- Email: [email protected]
H3 K27M Mutations in Thalamic Pilocytic Astrocytomas with Anaplasia
Case Report
H3 K27M Mutations in Thalamic Pilocytic Astrocytomas with Anaplasia Tarek Y. El Ahmadieh1, Aaron Plitt1, Benjamin Kafka1, Salah G. Aoun1, Jack M. Raisanen2, Brent Orr5, Edward Pan3, Zabi Wardak4, Lucien A. Nedzi4, Toral R. Patel1
Key words Anaplasia - Chemotherapy - H3 K27M mutation - Pilocytic astrocytoma - Radiation - Surgery - Thalamic -
Abbreviations and Acronyms EBRT: External beam radiation therapy MRI: Magnetic resonance imaging PA: Pilocytic astrocytoma WHO: World Health Organization From the Departments of 1Neurological Surgery, 2Pathology, 3 Neurology and Neurotherapeutics, and 4Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas; and 5Department of Pathology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA To whom correspondence should be addressed: Toral R. Patel, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2019) 124:87-92. https://doi.org/10.1016/j.wneu.2018.12.147
- BACKGROUND:
The revised World Health Organization classification of central nervous system tumors, published in 2016, has recognized the H3 K27M mutation as a critical genetic signature defining a new group of infiltrative astrocytomas designated as diffuse midline glioma, H3 K27M mutant. Although most H3 K27M mutations arise in the setting of diffusely infiltrative tumors, there are rare reports of compact tumors with low-grade histologic features harboring this mutation. The prevalence and clinical significance of this mutation in pilocytic astrocytomas remain unclear.
- CASE
DESCRIPTION: We report 2 young adult patients with H3 K27Me mutated thalamic pilocytic astrocytomas who presented to medical attention with symptomatic hydrocephalus requiring urgent intervention. We present our experience with this unusual tumor and recommend a treatment paradigm of maximal safe surgical resection followed by chemotherapy and radiation.
- CONCLUSIONS:
Stereotactic biopsies may undergrade some adult thalamic pilocytic astrocytomas. Therefore, we recommend that all these tumors be evaluated for the H3 K27M mutation. Further, we think H3 K27Memutant thalamic pilocytic astrocytomas require aggressive multimodality treatment and these treatments should be guided by the molecular findings, as opposed to the histologic ones.
Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
INTRODUCTION Pilocytic astrocytomas (PAs) are wellcircumscribed lesions designated as World Health Organization (WHO) grade I tumors.1,2 These lesions are associated with a better prognosis than diffuse astrocytomas, but they can occasionally demonstrate a more aggressive phenotype, including leptomeningeal dissemination.3 Overall, they have a better prognosis in children than adults.4 Recent studies have identified histone H3 K27M mutations in high-grade diffusely infiltrating astrocytomas of midline structures in both children and young adults, a finding that portends an aggressive clinical course.5 The revised WHO classification of central nervous system tumors, published in 2016, has recognized this mutation as a critical genetic signature defining a new group of infiltrative astrocytomas
designated as diffuse midline glioma, H3 K27M mutant.1 Diffuse midline gliomas, H3 K27M mutant, are considered grade IV lesions, independent of traditional histopathologic features. Although most H3 K27M mutations arise in the setting of diffusely infiltrative tumors, there are rare reports of compact tumors with low-grade histologic features harboring this mutation.5,6 The prevalence and clinical significance of this mutation in PAs remains unclear. We have recently treated 2 young adult patients with thalamic PAs with anaplasia whose tumors were both H3 K27M mutated. In this paper, we present our experience with this unusual tumor and propose an aggressive treatment paradigm of surgical resection followed by adjuvant chemotherapy and radiation. CASE 1 A 21-year-old woman presented to medical attention with worsening headaches. Intracranial imaging revealed a large,
WORLD NEUROSURGERY 124: 87-92, APRIL 2019
enhancing left thalamic mass with resultant obstructive hydrocephalus (Figure 1Ae1D). Advanced imaging studies, including magnetic resonance spectroscopy, revealed a marked elevation in the choline to creatine ratio, depletion of N-acetylaspartate, an elevation of the lactate/lipid peak, and mild restricted diffusion. These imaging findings were most suggestive of a highgrade neoplasm. The patient was admitted to the hospital and underwent frameless stereotactic biopsy and placement of a right frontal ventriculoperitoneal shunt. Her postoperative course was complicated by significant intratumoral hemorrhage with intraventricular extension (Figure 2), requiring placement of a left frontal external ventricular drain. The patient had a prolonged hospital course, marked by a seizure, bacterial ventriculitis, complex hydrocephalus management, and right hemiparesis. She ultimately made a good recovery and was discharged to an inpatient rehabilitation
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CASE REPORT TAREK Y. EL AHMADIEH ET AL.
H3 K27MeMUTATED THALAMIC PILOCYTIC ASTROCYTOMAS
Figure 1. (A) Axial noncontrast computed tomography brain scan demonstrates a partially calcified left thalamic mass. (B) Axial, (C) coronal, and (D) sagittal postgadolinium T1-weighted magnetic resonance images demonstrate a large, enhancing left thalamic mass with mass effect on the third ventricle and resultant obstructive hydrocephalus.
center, where she regained her functional independence. Histologic sections of the biopsied mass revealed features of PA, WHO grade I (Figure 3A). The sections demonstrated
well-differentiated piloid astrocytes arranged in ill-defined fascicles. The architecture was not biphasic. Cell processes contained Rosenthal fibers or eosinophilic granular bodies, the latter of
Figure 2. Axial computed tomography brain scan demonstrating the postbiopsy intratumoral hemorrhage with intraventricular extension.
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which was abundant. A single mitotic figure was identified; there was no tumor necrosis. Immunohistochemical stains demonstrated expression of glial fibrillary acidic protein and H3 K27M by many of the neoplastic cells (Figure 3B). There was partial loss of H3K27 trimethylation. Only rare cells reacted with MIB-1. The stains failed to reveal BRAF/V600E. Duplication of BRAF (7q34) was not detected by fluorescence in situ hybridization and the BRAF/ KIAA1549 fusion was not detected by polymerase chain reaction. The patient was discussed at our multidisciplinary tumor board, and because of the H3 K27M mutation, the consensus was to proceed with open surgical resection followed by chemotherapy and external beam radiation therapy (EBRT). Approximately 6 months postbiopsy, the patient underwent a left parietal craniotomy for resection of the thalamic mass. The tumor was approached via the superior parietal lobule. The operation was uneventful, and the patient remained at her neurologic baseline postoperatively, with a mild right hemiparesis and apraxia. A postoperative magnetic resonance image of the brain demonstrated the expected small, enhancing residual tumor located anterolaterally, adjacent to the deep venous system (Figure 4). Histologic sections from the open resection (Figure 3C) demonstrated a more poorly differentiated astrocytoma. In comparison with sections from the initial biopsy, nuclear/cytoplasmic ratios were altered and, in general, cellularity was increased. There were no Rosenthal fibers or eosinophilic granular bodies and there was a higher mitotic rate and MIB-1 index. Immunohistochemical stains of these sections also failed to demonstrate expression of IDH1/R132H. After surgery, the patient underwent a 6-week course of concurrent chemotherapy (temozolomide 75 mg/m2) and EBRT (54 Gy in 27 fractions). She was then placed on monthly temozolomide (days 1e5; 200 mg/m2 for cycles 1e4, dose reduced to 150 mg/m2 starting with cycle 5 secondary to pancytopenia). She completed 12 cycles of monthly temozolomide and is now on surveillance. Followup magnetic resonance imaging (MRI) scans have been obtained every 2 months and have demonstrated largely stable
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2018.12.147
CASE REPORT TAREK Y. EL AHMADIEH ET AL.
H3 K27MeMUTATED THALAMIC PILOCYTIC ASTROCYTOMAS
Figure 3. (A) Well-differentiated piloid astrocytes arranged in ill-defined fascicles. Note the abundant eosinophilic granular bodies (arrows) (hematoxylin and eosin [H&E]; magnification, 100). (B) Diffuse nuclear expression of H3 K27M is identified (immunohistochemical stain; magnification, 20). (C) In comparison with the initial biopsy fragments, sections from the open resection demonstrate a more anaplastic neoplasm with poorly differentiated astrocytes, a higher mitotic rate (arrow), and a higher MIB-1 index (H&E; magnification, 100).
residual tumor, with minimal disease progression. She is now approximately 22 months postbiopsy and 16 months postresection (Figure 5). During this time, the patient has continued to improve neurologically, has completed her schoolwork to become a pharmacy technician, and has maintained a high degree of independence. CASE 2 A 25-year-old man presented to medical attention with progressive headaches. He subsequently developed diplopia. Intracranial imaging revealed a large,
enhancing left thalamic mass with moderate restricted diffusion, suggestive of a high-grade neoplasm, and obstructive hydrocephalus (Figure 6). Given the radiographic appearance, the patient’s age, the symptomatic presentation, and our institutional experience with the patient in case 1, the decision was made to perform a craniotomy for resection. The patient underwent a left parietal craniotomy for resection via the superior parietal lobule. An external ventricular drain was left in place. The operation was uneventful and, postoperatively, the patient experienced mild confusion and
right-sided neglect, but no other focal neurologic deficits. The ventricular drain was removed the following day. MRI demonstrated the expected minimal residual tumor along the medial margin of the resection cavity, adjacent to the internal cerebral vein (Figure 7). The patient’s diplopia and headaches improved postoperatively and he remained functionally independent. He cleared therapies and was discharged to home in good condition. Over the next several weeks, his confusion and apraxia resolved entirely, and he was able to resume working. Histologic sections of the mass demonstrated PA with foci of anaplasia. Most of the resected tumor exhibited classical features of grade I PA with biphasic architecture and compact areas composed of piloid astrocytes, many containing Rosenthal fibers. There was, however, a minor component composed of cells with highly pleomorphic nuclei, some containing mitotic figures. The MIB-1 labeling index in these areas was high. Immunohistochemical stains demonstrated expression of glial fibrillary acidic protein and H3 K27M by many of the neoplastic cells (Figure 8). Given these findings, the patient received a 6-week course of concurrent chemotherapy (temozolomide 75 mg/m2) and EBRT (60 Gy in 30 fractions). He was subsequently placed on monthly temozolomide (days 1e5; 200 mg/m2) and has completed 8 cycles. Follow-up MRI scans obtained every 2 months have shown largely stable residual tumor (Figure 9). He is approximately 11 months postresection and continues to do well, working full-time with no appreciable neurologic deficits. DISCUSSION
Figure 4. (A) Axial and (B) coronal postoperative magnetic resonance images demonstrate a small focus of residual tumor at the anterolateral aspect of the resection cavity.
WORLD NEUROSURGERY 124: 87-92, APRIL 2019
In 2016, the revised WHO classification of central nervous system tumors recognized diffuse midline glioma, H3 K27M-mutant as a new and distinct pathologic entity.1 For the first time, this classification incorporates molecular criteria to help distinguish between tumors with similar histopathologic features but different genetic profiles and potentially different clinical behavior.1,4 The H3 K27M mutation is a key event in gliomagenesis.7,8 It is associated with ATRX loss, unmethylated MGMT promoter, and the
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Figure 5. (A) Axial and (B) coronal magnetic resonance images at 15 months postsurgical resection demonstrate mild disease progression.
absence of IDH1 or IDH2 mutations. It has been demonstrated to be an independent predictor of poor prognosis.9 High-grade gliomas (based on traditional histopathologic criteria) with the H3 K27M mutation are more commonly seen in the pediatric population,1 but can occasionally occur in adults, typically in patients under the age of 40 years.4,7,10,11 Similarly, PAs more commonly occur in children, but are designated WHO grade I tumors with good prognosis and a low risk for malignant transformation.12 The overall survival rate of patients with PAs after surgical resection alone is more than 95% at 5 and 10 years.12-14 Rarely, PAs with largely classical low-grade histologic features contain areas composed of anaplastic cells that are more poorly differentiated and have a higher mitotic rate. Although not codified, the WHO recognizes these tumors as PAs with anaplasia. The anaplastic features in PAs do not correlate as well with prognosis as anaplastic features in diffusely
infiltrating astrocytomas; however, studies have demonstrated that PAs with anaplasia are clinically more aggressive and have a worse prognosis than typical PAs. Reports of PAs containing the H3 K27M mutation are sparse,4,7,10,11 with conflicting descriptions of the clinical course and behavior of these tumors. Given these discrepancies, there is very little guidance in the published literature regarding the prognosis and optimal treatment plan for patients with tumors bearing largely low-grade histopathologic features, but a high-grade mutation. In their report of a 53-year-old patient with a tectal PA, Morita et al.7 argue against the association of the H3 K27M mutation with a poor prognosis. Their patient presented with hydrocephalus and underwent an endoscopic third ventriculostomy. Subsequently, a neartotal resection (more than 95% extent of resection) was performed. Traditional histology findings were consistent with a WHO grade I PA. However,
Figure 6. (A) Axial, (B) coronal, and (C) sagittal postgadolinium T1-weighted magnetic resonance images demonstrate a large, mixed, solid, and cystic
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immunohistochemistry studies demonstrated the presence of the H3 K27M mutation. The authors opted to treat the patient as a WHO grade I PA, and adjuvant therapy was not given. The patient is now 4 years postsurgery and there has been no evidence of disease progression. Therefore, the authors conclude that an H3 K27M mutation may not necessarily determine the overall clinical behavior of PAs; however, they did recommend longterm surveillance imaging for these patients.7 Similarly, in their report on a thalamic PA in a 27-year-old patient, Orillac et al.11 argued that the H3 K27M mutation can be found not only in diffuse high-grade gliomas, but also in low-grade tumors with a benign clinical course. They suggest that the H3 K27M mutation should not be used as the sole criterion for the diagnosis of a WHO grade IV tumor.11 Their patient underwent neartotal surgical resection with no adjuvant therapy. However, the authors did report a local recurrence at 14-month postsurgery, for which they recommended further surgical resection and adjuvant therapy (with no further details provided regarding the clinical outcome).11 On the other hand, Hochart et al.10 presented a 17-year-old patient with a previously resected H3 K27Memutant PA of the cervical cord, who experienced rapid disease progression, with a clinical course similar to that of a high-grade glioma.10 The patient reportedly underwent complete resection of a C2-6 WHO grade I PA and did not initially receive any adjuvant therapy. She then presented 10 years later with malignant transformation of her original tumor and progressive
enhancing left thalamic mass with resultant obstructive hydrocephalus.
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2018.12.147
CASE REPORT TAREK Y. EL AHMADIEH ET AL.
H3 K27MeMUTATED THALAMIC PILOCYTIC ASTROCYTOMAS
Figure 7. (A) Axial and (B) coronal postoperative magnetic resonance images demonstrate mild residual enhancement along the medial margin of the resection cavity, adjacent to the internal cerebral vein.
neurologic decline. A subtotal resection was performed. Histology was consistent with a WHO grade IV glioblastoma, and she was treated with postoperative radiation therapy and concurrent and maintenance chemotherapy (temozolomide). The patient died 1 year after her second surgery.10 The authors concluded that the H3 K27M mutation is not restricted to high-grade histologies and recommended routine histone mutation studies for all pediatric gliomas. Furthermore, they postulate that they should have taken a more aggressive approach at the time of initial diagnosis, with upfront adjuvant chemotherapy and radiation.10
In this report, both of our patients presented to medical attention with symptomatic hydrocephalus requiring urgent intervention. Neither patient had a known history of a brain tumor. Patient 1 initially underwent a stereotactic biopsy which demonstrated a WHO grade I PA with an H3 K27M mutation. Based on the presence of this mutation, further surgical resection and adjuvant therapy were recommended. Histologic analysis of the resected tumor revealed clear areas of anaplasia, suggesting a high-grade phenotype. We hypothesize that these high-grade features were likely present in the original tumor, but that the solely low-
Figure 8. (A) Most of the specimen demonstrated closely apposed, well-differentiated piloid astrocytes, many containing Rosenthal fibers (arrows) (hematoxylin and eosin [H&E]; magnification, 100). (B) A minority of the specimen demonstrated highly pleomorphic astrocytes, some containing atypical mitotic figures (arrows) (H&E; magnification, 100). (C) Diffuse nuclear expression of H3 K27M is identified (immunohistochemical stain; magnification, 100).
WORLD NEUROSURGERY 124: 87-92, APRIL 2019
grade features noted in the original biopsy specimen represented a sampling bias. Patient 2, on the other hand, underwent open surgical resection at time of initial presentation. Histology findings were predominantly low grade; however, there were clear foci of anaplasia within the lesion, in addition to the presence of the H3 K27M mutation. Our patients received 2 different radiation doses (54 vs. 60 Gy). Patient 1 was treated with a low-grade glioma radiation dose, whereas patient 2 received a high-grade glioma radiation dose. The differences in radiation approach for these patients highlight the need for increased clinical outcome data for this pathologic subtype, such that evidence-based guidelines can be developed for future patients. The behavior of PAs with anaplastic features was described by Rodriguez et at.12 in their case series of 34 patients and review of the literature. The authors reported a median age at diagnosis of 35 years (range, 5e75 years). The median overall and progression-free survivals were 24 and 14 months, respectively. Compared with the survival rates for astrocytomas (WHO grades IeIV) from a historical cohort, PAs with anaplastic features had worse survival rates than conventional PAs and better survival rates than grade IV astrocytomas (P < 0.0001 for both). No statistically significant differences in survival were noted between PAs with anaplastic features and grade II or III astrocytomas. Consistent with prior reports on gliomas, in their case series, increased age was associated with a decreased overall survival rate (P < 0.05). Prior radiation exposure, history of PA precursor, increased mitoses, and necrosis were all associated with decreased overall and progression-free survival (P < 0.05). A history of radiation was reported in only 11% of their patients,12 in contrast with previous literature that suggested a stronger association between irradiation and anaplastic transformation.15,16 Neither of the patients presented in our paper had a prior history of radiation exposure. Although our sample size is small and our follow-up period relatively short, the findings suggest that PAs with anaplasia harbor the H3 K27M mutation and that it may be associated with anaplastic transformation of some of the astrocytes in these tumors. Moreover, if biopsies or subtotal resections of thalamic PAs in
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9. Karremann M, Gielen GH, Hoffmann M, et al. Diffuse high-grade gliomas with H3 K27M mutations carry a dismal prognosis independent of tumor location. Neuro Oncol. 2018;20:123-131. 10. Hochart A, Escande F, Rocourt N, et al. Long survival in a child with a mutated K27M-H3.3 pilocytic astrocytoma. Ann Clin Transl Neurol. 2015;2:439-443. 11. Orillac C, Thomas C, Dastagirzada Y, et al. Pilocytic astrocytoma and glioneuronal tumor with histone H3 K27M mutation. Acta Neuropathol Commun. 2016;4:84. Figure 9. (A) Axial and (B) coronal magnetic resonance images at 10.5 months postsurgical resection demonstrate stable residual disease.
young adults have classical features of grade I neoplasms, but are H3 K27M mutated, our findings raise the possibility of an unsampled anaplastic component that may require aggressive treatment. Additionally, we think advanced imaging studies, including magnetic resonance spectroscopy, may be of particular utility for this tumor type.
CONCLUSIONS Based on our experience, we recommend that all thalamic PAs be evaluated for H3 K27M mutations. We advise a treatment paradigm of maximal safe surgical resection followed by chemotherapy and radiation for adult patients with thalamic H3 K27Memutated PAs, irrespective of the histologic findings. We caution that stereotactic biopsies may underrepresent the true nature of some adult thalamic PAs and carry a non-negligible risk of hemorrhage. Additional studies are needed to better understand the impact of the H3 K27M mutation on the long-term clinical behavior of these tumors.
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REFERENCES 1. Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131:803-820. 2. Collins VP, Jones DT, Giannini C. Pilocytic astrocytoma: pathology, molecular mechanisms and markers. Acta Neuropathol. 2015;129:775-788. 3. Yong EX, McKelvie P, Murphy M, Wang YY. Anaplastic pilocytic astrocytoma. J Clin Neurosci. 2014;21:1993-1996. 4. Meyronet D, Esteban-Mader M, Bonnet C, et al. Characteristics of H3 K27M-mutant gliomas in adults. Neuro Oncol. 2017;19:1127-1134. 5. Aihara K, Mukasa A, Gotoh K, et al. H3F3A K27M mutations in thalamic gliomas from young adult patients. Neuro Oncol. 2014;16:140-146. 6. Solomon DA, Wood MD, Tihan T, et al. Diffuse midline gliomas with histone H3-K27M mutation: a series of 47 cases assessing the spectrum of morphologic variation and associated genetic alterations. Brain Pathol. 2016;26:569-580. 7. Morita S, Nitta M, Muragaki Y, et al. Brainstem pilocytic astrocytoma with H3 K27M mutation: case report. J Neurosurg. 2018;129:593-597. 8. Bechet D, Gielen GG, Korshunov A, et al. Specific detection of methionine 27 mutation in histone 3 variants (H3K27M) in fixed tissue from high-grade astrocytomas. Acta Neuropathol. 2014;128:733-741.
12. Rodriguez FJ, Scheithauer BW, Burger PC, Jenkins S, Giannini C. Anaplasia in pilocytic astrocytoma predicts aggressive behavior. Am J Surg Pathol. 2010;34:147-160. 13. Brown PD, Buckner JC, O’Fallon JR, et al. Adult patients with supratentorial pilocytic astrocytomas: a prospective multicenter clinical trial. Int J Radiat Oncol Biol Phys. 2004;58:1153-1160. 14. Forsyth PA, Shaw EG, Scheithauer BW, O’Fallon JR, Layton DD Jr, Katzmann JA. Supratentorial pilocytic astrocytomas. A clinicopathologic, prognostic, and flow cytometric study of 51 patients. Cancer. 1993;72:1335-1342. 15. Schwartz AM, Ghatak NR. Malignant transformation of benign cerebellar astrocytoma. Cancer. 1990;65:333-336. 16. Steinberg GK, Shuer LM, Conley FK, Hanbery JW. Evolution and outcome in malignant astroglial neoplasms of the cerebellum. J Neurosurg. 1985;62:9-17.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 31 August 2018; accepted 17 December 2018 Citation: World Neurosurg. (2019) 124:87-92. https://doi.org/10.1016/j.wneu.2018.12.147 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2018.12.147
H3 K27M Mutations in Thalamic Pilocytic Astrocytomas with Anaplasia Tarek Y. El Ahmadieh1, Aaron Plitt1, Benjamin Kafka1, Salah G. Aoun1, Jack M. Raisanen2, Brent Orr5, Edward Pan3, Zabi Wardak4, Lucien A. Nedzi4, Toral R. Patel1
Key words Anaplasia - Chemotherapy - H3 K27M mutation - Pilocytic astrocytoma - Radiation - Surgery - Thalamic -
Abbreviations and Acronyms EBRT: External beam radiation therapy MRI: Magnetic resonance imaging PA: Pilocytic astrocytoma WHO: World Health Organization From the Departments of 1Neurological Surgery, 2Pathology, 3 Neurology and Neurotherapeutics, and 4Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas; and 5Department of Pathology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA To whom correspondence should be addressed: Toral R. Patel, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2019) 124:87-92. https://doi.org/10.1016/j.wneu.2018.12.147
- BACKGROUND:
The revised World Health Organization classification of central nervous system tumors, published in 2016, has recognized the H3 K27M mutation as a critical genetic signature defining a new group of infiltrative astrocytomas designated as diffuse midline glioma, H3 K27M mutant. Although most H3 K27M mutations arise in the setting of diffusely infiltrative tumors, there are rare reports of compact tumors with low-grade histologic features harboring this mutation. The prevalence and clinical significance of this mutation in pilocytic astrocytomas remain unclear.
- CASE
DESCRIPTION: We report 2 young adult patients with H3 K27Me mutated thalamic pilocytic astrocytomas who presented to medical attention with symptomatic hydrocephalus requiring urgent intervention. We present our experience with this unusual tumor and recommend a treatment paradigm of maximal safe surgical resection followed by chemotherapy and radiation.
- CONCLUSIONS:
Stereotactic biopsies may undergrade some adult thalamic pilocytic astrocytomas. Therefore, we recommend that all these tumors be evaluated for the H3 K27M mutation. Further, we think H3 K27Memutant thalamic pilocytic astrocytomas require aggressive multimodality treatment and these treatments should be guided by the molecular findings, as opposed to the histologic ones.
Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
INTRODUCTION Pilocytic astrocytomas (PAs) are wellcircumscribed lesions designated as World Health Organization (WHO) grade I tumors.1,2 These lesions are associated with a better prognosis than diffuse astrocytomas, but they can occasionally demonstrate a more aggressive phenotype, including leptomeningeal dissemination.3 Overall, they have a better prognosis in children than adults.4 Recent studies have identified histone H3 K27M mutations in high-grade diffusely infiltrating astrocytomas of midline structures in both children and young adults, a finding that portends an aggressive clinical course.5 The revised WHO classification of central nervous system tumors, published in 2016, has recognized this mutation as a critical genetic signature defining a new group of infiltrative astrocytomas
designated as diffuse midline glioma, H3 K27M mutant.1 Diffuse midline gliomas, H3 K27M mutant, are considered grade IV lesions, independent of traditional histopathologic features. Although most H3 K27M mutations arise in the setting of diffusely infiltrative tumors, there are rare reports of compact tumors with low-grade histologic features harboring this mutation.5,6 The prevalence and clinical significance of this mutation in PAs remains unclear. We have recently treated 2 young adult patients with thalamic PAs with anaplasia whose tumors were both H3 K27M mutated. In this paper, we present our experience with this unusual tumor and propose an aggressive treatment paradigm of surgical resection followed by adjuvant chemotherapy and radiation. CASE 1 A 21-year-old woman presented to medical attention with worsening headaches. Intracranial imaging revealed a large,
WORLD NEUROSURGERY 124: 87-92, APRIL 2019
enhancing left thalamic mass with resultant obstructive hydrocephalus (Figure 1Ae1D). Advanced imaging studies, including magnetic resonance spectroscopy, revealed a marked elevation in the choline to creatine ratio, depletion of N-acetylaspartate, an elevation of the lactate/lipid peak, and mild restricted diffusion. These imaging findings were most suggestive of a highgrade neoplasm. The patient was admitted to the hospital and underwent frameless stereotactic biopsy and placement of a right frontal ventriculoperitoneal shunt. Her postoperative course was complicated by significant intratumoral hemorrhage with intraventricular extension (Figure 2), requiring placement of a left frontal external ventricular drain. The patient had a prolonged hospital course, marked by a seizure, bacterial ventriculitis, complex hydrocephalus management, and right hemiparesis. She ultimately made a good recovery and was discharged to an inpatient rehabilitation
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CASE REPORT TAREK Y. EL AHMADIEH ET AL.
H3 K27MeMUTATED THALAMIC PILOCYTIC ASTROCYTOMAS
Figure 1. (A) Axial noncontrast computed tomography brain scan demonstrates a partially calcified left thalamic mass. (B) Axial, (C) coronal, and (D) sagittal postgadolinium T1-weighted magnetic resonance images demonstrate a large, enhancing left thalamic mass with mass effect on the third ventricle and resultant obstructive hydrocephalus.
center, where she regained her functional independence. Histologic sections of the biopsied mass revealed features of PA, WHO grade I (Figure 3A). The sections demonstrated
well-differentiated piloid astrocytes arranged in ill-defined fascicles. The architecture was not biphasic. Cell processes contained Rosenthal fibers or eosinophilic granular bodies, the latter of
Figure 2. Axial computed tomography brain scan demonstrating the postbiopsy intratumoral hemorrhage with intraventricular extension.
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which was abundant. A single mitotic figure was identified; there was no tumor necrosis. Immunohistochemical stains demonstrated expression of glial fibrillary acidic protein and H3 K27M by many of the neoplastic cells (Figure 3B). There was partial loss of H3K27 trimethylation. Only rare cells reacted with MIB-1. The stains failed to reveal BRAF/V600E. Duplication of BRAF (7q34) was not detected by fluorescence in situ hybridization and the BRAF/ KIAA1549 fusion was not detected by polymerase chain reaction. The patient was discussed at our multidisciplinary tumor board, and because of the H3 K27M mutation, the consensus was to proceed with open surgical resection followed by chemotherapy and external beam radiation therapy (EBRT). Approximately 6 months postbiopsy, the patient underwent a left parietal craniotomy for resection of the thalamic mass. The tumor was approached via the superior parietal lobule. The operation was uneventful, and the patient remained at her neurologic baseline postoperatively, with a mild right hemiparesis and apraxia. A postoperative magnetic resonance image of the brain demonstrated the expected small, enhancing residual tumor located anterolaterally, adjacent to the deep venous system (Figure 4). Histologic sections from the open resection (Figure 3C) demonstrated a more poorly differentiated astrocytoma. In comparison with sections from the initial biopsy, nuclear/cytoplasmic ratios were altered and, in general, cellularity was increased. There were no Rosenthal fibers or eosinophilic granular bodies and there was a higher mitotic rate and MIB-1 index. Immunohistochemical stains of these sections also failed to demonstrate expression of IDH1/R132H. After surgery, the patient underwent a 6-week course of concurrent chemotherapy (temozolomide 75 mg/m2) and EBRT (54 Gy in 27 fractions). She was then placed on monthly temozolomide (days 1e5; 200 mg/m2 for cycles 1e4, dose reduced to 150 mg/m2 starting with cycle 5 secondary to pancytopenia). She completed 12 cycles of monthly temozolomide and is now on surveillance. Followup magnetic resonance imaging (MRI) scans have been obtained every 2 months and have demonstrated largely stable
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2018.12.147
CASE REPORT TAREK Y. EL AHMADIEH ET AL.
H3 K27MeMUTATED THALAMIC PILOCYTIC ASTROCYTOMAS
Figure 3. (A) Well-differentiated piloid astrocytes arranged in ill-defined fascicles. Note the abundant eosinophilic granular bodies (arrows) (hematoxylin and eosin [H&E]; magnification, 100). (B) Diffuse nuclear expression of H3 K27M is identified (immunohistochemical stain; magnification, 20). (C) In comparison with the initial biopsy fragments, sections from the open resection demonstrate a more anaplastic neoplasm with poorly differentiated astrocytes, a higher mitotic rate (arrow), and a higher MIB-1 index (H&E; magnification, 100).
residual tumor, with minimal disease progression. She is now approximately 22 months postbiopsy and 16 months postresection (Figure 5). During this time, the patient has continued to improve neurologically, has completed her schoolwork to become a pharmacy technician, and has maintained a high degree of independence. CASE 2 A 25-year-old man presented to medical attention with progressive headaches. He subsequently developed diplopia. Intracranial imaging revealed a large,
enhancing left thalamic mass with moderate restricted diffusion, suggestive of a high-grade neoplasm, and obstructive hydrocephalus (Figure 6). Given the radiographic appearance, the patient’s age, the symptomatic presentation, and our institutional experience with the patient in case 1, the decision was made to perform a craniotomy for resection. The patient underwent a left parietal craniotomy for resection via the superior parietal lobule. An external ventricular drain was left in place. The operation was uneventful and, postoperatively, the patient experienced mild confusion and
right-sided neglect, but no other focal neurologic deficits. The ventricular drain was removed the following day. MRI demonstrated the expected minimal residual tumor along the medial margin of the resection cavity, adjacent to the internal cerebral vein (Figure 7). The patient’s diplopia and headaches improved postoperatively and he remained functionally independent. He cleared therapies and was discharged to home in good condition. Over the next several weeks, his confusion and apraxia resolved entirely, and he was able to resume working. Histologic sections of the mass demonstrated PA with foci of anaplasia. Most of the resected tumor exhibited classical features of grade I PA with biphasic architecture and compact areas composed of piloid astrocytes, many containing Rosenthal fibers. There was, however, a minor component composed of cells with highly pleomorphic nuclei, some containing mitotic figures. The MIB-1 labeling index in these areas was high. Immunohistochemical stains demonstrated expression of glial fibrillary acidic protein and H3 K27M by many of the neoplastic cells (Figure 8). Given these findings, the patient received a 6-week course of concurrent chemotherapy (temozolomide 75 mg/m2) and EBRT (60 Gy in 30 fractions). He was subsequently placed on monthly temozolomide (days 1e5; 200 mg/m2) and has completed 8 cycles. Follow-up MRI scans obtained every 2 months have shown largely stable residual tumor (Figure 9). He is approximately 11 months postresection and continues to do well, working full-time with no appreciable neurologic deficits. DISCUSSION
Figure 4. (A) Axial and (B) coronal postoperative magnetic resonance images demonstrate a small focus of residual tumor at the anterolateral aspect of the resection cavity.
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In 2016, the revised WHO classification of central nervous system tumors recognized diffuse midline glioma, H3 K27M-mutant as a new and distinct pathologic entity.1 For the first time, this classification incorporates molecular criteria to help distinguish between tumors with similar histopathologic features but different genetic profiles and potentially different clinical behavior.1,4 The H3 K27M mutation is a key event in gliomagenesis.7,8 It is associated with ATRX loss, unmethylated MGMT promoter, and the
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Figure 5. (A) Axial and (B) coronal magnetic resonance images at 15 months postsurgical resection demonstrate mild disease progression.
absence of IDH1 or IDH2 mutations. It has been demonstrated to be an independent predictor of poor prognosis.9 High-grade gliomas (based on traditional histopathologic criteria) with the H3 K27M mutation are more commonly seen in the pediatric population,1 but can occasionally occur in adults, typically in patients under the age of 40 years.4,7,10,11 Similarly, PAs more commonly occur in children, but are designated WHO grade I tumors with good prognosis and a low risk for malignant transformation.12 The overall survival rate of patients with PAs after surgical resection alone is more than 95% at 5 and 10 years.12-14 Rarely, PAs with largely classical low-grade histologic features contain areas composed of anaplastic cells that are more poorly differentiated and have a higher mitotic rate. Although not codified, the WHO recognizes these tumors as PAs with anaplasia. The anaplastic features in PAs do not correlate as well with prognosis as anaplastic features in diffusely
infiltrating astrocytomas; however, studies have demonstrated that PAs with anaplasia are clinically more aggressive and have a worse prognosis than typical PAs. Reports of PAs containing the H3 K27M mutation are sparse,4,7,10,11 with conflicting descriptions of the clinical course and behavior of these tumors. Given these discrepancies, there is very little guidance in the published literature regarding the prognosis and optimal treatment plan for patients with tumors bearing largely low-grade histopathologic features, but a high-grade mutation. In their report of a 53-year-old patient with a tectal PA, Morita et al.7 argue against the association of the H3 K27M mutation with a poor prognosis. Their patient presented with hydrocephalus and underwent an endoscopic third ventriculostomy. Subsequently, a neartotal resection (more than 95% extent of resection) was performed. Traditional histology findings were consistent with a WHO grade I PA. However,
Figure 6. (A) Axial, (B) coronal, and (C) sagittal postgadolinium T1-weighted magnetic resonance images demonstrate a large, mixed, solid, and cystic
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immunohistochemistry studies demonstrated the presence of the H3 K27M mutation. The authors opted to treat the patient as a WHO grade I PA, and adjuvant therapy was not given. The patient is now 4 years postsurgery and there has been no evidence of disease progression. Therefore, the authors conclude that an H3 K27M mutation may not necessarily determine the overall clinical behavior of PAs; however, they did recommend longterm surveillance imaging for these patients.7 Similarly, in their report on a thalamic PA in a 27-year-old patient, Orillac et al.11 argued that the H3 K27M mutation can be found not only in diffuse high-grade gliomas, but also in low-grade tumors with a benign clinical course. They suggest that the H3 K27M mutation should not be used as the sole criterion for the diagnosis of a WHO grade IV tumor.11 Their patient underwent neartotal surgical resection with no adjuvant therapy. However, the authors did report a local recurrence at 14-month postsurgery, for which they recommended further surgical resection and adjuvant therapy (with no further details provided regarding the clinical outcome).11 On the other hand, Hochart et al.10 presented a 17-year-old patient with a previously resected H3 K27Memutant PA of the cervical cord, who experienced rapid disease progression, with a clinical course similar to that of a high-grade glioma.10 The patient reportedly underwent complete resection of a C2-6 WHO grade I PA and did not initially receive any adjuvant therapy. She then presented 10 years later with malignant transformation of her original tumor and progressive
enhancing left thalamic mass with resultant obstructive hydrocephalus.
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CASE REPORT TAREK Y. EL AHMADIEH ET AL.
H3 K27MeMUTATED THALAMIC PILOCYTIC ASTROCYTOMAS
Figure 7. (A) Axial and (B) coronal postoperative magnetic resonance images demonstrate mild residual enhancement along the medial margin of the resection cavity, adjacent to the internal cerebral vein.
neurologic decline. A subtotal resection was performed. Histology was consistent with a WHO grade IV glioblastoma, and she was treated with postoperative radiation therapy and concurrent and maintenance chemotherapy (temozolomide). The patient died 1 year after her second surgery.10 The authors concluded that the H3 K27M mutation is not restricted to high-grade histologies and recommended routine histone mutation studies for all pediatric gliomas. Furthermore, they postulate that they should have taken a more aggressive approach at the time of initial diagnosis, with upfront adjuvant chemotherapy and radiation.10
In this report, both of our patients presented to medical attention with symptomatic hydrocephalus requiring urgent intervention. Neither patient had a known history of a brain tumor. Patient 1 initially underwent a stereotactic biopsy which demonstrated a WHO grade I PA with an H3 K27M mutation. Based on the presence of this mutation, further surgical resection and adjuvant therapy were recommended. Histologic analysis of the resected tumor revealed clear areas of anaplasia, suggesting a high-grade phenotype. We hypothesize that these high-grade features were likely present in the original tumor, but that the solely low-
Figure 8. (A) Most of the specimen demonstrated closely apposed, well-differentiated piloid astrocytes, many containing Rosenthal fibers (arrows) (hematoxylin and eosin [H&E]; magnification, 100). (B) A minority of the specimen demonstrated highly pleomorphic astrocytes, some containing atypical mitotic figures (arrows) (H&E; magnification, 100). (C) Diffuse nuclear expression of H3 K27M is identified (immunohistochemical stain; magnification, 100).
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grade features noted in the original biopsy specimen represented a sampling bias. Patient 2, on the other hand, underwent open surgical resection at time of initial presentation. Histology findings were predominantly low grade; however, there were clear foci of anaplasia within the lesion, in addition to the presence of the H3 K27M mutation. Our patients received 2 different radiation doses (54 vs. 60 Gy). Patient 1 was treated with a low-grade glioma radiation dose, whereas patient 2 received a high-grade glioma radiation dose. The differences in radiation approach for these patients highlight the need for increased clinical outcome data for this pathologic subtype, such that evidence-based guidelines can be developed for future patients. The behavior of PAs with anaplastic features was described by Rodriguez et at.12 in their case series of 34 patients and review of the literature. The authors reported a median age at diagnosis of 35 years (range, 5e75 years). The median overall and progression-free survivals were 24 and 14 months, respectively. Compared with the survival rates for astrocytomas (WHO grades IeIV) from a historical cohort, PAs with anaplastic features had worse survival rates than conventional PAs and better survival rates than grade IV astrocytomas (P < 0.0001 for both). No statistically significant differences in survival were noted between PAs with anaplastic features and grade II or III astrocytomas. Consistent with prior reports on gliomas, in their case series, increased age was associated with a decreased overall survival rate (P < 0.05). Prior radiation exposure, history of PA precursor, increased mitoses, and necrosis were all associated with decreased overall and progression-free survival (P < 0.05). A history of radiation was reported in only 11% of their patients,12 in contrast with previous literature that suggested a stronger association between irradiation and anaplastic transformation.15,16 Neither of the patients presented in our paper had a prior history of radiation exposure. Although our sample size is small and our follow-up period relatively short, the findings suggest that PAs with anaplasia harbor the H3 K27M mutation and that it may be associated with anaplastic transformation of some of the astrocytes in these tumors. Moreover, if biopsies or subtotal resections of thalamic PAs in
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9. Karremann M, Gielen GH, Hoffmann M, et al. Diffuse high-grade gliomas with H3 K27M mutations carry a dismal prognosis independent of tumor location. Neuro Oncol. 2018;20:123-131. 10. Hochart A, Escande F, Rocourt N, et al. Long survival in a child with a mutated K27M-H3.3 pilocytic astrocytoma. Ann Clin Transl Neurol. 2015;2:439-443. 11. Orillac C, Thomas C, Dastagirzada Y, et al. Pilocytic astrocytoma and glioneuronal tumor with histone H3 K27M mutation. Acta Neuropathol Commun. 2016;4:84. Figure 9. (A) Axial and (B) coronal magnetic resonance images at 10.5 months postsurgical resection demonstrate stable residual disease.
young adults have classical features of grade I neoplasms, but are H3 K27M mutated, our findings raise the possibility of an unsampled anaplastic component that may require aggressive treatment. Additionally, we think advanced imaging studies, including magnetic resonance spectroscopy, may be of particular utility for this tumor type.
CONCLUSIONS Based on our experience, we recommend that all thalamic PAs be evaluated for H3 K27M mutations. We advise a treatment paradigm of maximal safe surgical resection followed by chemotherapy and radiation for adult patients with thalamic H3 K27Memutated PAs, irrespective of the histologic findings. We caution that stereotactic biopsies may underrepresent the true nature of some adult thalamic PAs and carry a non-negligible risk of hemorrhage. Additional studies are needed to better understand the impact of the H3 K27M mutation on the long-term clinical behavior of these tumors.
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REFERENCES 1. Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131:803-820. 2. Collins VP, Jones DT, Giannini C. Pilocytic astrocytoma: pathology, molecular mechanisms and markers. Acta Neuropathol. 2015;129:775-788. 3. Yong EX, McKelvie P, Murphy M, Wang YY. Anaplastic pilocytic astrocytoma. J Clin Neurosci. 2014;21:1993-1996. 4. Meyronet D, Esteban-Mader M, Bonnet C, et al. Characteristics of H3 K27M-mutant gliomas in adults. Neuro Oncol. 2017;19:1127-1134. 5. Aihara K, Mukasa A, Gotoh K, et al. H3F3A K27M mutations in thalamic gliomas from young adult patients. Neuro Oncol. 2014;16:140-146. 6. Solomon DA, Wood MD, Tihan T, et al. Diffuse midline gliomas with histone H3-K27M mutation: a series of 47 cases assessing the spectrum of morphologic variation and associated genetic alterations. Brain Pathol. 2016;26:569-580. 7. Morita S, Nitta M, Muragaki Y, et al. Brainstem pilocytic astrocytoma with H3 K27M mutation: case report. J Neurosurg. 2018;129:593-597. 8. Bechet D, Gielen GG, Korshunov A, et al. Specific detection of methionine 27 mutation in histone 3 variants (H3K27M) in fixed tissue from high-grade astrocytomas. Acta Neuropathol. 2014;128:733-741.
12. Rodriguez FJ, Scheithauer BW, Burger PC, Jenkins S, Giannini C. Anaplasia in pilocytic astrocytoma predicts aggressive behavior. Am J Surg Pathol. 2010;34:147-160. 13. Brown PD, Buckner JC, O’Fallon JR, et al. Adult patients with supratentorial pilocytic astrocytomas: a prospective multicenter clinical trial. Int J Radiat Oncol Biol Phys. 2004;58:1153-1160. 14. Forsyth PA, Shaw EG, Scheithauer BW, O’Fallon JR, Layton DD Jr, Katzmann JA. Supratentorial pilocytic astrocytomas. A clinicopathologic, prognostic, and flow cytometric study of 51 patients. Cancer. 1993;72:1335-1342. 15. Schwartz AM, Ghatak NR. Malignant transformation of benign cerebellar astrocytoma. Cancer. 1990;65:333-336. 16. Steinberg GK, Shuer LM, Conley FK, Hanbery JW. Evolution and outcome in malignant astroglial neoplasms of the cerebellum. J Neurosurg. 1985;62:9-17.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 31 August 2018; accepted 17 December 2018 Citation: World Neurosurg. (2019) 124:87-92. https://doi.org/10.1016/j.wneu.2018.12.147 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2018.12.147