- Email: [email protected]
A Rare High-Grade Glioma with a Histone H3 K27M Mutation in the Hypothalamus of an Adult Patient
Case Report
A Rare High-Grade Glioma with a Histone H3 K27M Mutation in the Hypothalamus of an Adult Patient Pin He1,3, Wei Chen4,5, Xi Xiong Qiu1,3, Yi Bin Xi6, Hong Guan2,3, Jun Xia1,3
Key words Adult patient - Glioma - H3 K27M mutation - Hypothalamus -
Abbreviations and Acronyms H3K27me3: Trimethylated H3K27 MRI: Magnetic resonance imaging WHO: World Health Organization From the Departments of 1Radiology and 2Pathology, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen; 3Shenzhen Second People’s Hospital, Shenzhen; 4Department of Radiology, Tongji Hospital, Tongji University School of Medicine, Shanghai; 5 Department of Radiology, Pingshan District People’s Hospital, Hubei University of Medicine, Shenzhen, Guangdong; and 6Department of Radiology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shanxi, China To whom correspondence should be addressed: Jun Xia, M.D. [E-mail: [email protected]] Pin He and Wei Chen are coefirst authors. Citation: World Neurosurg. (2019) 128:527-531. https://doi.org/10.1016/j.wneu.2019.04.172 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com
- BACKGROUND:
Diffuse midline glioma H3 K27M mutant is a new tumor entity described in the revised 2016 World Health Organization classification. It is most frequently observed in children and develops in midline structures, including the brainstem, thalamus, and spine. We describe a rare diffuse midline glioma with an H3 K27M mutation arising in the hypothalamus of an adult.
- CASE
DESCRIPTION: A 27-year-old woman was admitted to our department complaining of amenorrhea, polydipsia, and diuresis for the previous 3 months, and headache and lethargy for approximately 10 days. Computed tomography scan showed an oval isodense solid mass extending from the pituitary toward the suprasellar cistern. A gadolinium-enhanced magnetic resonance imaging (MRI) showed a strongly heterogeneous enhanced solid lesion and nonenhanced cystic lesion. The patient underwent surgery and chemoradiotherapy with temozolomide. Histologic and immunohistochemical analyses revealed H3 K27Memutant diffuse midline glioma. The patient underwent another resection for a recurrent tumor 5 months after the first surgery. Three months after the second operation, the patient relapsed, with MRI revealing spinal cord and meningeal metastases; she died shortly afterward.
- CONCLUSIONS:
Diffuse midline glioma with an H3 K27M mutation occurring in the hypothalamus of an adult is rare but should be considered in differential diagnoses. Because histone H3 K27M mutations are associated with aggressive clinical behavior and poor prognosis, molecular analyses should be used to determine the clinical and histopathologic features of such tumors. This will contribute to developing targeted drugs and gene therapy going forward.
1878-8750/$ - see front matter ª 2019 Published by Elsevier Inc.
INTRODUCTION Diffuse midline glioma H3 K27M mutant is a new tumor entity described in the revised 2016 World Health Organization (WHO) classification.1 It is recognized as a distinct entity that corresponds to grade IV glioma and is characterized by K27M mutations in the histone H3 gene H3F3A (or less commonly in the related HIST1H3B gene), a diffuse growth pattern, and a midline location (thalamus, brainstem, or spinal cord).1 Diffuse midline glioma H3 K27M mutant is most frequently observed in children; however, H3 K27M mutations are also frequent in adult midline gliomas.2 The disease appears to be equally prevalent in both men and women; furthermore, Solomon et al.3 found that the specific sites on midline locations
appear to vary with age. In children, H3 K27Memutant gliomas are frequently located within the pontes; in adults, they appear to be more commonly located within the spinal cord and thalamus. The K27 signature appears to be most closely expressed in mid-to-late stages of fetal striatum and thalamus development.4 Recent studies have revealed that the presence of H3 K27M mutations has an impact on the prognosis of patients with gliomas5; the median survival of adults with gliomas carrying this mutation is 19.7 months.6 The prognoses of patients with such tumors is dependent on the locations of the lesions, but not on their histologic grades. Recent studies show that patients with H3 K27Memutant gliomas located in the brainstem have worse prognoses than those with corresponding tumors in unusual
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anatomic locations, such as the cerebellum, corpus callosum, and lateral ventricle.7 Moreover, survival outcomes are not associated with the extent of tumor resection. Herein, we report a young woman with a rare H3 K27Memutant glioblastoma in the hypothalamus. CASE REPORT A 27-year-old right-handed woman was referred to our institution after experiencing amenorrhea, polydipsia, and diuresis for 3 months, and headache and lethargy for approximately 10 days. Magnetic resonance imaging (MRI) performed at her former hospital revealed a mass in the suprasellar region; a pituitary adenoma was highly suspected based on at her diagnostic report. At admission to our facility, a
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H3 K27M MUTATED HYPOTHALAMUS GLIOBLASTOMA
Figure 1. Preoperative images of the tumor. (A) Axial noncontrast-enhanced computed tomography brain image shows an isodense mass in the suprasellar cistern area (arrowhead). (B) Sagittal T1-weighted magnetic resonance imaging (MRI) shows the mass extending from the pituitary toward the thalamus (arrowhead). (C) Coronal T2-weighted MRI shows the mass in the suprasellar cistern. There is a region of focal cyst lesion within the mass (arrow). (D) Contrast-enhanced MRI shows a heterogeneous enhancement mass (arrow).
physical examination and routine laboratory tests showed unremarkable results. Initial computed tomography scan at our hospital showed an oval isodense solid mass extending from the pituitary toward the suprasellar cistern (Figure 1A). MRI revealed a tumor in the suprasellar region with an iso-to hypointensive lesion on T1weighted images and sagittal expansion of the sella turcica (Figure 1B). The mass was predominantly hyperintensive on T2weighted imaging and was hyper-to isointense to cerebrospinal fluid (Figure 1C). Gadolinium-based contrast MRI showed a strongly heterogeneous enhanced solid lesion (Figure 1D) and nonenhanced cystic lesion. These findings were mostly consistent with a pituitary adenoma, and the patient underwent transsphenoidal
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surgery for total tumor resection using an endonasal endoscopic approach. After surgery, laboratory examination revealed hypernatremia (Naþ 161 mmol/L) and hyperchloremia (Cl 119 mmol/L), decreased free triiodothyronine (2.100 pmol/L; reference range, 3.5e6.59 pmol/ L), and total thyroxine (37.30 ng/mL; reference range, 45e133 ng/mL); no other atypical features were found. After surgery, the patient required chronic hormone replacement. Neuropathologic and immunohistochemical analysis of the resected tumor produced a diagnosis of diffuse midline glioma H3 K27M mutant based on a highly pleomorphic infiltrating glioblastoma with microvascular proliferation (Figures 2A and B). The tumor cell nuclei were strongly positive
for the histone H3 K27M mutant protein (Figure 2C); the cells were also positive for glial fibrillary acidic protein, alpha thalassemia/mental retardation syndrome X-linked protein, p53, and OLIG2, but negative for IDH1R132H. The median Ki67 labeling was 30%; nuclear staining for trimethylated H3K27 (H3K27me3) was negative (Figure 2D). Because of the presence of an H3 K27M mutation, the patient commenced chemotherapy with temozolomide, which was subsequently administered monthly (days 1e5; 150 mg/m2 for cycle 1 and dose reduced to 200 mg/m2 for cycles 2e5). She recovered well after surgery. Five months after, the patient presented with visual field loss on the left side of the vertical midline. Endocrinologically, hypopituitarism was identified with low blood levels of total triiodothyronine (0.140 ng/ mL; reference range, 0.6e1.81 ng/mL), total thyroxine (1.40 ng/mL; reference range, 45e133 ng/mL), triiodothyronine (0.430 pmol/L; reference range, 3.5e6.59 pmol/L), free thyroxine (1.98 pmol/L; reference range, 11.5e22.7 pmol/L), and thyroid stimulating hormone (0.014 mTU/L, reference range, 0.55e4.78 mTU/L). The patient also had decreased levels of blood cortisol (0.50 mg/dL, reference range, 3.09e22.4 mg/dL). However, the patient had normal levels of prolactin and testosterone. Contrast-enhanced MRI base apparent diffusion coefficient maps and perfusion images revealed a recurred tumor at the resection site (Figure 3), whereupon the patient underwent a left frontal craniotomy for resection of the sellar mass. Postsurgery, the patient experienced mild confusion and rightsided neglect but no other focal neurologic deficits. Postoperatively, the visual acuity in her left eye remained impaired, and she continued to receive chemotherapy. Follow-up MRI scans performed 2 months afterward showed no sign of tumor recurrence. Three months after the second surgery, the patient experienced mild dizziness and headaches with left upper limb numbness for 7 days after a 50-Gy radiotherapy session that she underwent at another facility. MRI revealed multiple enhanced nodular lesions in the spinal cord and pia mater (Figure 4). She decided to suspend
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CASE REPORT PIN HE ET AL.
H3 K27M MUTATED HYPOTHALAMUS GLIOBLASTOMA
Figure 2. Microscopic features of the tumor. (A) Hematoxylin and eosin staining of cross sections of the hypothalamus show the cells heteromorphic and numerous nuclear divisions (4 light microscopy [inset]) and (B) show numerous glioblastomas cells with high-grade histologic features (10 light microscopy [inset]). (C) Immunohistochemistry for histone H3 K27M mutant protein reveals a mosaic expression (20 light microscopy [inset]). (D) The tumor cells lack H3K27me3 expression (20 light microscopy [inset]).
treatment and died 4 months after the second operation. DISCUSSION Cerebellar glioblastomas more commonly occur in adults, with most arising in the subcortical white matter of the cerebral hemispheres. They are designated WHO grade IV tumors that are highly aggressive and have a high risk of malignant transformation, at which point they become deadly because of the lack of effective treatment. Recently, genomic sequencing studies have found that approximately 30% of recurrent pediatric glioblastomas carry the H3 K27M mutation.8 However, this tumor can occasionally occur in adults; Picart et al.9 suggested that adult cerebellar glioblastomas differ from their supratentorial counterparts because they are associated with H3 K27M mutations. Another published case report describing a 28-year-old woman who died of primary spinal glioblastoma multiforme carrying the H3 K27M mutation was recently published.10 The H3 K27M mutation is found not only in diffuse high-grade gliomas but also
in low-grade tumors that have a benign clinical course.11,12 A previous investigation of 21 adults with gliomas revealed that 3 patients who were initially diagnosed with diffuse low-grade disease had their conditions reclassified as WHO grade IV on the discovery of the presence of an H3 K27M mutation.6 This mutation may also underlie the malignant potential of such tumors even when microvascular proliferation or necrosis is not observed.1,13 Such data suggest that gliomas with H3 K27M mutations display an extensive spectrum of morphologic patterns. Notably, nondiffuse midline gliomas that carry the same H3 K27M mutation have also been reported in some patients; these include pilocytic astrocytoma, ependymoma, pediatric diffuse astrocytoma, and ganglioglioma.11,12,14,15 For these reasons, a working committee has considered that the term diffuse midline glioma H3 K27M mutant should be reserved only for gliomas with the H3 K27M mutant that are diffuse or infiltrating.13 Our patient underwent extended tumor resection and adjuvant therapy; her overall
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survival was 9 months, with the disease recurring 5 months after primary treatment. However, a previous study in Australia revealed that patients with glioblastoma who underwent optimal treatment regimens that involved maximal safe resection, radiotherapy, and adjuvant chemotherapy experienced a median overall survival of 14.4 months from the date of diagnosis,16 and recurrence is usually detected 6e9 months after the primary treatment.17 Hence, the poorer outcome in our patient appears to be related to the H3 K27M mutation. Karremann et al.18 posited that the H3 K27M mutation is the only independent parameter predictive of overall survival in patients with H3 K27Memutant tumors and that anatomic midline location, histopathologic grading, and treatment regimens had no influence on survival. K27M mutations occur in 2 genes, H3F3A or HIST1H3B/C, which encode the histone H3 variants H3.3 and H3.1, respectively.19 Somatic gain-of-function mutations of the H3F3A gene induce the derepression of pro-oncogenic transcription factors via global reduction of H3K27me3, leading to a lysine-to-methionine substitution on position 27 of the histone H3 tail and a subsequent loss of trimethylation at that position via the inhibition of the polycomb repressive complex 2.20 Hence, H3 K27M mutant protein positivity has been linked to H3K27me3 expression, and the resulting dominant alterations in both gene expression patterns and the epigenetic landscape may contribute to impeding physiologic differentiation and carcinogenesis.21 Our patient was an example of how the presence of an H3 K27M mutation is associated with poorer survival. Previous studies also found that gene expression can affect clinical prognosis. Castel et al.22 found patients with diffuse intrinsic pontine glioma who had a K27M mutation in H3.3 had worse outcomes than those who had this mutation in H3.1. Moreover, Meyronet et al.6 showed that adults with H3 K27M mutations comprise a distinct subgroup of patients with isocitrate dehydrogenase wild-type gliomas and, similar to their pediatric counterparts, have tumors with midline location, low rate of MGMT promoter methylation, and poor prognoses. This information should to be helpful for
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H3 K27M MUTATED HYPOTHALAMUS GLIOBLASTOMA
Figure 3. Perfusion-weighted magnetic resonance imaging (MRI) of the patient 5 months after the first operation. (A) Sagittal contrast-enhanced T1-weighted MRI reveals an enhanced tumor at the site of resection after the first operation (arrowheads). (B) Apparent diffusion coefficient map shows a mass with a decreased diffusion coefficient of 1.2806 10e3 mm2/s. (C) Perfusion map shows an increased relative cerebral blood volume in the tumor. (D) Perfusion map shows an increased relative cerebral blood volume in the tumor.
Figure 4. Three months after the second operation, sagittal contrast-enhanced T1-weighted magnetic resonance images show multiple enhancing lesions in the intramedullary and pia mater.
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developing novel strategies for targeted therapeutics. Although there have been a few case reports of patients with glioblastomas in the suprasellar and hypothalamic/chiasmatic regions, to our knowledge, our patient is the first reported to have experienced acute clinical deterioration as potentially related to mutant H3 K27M. From a radiologic perspective, our patient’s MRI characteristics included hypo- or isointensity on T1-weighted imaging with moderate intensity on T2-weighted imaging and the lack of invasion into surrounding structures. Likewise, pituitary macroadenomas are usually isointense on T1-weighted imaging relative to gray matter. The diagnosis of such types prior to obtaining tissue for histologic analysis is difficult because the MRI characteristics of H3 K27Memutant gliomas are heterogeneous. These tumors are mainly located in the brainstem, thalamus, and spinal cord, with different radiologic features depending on anatomic locations. MRI shows contrast enhancement and necrosis in thalamic gliomas. Cervical spine gliomas are uniformly enhanced, and thalamic and pontine gliomas appear as slightly enhanced, diffusely swollen T2hyperintense lesions with a variety of progressive patterns and most commonly seen as local recurrence. Cervical spine gliomas with histone H3 K27M mutations demonstrate prominent cerebrospinal fluidebased metastatic spreading.23 Nevertheless, tumors can also arise in the cerebellum, corpus callosum, and lateral ventricle. Nakata et al.24 reported that adult H3 K27Memutant gliomas appear as cystic, enhanced mass lesions with a limited T2-hyperintense area. Such imaging characteristics of H3 K27Memutant gliomas are not distinguishable from histone H3 wild-type diffuse gliomas.17 In summary, our adult patient had a rare hypothalamic glioma with an H3 K27M mutation. Although she underwent surgical resection followed by chemotherapy and radiation, she nevertheless experienced recurrence. As such, a substantial increase in basic research and development to devise dedicated therapeutic strategies is urgently needed. Potential drugs targeting epigenetic alterations such as H3F3A K27M have recently
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CASE REPORT PIN HE ET AL.
been identified,25 and disialogangliosidetargeted chimeric antigen receptor T cell therapy for H3 K27Memutant diffuse midline glioma was also shown to be effective.26 Molecular profiling is critical for the accurate diagnosis of patients with this tumor type, and also for designing targeted drugs and gene therapy strategies to treat patients with such high-risk diseases. 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. Ebrahimi A, Skardelly M, Schuhmann MU, et al. High frequency of H3 K27M mutations in adult midline gliomas. J Cancer Res Clin Oncol. 2019;145: 839-850. 3. 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.
H3 K27M MUTATED HYPOTHALAMUS GLIOBLASTOMA
9. Picart T, Barritault M, Berthillier J, et al. Characteristics of cerebellar glioblastomas in adults. J Neurooncol. 2018;136:555-563. 10. Uppar A, Konar SK, Nandeesh BN, Shukla D. H3k27m- positive primary spinal gliobastoma presenting with haemorrhage- a rare clinical entity [e-pub ahead of print]. World Neurosurg https://doi. org/10.1016/j.wneu.2019.03.025, accessed March 12, 2019. 11. Orillac C, Thomas C, Dastagirzada Y, et al. Pilocytic astrocytoma and glioneuronal tumor with 307 histone H3 K27M mutation. Acta Neuropathol Commun. 2016;4:84. 12. El Ahmadieh TY, Plitt A, Kafka B, et al. H3 K27M mutations in thalamic pilocytic astrocytomas with anaplasia [e-pub ahead of print]. World Neurosurg https://doi.org/10.1016/j.wneu.2018.12.147, accessed January 10, 2019. 13. Louis DN, Giannini C, Capper D, et al. cIMPACTNOW update 2: diagnostic clarifications for diffuse midline glioma, H3 K27M-mutant and diffuse astrocytoma/anaplastic astrocytoma, IDHmutant. Acta Neuropathol. 2018;135:639-642. 14. Gessi M, Capper D, Sahm F, et al. Evidence of H3 K27M mutations in posterior fossa ependymomas. Acta Neuropathol. 2016;132:635-637.
4. Venneti S, Santi M, Felicella MM, et al. A sensitive and specific histopathologic prognostic marker for H3F3A K27M mutant pediatric glioblastomas. Acta Neuropathol. 2014;128:743-753.
15. Pratt D, Natarajan SK, Banda A, et al. Circumscribed/non-diffuse histology confers a better prognosis in H3K27M-mutant gliomas. Acta Neuropathol. 2018;135:299-301.
5. Khuong-Quang DA, Buczkowicz P, Rakopoulos P, et al. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol. 2012;124:439-447.
16. Gan HK, Rosenthal MA, Cher L, et al. Management of glioblastoma in Victoria, Australia (20062008). J Clin Neurosci. 2015;22:1462-1466.
6. Meyronet D, Esteban-Mader M, Bonnet C, et al. Characteristics of H3 K27M-mutant gliomas in adults. Neuro Oncol. 2017;19:1127-1134.
17. Mallick S, Benson R, Hakim A, Rath GK. Management of glioblastoma after recurrence: a changing paradigm. J Egypt Natl Canc Inst. 2016;28: 199-210.
7. Wang L, Li Z, Zhang M, et al. H3 K27M-mutant diffuse midline gliomas in different anatomical locations. Hum Pathol. 2018;78:89-96.
18. 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.
8. Bozkurt SU, Dagcinar A, Tanrikulu B, et al. Significance of H3K27M mutation with specific histomorphological features and associated molecular alterations in pediatric high-grade glial tumors. Childs Nerv Syst. 2018;34:107-116.
19. Bender S, Tang Y, Lindroth AM, et al. Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell. 2013;24: 660-672.
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20. Lewis PW, Müller MM, Koletsky MS, et al. Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science. 2013;340:857-861.
21. Chan KM, Fang D, Gan H, et al. The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression. Genes Dev. 2013;27:985-990.
22. Castel D, Philippe C, Calmon R, et al. Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes. Acta Neuropathol. 2015;130:815-827.
23. Aboian MS, Solomon DA, Felton E, et al. Imaging characteristics of pediatric diffuse midline gliomas with histone H3 K27M mutation. AJNR Am J Neuroradiol. 2017;38:795-800.
24. Nakata S, Nobusawa S, Yamazaki T, et al. Histone H3 K27M mutations in adult cerebellar high-grade gliomas. Brain Tumor Pathol. 2017;34:113-119.
25. Ochs K, Ott M, Bunse T, et al. K27M-mutant histone-3 as a novel target for glioma immunotherapy. Oncoimmunology. 2017;6:e1328340.
26. Mount CW, Majzner RG, Sundaresh S, et al. Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M diffuse midline gliomas. Nat Med. 2018;24:572-579.
Conflict of interest statement: This work was supported by the Scientific Plan Program of Guangdong (2017A020215160) and Shenzhen Innovation Funding under Grant (JCYJ20170413161314734). Received 6 February 2019; accepted 20 April 2019 Citation: World Neurosurg. (2019) 128:527-531. https://doi.org/10.1016/j.wneu.2019.04.172 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Published by Elsevier Inc.
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A Rare High-Grade Glioma with a Histone H3 K27M Mutation in the Hypothalamus of an Adult Patient Pin He1,3, Wei Chen4,5, Xi Xiong Qiu1,3, Yi Bin Xi6, Hong Guan2,3, Jun Xia1,3
Key words Adult patient - Glioma - H3 K27M mutation - Hypothalamus -
Abbreviations and Acronyms H3K27me3: Trimethylated H3K27 MRI: Magnetic resonance imaging WHO: World Health Organization From the Departments of 1Radiology and 2Pathology, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen; 3Shenzhen Second People’s Hospital, Shenzhen; 4Department of Radiology, Tongji Hospital, Tongji University School of Medicine, Shanghai; 5 Department of Radiology, Pingshan District People’s Hospital, Hubei University of Medicine, Shenzhen, Guangdong; and 6Department of Radiology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shanxi, China To whom correspondence should be addressed: Jun Xia, M.D. [E-mail: [email protected]] Pin He and Wei Chen are coefirst authors. Citation: World Neurosurg. (2019) 128:527-531. https://doi.org/10.1016/j.wneu.2019.04.172 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com
- BACKGROUND:
Diffuse midline glioma H3 K27M mutant is a new tumor entity described in the revised 2016 World Health Organization classification. It is most frequently observed in children and develops in midline structures, including the brainstem, thalamus, and spine. We describe a rare diffuse midline glioma with an H3 K27M mutation arising in the hypothalamus of an adult.
- CASE
DESCRIPTION: A 27-year-old woman was admitted to our department complaining of amenorrhea, polydipsia, and diuresis for the previous 3 months, and headache and lethargy for approximately 10 days. Computed tomography scan showed an oval isodense solid mass extending from the pituitary toward the suprasellar cistern. A gadolinium-enhanced magnetic resonance imaging (MRI) showed a strongly heterogeneous enhanced solid lesion and nonenhanced cystic lesion. The patient underwent surgery and chemoradiotherapy with temozolomide. Histologic and immunohistochemical analyses revealed H3 K27Memutant diffuse midline glioma. The patient underwent another resection for a recurrent tumor 5 months after the first surgery. Three months after the second operation, the patient relapsed, with MRI revealing spinal cord and meningeal metastases; she died shortly afterward.
- CONCLUSIONS:
Diffuse midline glioma with an H3 K27M mutation occurring in the hypothalamus of an adult is rare but should be considered in differential diagnoses. Because histone H3 K27M mutations are associated with aggressive clinical behavior and poor prognosis, molecular analyses should be used to determine the clinical and histopathologic features of such tumors. This will contribute to developing targeted drugs and gene therapy going forward.
1878-8750/$ - see front matter ª 2019 Published by Elsevier Inc.
INTRODUCTION Diffuse midline glioma H3 K27M mutant is a new tumor entity described in the revised 2016 World Health Organization (WHO) classification.1 It is recognized as a distinct entity that corresponds to grade IV glioma and is characterized by K27M mutations in the histone H3 gene H3F3A (or less commonly in the related HIST1H3B gene), a diffuse growth pattern, and a midline location (thalamus, brainstem, or spinal cord).1 Diffuse midline glioma H3 K27M mutant is most frequently observed in children; however, H3 K27M mutations are also frequent in adult midline gliomas.2 The disease appears to be equally prevalent in both men and women; furthermore, Solomon et al.3 found that the specific sites on midline locations
appear to vary with age. In children, H3 K27Memutant gliomas are frequently located within the pontes; in adults, they appear to be more commonly located within the spinal cord and thalamus. The K27 signature appears to be most closely expressed in mid-to-late stages of fetal striatum and thalamus development.4 Recent studies have revealed that the presence of H3 K27M mutations has an impact on the prognosis of patients with gliomas5; the median survival of adults with gliomas carrying this mutation is 19.7 months.6 The prognoses of patients with such tumors is dependent on the locations of the lesions, but not on their histologic grades. Recent studies show that patients with H3 K27Memutant gliomas located in the brainstem have worse prognoses than those with corresponding tumors in unusual
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anatomic locations, such as the cerebellum, corpus callosum, and lateral ventricle.7 Moreover, survival outcomes are not associated with the extent of tumor resection. Herein, we report a young woman with a rare H3 K27Memutant glioblastoma in the hypothalamus. CASE REPORT A 27-year-old right-handed woman was referred to our institution after experiencing amenorrhea, polydipsia, and diuresis for 3 months, and headache and lethargy for approximately 10 days. Magnetic resonance imaging (MRI) performed at her former hospital revealed a mass in the suprasellar region; a pituitary adenoma was highly suspected based on at her diagnostic report. At admission to our facility, a
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Figure 1. Preoperative images of the tumor. (A) Axial noncontrast-enhanced computed tomography brain image shows an isodense mass in the suprasellar cistern area (arrowhead). (B) Sagittal T1-weighted magnetic resonance imaging (MRI) shows the mass extending from the pituitary toward the thalamus (arrowhead). (C) Coronal T2-weighted MRI shows the mass in the suprasellar cistern. There is a region of focal cyst lesion within the mass (arrow). (D) Contrast-enhanced MRI shows a heterogeneous enhancement mass (arrow).
physical examination and routine laboratory tests showed unremarkable results. Initial computed tomography scan at our hospital showed an oval isodense solid mass extending from the pituitary toward the suprasellar cistern (Figure 1A). MRI revealed a tumor in the suprasellar region with an iso-to hypointensive lesion on T1weighted images and sagittal expansion of the sella turcica (Figure 1B). The mass was predominantly hyperintensive on T2weighted imaging and was hyper-to isointense to cerebrospinal fluid (Figure 1C). Gadolinium-based contrast MRI showed a strongly heterogeneous enhanced solid lesion (Figure 1D) and nonenhanced cystic lesion. These findings were mostly consistent with a pituitary adenoma, and the patient underwent transsphenoidal
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surgery for total tumor resection using an endonasal endoscopic approach. After surgery, laboratory examination revealed hypernatremia (Naþ 161 mmol/L) and hyperchloremia (Cl 119 mmol/L), decreased free triiodothyronine (2.100 pmol/L; reference range, 3.5e6.59 pmol/ L), and total thyroxine (37.30 ng/mL; reference range, 45e133 ng/mL); no other atypical features were found. After surgery, the patient required chronic hormone replacement. Neuropathologic and immunohistochemical analysis of the resected tumor produced a diagnosis of diffuse midline glioma H3 K27M mutant based on a highly pleomorphic infiltrating glioblastoma with microvascular proliferation (Figures 2A and B). The tumor cell nuclei were strongly positive
for the histone H3 K27M mutant protein (Figure 2C); the cells were also positive for glial fibrillary acidic protein, alpha thalassemia/mental retardation syndrome X-linked protein, p53, and OLIG2, but negative for IDH1R132H. The median Ki67 labeling was 30%; nuclear staining for trimethylated H3K27 (H3K27me3) was negative (Figure 2D). Because of the presence of an H3 K27M mutation, the patient commenced chemotherapy with temozolomide, which was subsequently administered monthly (days 1e5; 150 mg/m2 for cycle 1 and dose reduced to 200 mg/m2 for cycles 2e5). She recovered well after surgery. Five months after, the patient presented with visual field loss on the left side of the vertical midline. Endocrinologically, hypopituitarism was identified with low blood levels of total triiodothyronine (0.140 ng/ mL; reference range, 0.6e1.81 ng/mL), total thyroxine (1.40 ng/mL; reference range, 45e133 ng/mL), triiodothyronine (0.430 pmol/L; reference range, 3.5e6.59 pmol/L), free thyroxine (1.98 pmol/L; reference range, 11.5e22.7 pmol/L), and thyroid stimulating hormone (0.014 mTU/L, reference range, 0.55e4.78 mTU/L). The patient also had decreased levels of blood cortisol (0.50 mg/dL, reference range, 3.09e22.4 mg/dL). However, the patient had normal levels of prolactin and testosterone. Contrast-enhanced MRI base apparent diffusion coefficient maps and perfusion images revealed a recurred tumor at the resection site (Figure 3), whereupon the patient underwent a left frontal craniotomy for resection of the sellar mass. Postsurgery, the patient experienced mild confusion and rightsided neglect but no other focal neurologic deficits. Postoperatively, the visual acuity in her left eye remained impaired, and she continued to receive chemotherapy. Follow-up MRI scans performed 2 months afterward showed no sign of tumor recurrence. Three months after the second surgery, the patient experienced mild dizziness and headaches with left upper limb numbness for 7 days after a 50-Gy radiotherapy session that she underwent at another facility. MRI revealed multiple enhanced nodular lesions in the spinal cord and pia mater (Figure 4). She decided to suspend
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Figure 2. Microscopic features of the tumor. (A) Hematoxylin and eosin staining of cross sections of the hypothalamus show the cells heteromorphic and numerous nuclear divisions (4 light microscopy [inset]) and (B) show numerous glioblastomas cells with high-grade histologic features (10 light microscopy [inset]). (C) Immunohistochemistry for histone H3 K27M mutant protein reveals a mosaic expression (20 light microscopy [inset]). (D) The tumor cells lack H3K27me3 expression (20 light microscopy [inset]).
treatment and died 4 months after the second operation. DISCUSSION Cerebellar glioblastomas more commonly occur in adults, with most arising in the subcortical white matter of the cerebral hemispheres. They are designated WHO grade IV tumors that are highly aggressive and have a high risk of malignant transformation, at which point they become deadly because of the lack of effective treatment. Recently, genomic sequencing studies have found that approximately 30% of recurrent pediatric glioblastomas carry the H3 K27M mutation.8 However, this tumor can occasionally occur in adults; Picart et al.9 suggested that adult cerebellar glioblastomas differ from their supratentorial counterparts because they are associated with H3 K27M mutations. Another published case report describing a 28-year-old woman who died of primary spinal glioblastoma multiforme carrying the H3 K27M mutation was recently published.10 The H3 K27M mutation is found not only in diffuse high-grade gliomas but also
in low-grade tumors that have a benign clinical course.11,12 A previous investigation of 21 adults with gliomas revealed that 3 patients who were initially diagnosed with diffuse low-grade disease had their conditions reclassified as WHO grade IV on the discovery of the presence of an H3 K27M mutation.6 This mutation may also underlie the malignant potential of such tumors even when microvascular proliferation or necrosis is not observed.1,13 Such data suggest that gliomas with H3 K27M mutations display an extensive spectrum of morphologic patterns. Notably, nondiffuse midline gliomas that carry the same H3 K27M mutation have also been reported in some patients; these include pilocytic astrocytoma, ependymoma, pediatric diffuse astrocytoma, and ganglioglioma.11,12,14,15 For these reasons, a working committee has considered that the term diffuse midline glioma H3 K27M mutant should be reserved only for gliomas with the H3 K27M mutant that are diffuse or infiltrating.13 Our patient underwent extended tumor resection and adjuvant therapy; her overall
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survival was 9 months, with the disease recurring 5 months after primary treatment. However, a previous study in Australia revealed that patients with glioblastoma who underwent optimal treatment regimens that involved maximal safe resection, radiotherapy, and adjuvant chemotherapy experienced a median overall survival of 14.4 months from the date of diagnosis,16 and recurrence is usually detected 6e9 months after the primary treatment.17 Hence, the poorer outcome in our patient appears to be related to the H3 K27M mutation. Karremann et al.18 posited that the H3 K27M mutation is the only independent parameter predictive of overall survival in patients with H3 K27Memutant tumors and that anatomic midline location, histopathologic grading, and treatment regimens had no influence on survival. K27M mutations occur in 2 genes, H3F3A or HIST1H3B/C, which encode the histone H3 variants H3.3 and H3.1, respectively.19 Somatic gain-of-function mutations of the H3F3A gene induce the derepression of pro-oncogenic transcription factors via global reduction of H3K27me3, leading to a lysine-to-methionine substitution on position 27 of the histone H3 tail and a subsequent loss of trimethylation at that position via the inhibition of the polycomb repressive complex 2.20 Hence, H3 K27M mutant protein positivity has been linked to H3K27me3 expression, and the resulting dominant alterations in both gene expression patterns and the epigenetic landscape may contribute to impeding physiologic differentiation and carcinogenesis.21 Our patient was an example of how the presence of an H3 K27M mutation is associated with poorer survival. Previous studies also found that gene expression can affect clinical prognosis. Castel et al.22 found patients with diffuse intrinsic pontine glioma who had a K27M mutation in H3.3 had worse outcomes than those who had this mutation in H3.1. Moreover, Meyronet et al.6 showed that adults with H3 K27M mutations comprise a distinct subgroup of patients with isocitrate dehydrogenase wild-type gliomas and, similar to their pediatric counterparts, have tumors with midline location, low rate of MGMT promoter methylation, and poor prognoses. This information should to be helpful for
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Figure 3. Perfusion-weighted magnetic resonance imaging (MRI) of the patient 5 months after the first operation. (A) Sagittal contrast-enhanced T1-weighted MRI reveals an enhanced tumor at the site of resection after the first operation (arrowheads). (B) Apparent diffusion coefficient map shows a mass with a decreased diffusion coefficient of 1.2806 10e3 mm2/s. (C) Perfusion map shows an increased relative cerebral blood volume in the tumor. (D) Perfusion map shows an increased relative cerebral blood volume in the tumor.
Figure 4. Three months after the second operation, sagittal contrast-enhanced T1-weighted magnetic resonance images show multiple enhancing lesions in the intramedullary and pia mater.
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developing novel strategies for targeted therapeutics. Although there have been a few case reports of patients with glioblastomas in the suprasellar and hypothalamic/chiasmatic regions, to our knowledge, our patient is the first reported to have experienced acute clinical deterioration as potentially related to mutant H3 K27M. From a radiologic perspective, our patient’s MRI characteristics included hypo- or isointensity on T1-weighted imaging with moderate intensity on T2-weighted imaging and the lack of invasion into surrounding structures. Likewise, pituitary macroadenomas are usually isointense on T1-weighted imaging relative to gray matter. The diagnosis of such types prior to obtaining tissue for histologic analysis is difficult because the MRI characteristics of H3 K27Memutant gliomas are heterogeneous. These tumors are mainly located in the brainstem, thalamus, and spinal cord, with different radiologic features depending on anatomic locations. MRI shows contrast enhancement and necrosis in thalamic gliomas. Cervical spine gliomas are uniformly enhanced, and thalamic and pontine gliomas appear as slightly enhanced, diffusely swollen T2hyperintense lesions with a variety of progressive patterns and most commonly seen as local recurrence. Cervical spine gliomas with histone H3 K27M mutations demonstrate prominent cerebrospinal fluidebased metastatic spreading.23 Nevertheless, tumors can also arise in the cerebellum, corpus callosum, and lateral ventricle. Nakata et al.24 reported that adult H3 K27Memutant gliomas appear as cystic, enhanced mass lesions with a limited T2-hyperintense area. Such imaging characteristics of H3 K27Memutant gliomas are not distinguishable from histone H3 wild-type diffuse gliomas.17 In summary, our adult patient had a rare hypothalamic glioma with an H3 K27M mutation. Although she underwent surgical resection followed by chemotherapy and radiation, she nevertheless experienced recurrence. As such, a substantial increase in basic research and development to devise dedicated therapeutic strategies is urgently needed. Potential drugs targeting epigenetic alterations such as H3F3A K27M have recently
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CASE REPORT PIN HE ET AL.
been identified,25 and disialogangliosidetargeted chimeric antigen receptor T cell therapy for H3 K27Memutant diffuse midline glioma was also shown to be effective.26 Molecular profiling is critical for the accurate diagnosis of patients with this tumor type, and also for designing targeted drugs and gene therapy strategies to treat patients with such high-risk diseases. 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. Ebrahimi A, Skardelly M, Schuhmann MU, et al. High frequency of H3 K27M mutations in adult midline gliomas. J Cancer Res Clin Oncol. 2019;145: 839-850. 3. 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.
H3 K27M MUTATED HYPOTHALAMUS GLIOBLASTOMA
9. Picart T, Barritault M, Berthillier J, et al. Characteristics of cerebellar glioblastomas in adults. J Neurooncol. 2018;136:555-563. 10. Uppar A, Konar SK, Nandeesh BN, Shukla D. H3k27m- positive primary spinal gliobastoma presenting with haemorrhage- a rare clinical entity [e-pub ahead of print]. World Neurosurg https://doi. org/10.1016/j.wneu.2019.03.025, accessed March 12, 2019. 11. Orillac C, Thomas C, Dastagirzada Y, et al. Pilocytic astrocytoma and glioneuronal tumor with 307 histone H3 K27M mutation. Acta Neuropathol Commun. 2016;4:84. 12. El Ahmadieh TY, Plitt A, Kafka B, et al. H3 K27M mutations in thalamic pilocytic astrocytomas with anaplasia [e-pub ahead of print]. World Neurosurg https://doi.org/10.1016/j.wneu.2018.12.147, accessed January 10, 2019. 13. Louis DN, Giannini C, Capper D, et al. cIMPACTNOW update 2: diagnostic clarifications for diffuse midline glioma, H3 K27M-mutant and diffuse astrocytoma/anaplastic astrocytoma, IDHmutant. Acta Neuropathol. 2018;135:639-642. 14. Gessi M, Capper D, Sahm F, et al. Evidence of H3 K27M mutations in posterior fossa ependymomas. Acta Neuropathol. 2016;132:635-637.
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20. Lewis PW, Müller MM, Koletsky MS, et al. Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science. 2013;340:857-861.
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22. Castel D, Philippe C, Calmon R, et al. Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes. Acta Neuropathol. 2015;130:815-827.
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Conflict of interest statement: This work was supported by the Scientific Plan Program of Guangdong (2017A020215160) and Shenzhen Innovation Funding under Grant (JCYJ20170413161314734). Received 6 February 2019; accepted 20 April 2019 Citation: World Neurosurg. (2019) 128:527-531. https://doi.org/10.1016/j.wneu.2019.04.172 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Published by Elsevier Inc.
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