This case was originally published in 2019. 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.
The patient is a 69-year-old woman with a history of breast cancer (status post-left partial mastectomy and adjuvant radiation six years prior) who presents with several months of intermittent dizziness progressing to two episodes of loss of consciousness, each preceded by an alteration in facial sensation. MRI showed a 5.6 x 3.5 x 1.7-cm T2-hyperintense nonenhancing mass in the left medial temporal lobe with mild local mass effect. She underwent a craniotomy and resection of the mass. In addition to the below histologic and IHC studies, molecular analysis for alternate IDH mutations was negative.
Left medial temporal lobe
Whole Slide Image
The whole slide image provided is an H&E-stained image of the brain from a resection.
Which of the following is the BEST histologic diagnosis?
Identification of which of the following would be MOST helpful in predicting this patient’s prognosis and guiding treatment?
Gain of chromosome 7, loss of chromosome 10, and TERT promoter mutation are all identified in this patient’s tumor.
Which of the following is the BEST integrated diagnosis?
Anaplastic astrocytoma, IDH-wildtype, WHO grade III
Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade I
Diffuse astrocytoma, IDH-wildtype, WHO grade II
Oligodendroglioma, IDH-wildtype, WHO grade II
Pleomorphic xanthoastrocytoma, WHO grade II
Discussion and Diagnosis
H&E-stained sections (Image A, Image B, and Image C) show a moderately cellular infiltrating glial neoplasm. Tumor cells display ovoid to slightly irregular nuclei with vesicular chromatin and ill-defined cytoplasmic borders. There is mild nuclear pleomorphism. Mitotic activity is not evident. No necrosis or vascular endothelial proliferation is identified. The tumor is diffusely immunoreactive for GFAP (Image D). IDH1 R132H is nonimmunoreactive (Image E) and molecular testing for alternate IDH mutations was negative, indicating that this tumor is IDH-wildtype. ATRX nuclear immunoreactivity is intact (Image F), suggesting that it does not harbor an ATRX mutation. An immunostain for p53 shows only weak staining in occasional tumor cells (Image G), suggestive of TP53-wildtype phenotype. Ki67 proliferative index is low, estimated at 3% to 4% (Image H). Based on the histology alone, this tumor would be best classified as diffuse astrocytoma, WHO grade II. However, the existence of IDH-wildtype grade II diffuse astrocytoma is controversial in the adult population, and studies suggest that they can generally be reclassified based on their molecular phenotype. Therefore, the updated 2016 WHO Classification of Tumours of the Central Nervous System considers IDH-wildtype diffuse astrocytoma to be a provisional entity.
Additional testing on this patient’s tumor revealed EGFR amplification in addition to chromosome 7 gain, chromosome 10 loss, and TERT promoter mutation. These molecular alterations are characteristic of IDH-wildtype glioblastoma. Lower grade IDH-wildtype infiltrating astrocytic tumors with this molecular phenotype have been shown to behave similarly to glioblastoma, IDH-wildtype. As such, a more appropriate integrated diagnosis would be diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV.
The majority of histologically defined IDH-wildtype diffuse astrocytomas display a molecular phenotype of classic IDH-wildtype glioblastoma, as was seen in this case. Molecular alterations in such cases include EGFR amplification, combined gain of chromosome 7 and loss of chromosome 10, and/or TERT promoter mutations. Smaller subsets of IDH-wildtype diffuse astrocytomas harbor H3 mutations or exhibit a molecular phenotype similar to other low-grade neuroepithelial tumors such as pilocytic astrocytoma and ganglioglioma. This latter group of tumors has a better prognosis than classic glioblastoma-like cases and H3-mutated cases.
The detection of EGFR amplification is a robust surrogate marker for glioblastoma-like behavior in lower grade IDH-wildtype infiltrating astrocytomas. Detection of EGFR amplification can be accomplished by FISH or colorimetric in situ hybridization (CISH), which may be especially useful in centers without access to more complex molecular testing such as array comparative genomic hybridization or targeted next-generation sequencing. IHC for wildtype EGFR is highly sensitive for EGFR amplification, but has a low specificity and should not be used in isolation since many cases without amplification also show EGFR immunoreactivity. Along with EGFR amplification, the presence of combined chromosome 7 gain and chromosome 10 loss, and/or TERT promoter mutation are also indicative of IDH-wildtype glioblastoma molecular phenotype.
In this case, the patient received adjuvant radiation and temozolomide, but eight months after her initial surgery, brain MRI showed new foci of nodular enhancement in the resection cavity. Re-resection revealed focal vascular endothelial proliferation in the recurrent tumor. She passed away 23 months after her initial diagnosis. This case highlights the importance of further characterizing IDH-wildtype lower grade infiltrating astrocytomas. Those with IDH-wildtype glioblastoma molecular features should be treated as glioblastoma with upfront adjuvant therapy, while tumors with low-grade neuroepithelial molecular phenotypes may not require additional therapy.
Take Home Points
- The majority of IDH-wildtype lower grade infiltrating astrocytomas harbor molecular alterations similar to those found in IDH-wildtype glioblastoma and display clinical behavior similar to glioblastoma.
- A small subset of IDH-wildtype lower grade infiltrating astrocytomas have molecular characteristics similar to low-grade neuroepithelial tumors such as pilocytic astrocytoma or ganglioglioma and demonstrate a favorable outcome.
- It is important to further molecularly characterize IDH-wildtype diffuse astrocytomas, including testing for EGFR amplification among others.
- FISH and CISH are excellent testing modalities for EGFR amplification. EGFR IHC is not specific, as many nonamplified tumors are also immunoreactive.
- Aibaidula A, Chan AK, Shi Z, et al. Adult IDH wild-type lower-grade gliomas should be further stratified. Neuro-Oncology. 2017;19(10):1327-37.
- Bale TA, Jordan JT, Rapalino O, et al. Financially effective test algorithm to identify an aggressive, EGFR-amplified variant of IDH-wildtype, lower-grade diffuse glioma. Neuro-Oncology. 2018 Nov 28.
- Brat DJ, Aldape K, Colman H, et al. cIMPACT-NOW update 3: recommended diagnostic criteria for “Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV.” Acta Neuropathol. 2018;136:805-10.
- Brat DJ, Verhaak RGW, Aldape KD, et al. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med. 2015;372(26):2481-98.
- Lee M, Kang SY, Suh YL. Genetic alterations of epidermal growth factor receptor in glioblastoma: the usefulness of immunohistochemistry. Appl Immunohistochem Mol Morphol. 2018 Jun 15. doi:10.1097/PAI.0000000000000669.
- Louis DN, Ohgaki H, Wiestler OD, et al. WHO Classification of Tumours of the Central Nervous System. Revised 4th ed. Lyon, France: International Agency for Research on Cancer; 2016.
- Maire CL, Ligon KL. Molecular pathologic diagnosis of epidermal growth factor receptor. Neuro-Oncology. 2014;16:viii1-viii6.
- Reuss DE, Kratz A, Sahm F, et al. Adult IDH wild type astrocytomas biologically and clinically resolve into other tumor entities. Acta Neuropathol. 2015;130:407-17.
- Stichel D, Ebrahimi A, Reuss D, et al. Distribution of EGFR amplification, combined chromosome 7 gain and chromosome 10 loss, and TERT promoter mutation in brain tumors and their potential for the reclassification of IDH wildtype astrocytoma to glioblastoma. Acta Neuropathol. 2018 Nov;136(5)793-803.
- Which of the following is the BEST histologic diagnosis?
- A. Diffuse astrocytoma
- B. Ganglioglioma
- C. Glioblastoma
- D. Oligodendroglioma
- E. Pilocytic astrocytoma
- Identification of which of the following would be MOST
helpful in predicting this patient’s prognosis and guiding treatment?
- A. L1CAM expression
- B. BRG1 loss
- C. EGFR amplification
- D. TP53 mutation
- E. STAT6 fusion
- Gain of chromosome 7, loss of chromosome 10, and TERT
promoter mutation are all identified in this patient’s tumor.
Which of the following is the BEST integrated diagnosis?
- A. Anaplastic astrocytoma, IDH-wildtype, WHO grade III
- B. Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade I
- C. Diffuse astrocytoma, IDH-wildtype, WHO grade II
- D. Oligodendroglioma, IDH-wildtype, WHO grade II
- E. Pleomorphic xanthoastrocytoma, WHO grade II