism, rare mitotic activity, necrosis, and endothelial proliferation can be seen, but these features, in the setting of a PA, do not warrant a higher WHO grade. Immunohistochemistry shows the tumor cells to be strongly positive for GFAP (Image C) and exhibit a low Ki-67/MIB1 proliferation index (Image D). Rarely will PAs recur and transform into more aggressive anaplastic astrocytomas. Another histologic pattern of PA found primarily in the hypothalamic region is known as pilomyxoid astrocytoma (PMA). The current WHO classification (2016) recognized PMA as a variant of PA with an uncertain grade.
Molecular characterization of PAs has yielded information about its pathogenesis and is becoming increasingly important for diagnosis. The first genetic association seen in PAs was with mutations in the NF1 gene, inactivating the protein product neurofibromin and leading to increased activation of the RAS/RAF/MEK/MAPK and the PI3K/AKT pathways. Cytogenetic and comparative genomic hybridization studies have also disclosed changes in the BRAF gene. The most common sporadic molecular change is a 1.9-mb gain at chromosome 7q34 that causes tandem duplication and a fusion between the KIAA1549 and BRAF genes. The FISH image provided (Image E) demonstrates two red signals on one copy of chromosome 7, indicating gain of the 3' end BRAF, which usually results in a KIAA1549-BRAF fusion. This fusion event leads to a deletion of the amino-terminal domain of BRAF and activation of its kinase activity. Other changes that have been reported less commonly in PAs are additional BRAF fusion products, rare BRAFV600E mutations, BRAF insertions, and KRAS mutations, among others. The frequency of each genetic abnormality varies depending on the location of the tumor. The KIAA1549-BRAF fusion is present in most posterior fossa PAs, a minority of hypothalamic PAs, and only occasionally in hemispheric examples. Optic gliomas outside of the context of NF1 have a high rate of the KIAA1549-BRAF fusion. BRAFV600E mutations have been identified in hemispheric PAs.
Pilocytic astrocytoma, WHO grade I
Take Home Points
- Pilocytic astrocytoma (PA) is a common pediatric CNS neoplasm that can occur in any location, is usually well-circumscribed, shows indolent growth, and recurs infrequently if adequately resected.
- Alterations in the MAPK pathway are found in most PAs, usually involving the BRAF or NF1 genes.
- The KIAA1549-BRAF fusion is present in the vast majority of cerebellar PAs, and less often in those located elsewhere.
- Optic pathway PAs are common in the clinical setting of Neurofibromatosis type 1.
References
- Louis DN, Ohgaki H, Wiestler OD, et al. WHO Classification of Tumours of the Central Nervous System. Revised 4th ed. Lyon: IARC; 2016.
- Reiss GF, Tihan R. Practical Molecular Pathologic Diagnosis of Pilocytic Astrocytomas. Surgl Pathol Clin. 2015;8:63-71.
- Waanders, AJ, Minturn, JE, Fisher, MJ. Pediatric low-grade gliomas: diagnosis, treatment, and future directions. In Hayat MA ed. Tumors of the Central Nervous System. Volume 14: Springer; 2015: 13-24.
Answer Key
- Which of the following histopathological feature is associated with the CORRECT diagnosis?
- A. Eosinophilic granular bodies and Rosenthal fibers
- B. High mitotic count and proliferative index
- C. Marked pleomorphism of tumor cells
- D. Palisading necrosis
- E. Verocay bodies
- Which of the following is TRUE regarding pilocytic astrocytoma?
- A. Can be WHO grade I, II, or III depending on histologic features
- B. Occur primarily in infants and children, but can be seen in adults
- C. Predominantly found in the spinal cord
- D. Usually exhibit an aggressive, diffusely infiltrating pattern of growth
- E. Usually recur as high-grade astrocytomas after gross total resection
- Which of the following is a genetic/molecular feature of this diagnosis?
- A. BRAFV600E mutation is the most common sporadic molecular change in this disease.
- B. Cytogenetic and comparative genomic hybridization studies usually show no large chromosomal alterations in this neoplasm.
- C. KIAA1549-BRAF gene fusion causes an inactivation of the BRAF kinase activity.
- D. Patients with neurofibromatosis type 2 (NF2) often have these neoplasms.
- E. The KIAA1549-BRAF gene fusion is a rarely found molecular alteration in this neoplasm.