- Email: [email protected]
Pediatric diffuse intrinsic anaplastic astrocytoma of the medulla oblongata
Accepted Manuscript Pediatric diffuse intrinsic anaplastic astrocytoma of the medulla oblongata
Amir Kershenovich, Amber Valeri PII: DOI: Reference:
S2214-7519(17)30188-3 doi:10.1016/j.inat.2018.02.006 INAT 291
To appear in:
Interdisciplinary Neurosurgery: Advanced Techniques and Case Management
Received date: Revised date: Accepted date:
19 May 2017 17 January 2018 11 February 2018
Please cite this article as: Amir Kershenovich, Amber Valeri , Pediatric diffuse intrinsic anaplastic astrocytoma of the medulla oblongata. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Inat(2017), doi:10.1016/j.inat.2018.02.006
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Pediatric Diffuse Intrinsic Anaplastic Astrocytoma of the Medulla Oblongata. Case report.
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Amir Kershenovicha,b*, M.D., M.H.A., and Amber Valerib, DO.
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Temple School of Medicine, 3500 N Broad St, Philadelphia, Pennsylvania, USA
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Department of Neurosurgery, Geisinger Health System. Geisinger Medical Center and Janet Weis Children’s Hospital, 100 North Academy Ave., Danville, Pennsylvania, USA.
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Amber Valeri, DO. E-mail: [email protected]
*Corresponding Author:
Director, Pediatric Neurosurgery
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Department of Neurosurgery Geisinger Health System
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M.C. 14-05, MH2 100 North Academy Avenue,
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Danville, PA (USA) 17822-1405 Phone: 570-271-6360 Option 3 Fax: 570-214-0083
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Amir Kershenovich, M.D.
E-mail: [email protected]
ACCEPTED MANUSCRIPT Abstract:
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Focal tumors of the brain stem are classically low grade astrocytomas. We present the rare case of a child with an anaplastic astrocytoma confined to the medulla oblongata. An 11-year-old male found to have an intrinsic tumor of the medulla oblongata; the initial MRI was equivocal for determining the focal or diffuse nature of the tumor. After a subtotal resection followed by aggressive adjuvant therapy, rapid deterioration and death occurred at 16 months after initial diagnosis and surgery. Diffuse intrinsic anaplastic astrocytomas confined to the medulla oblongata are extremely rare. Diffuse tension imaging, a short period of symptoms, and presence of cranial nerve deficits are suggestive of a malignant histopathology. Prognosis is poor.
ACCEPTED MANUSCRIPT Introduction: Within the United States, cancer in the pediatric population is the leading cause of death in children from ages 1-15 years old. Second only to leukemia in frequency, central nervous system tumors comprise 20% of childhood cancers. Approximately 60% of pediatric brain tumors are located infratentorially, with brain stem neoplasms, the majority of which are gliomas, comprising 25% of the posterior fossa tumors3,10.
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Brainstem gliomas (BSG) are a heterogeneous group of tumors that have been classified by location and pathology10. Arising from the midbrain, pons, medulla oblongata, or cervicomedullary junction, BSGs are characterized as diffuse, focal, dorsally exophytic, or cervicomedullary13,24.
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Diffuse intrinsic tumors comprise 80% of BSG and are typically high grade tumors2,3,10 and are located or centered in the pons10,12,13. Focal or dorsally exophytic tumors located in the midbrain, medulla or cervicomedullary junction are classically WHO-1 or 2 low grade astrocytomas2,3,10. The WHO in 2016 classified pediatric tumors located in the midline (e.g., thalamus, brain stem, and spinal cord) with a diffuse growth pattern as diffuse midline gliomas, characterized by a K27M mutation in the histone H3 gene H3F3A, or less commonly in the related HIST1H3B gene, which includes tumors previously referred to as diffuse intrinsic pontine glioma (DIPG)28.
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Here we present the rare case of a child with a diffuse intrinsic WHO-3 anaplastic astrocytoma of the medulla oblongata, thought per initial imaging to be a focal tumor.
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Case Report
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Presentation
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An 11-year-old Caucasian male presented with history of four weeks of dizziness, ataxia, epigastric pain, nausea and non-bloody, non-bilious daily intractable emesis, treated initially as viral gastritis. He then developed left arm monoparesis, had a single episode of headache, and was seen to have a hoarse voice, dysphagia, unintentional weight loss of 2.5 kilograms, and dysdiadochokinesis. A brain MRI demonstrated a brain stem tumor confined to the posterior medulla oblongata, suspected to be focal and intrinsic by the imaging characteristics. On exam, vital signs were within normal limits and stable, and the findings from the affected neurological functions were dysphonia and dysarthria, right palate and right vocal cord paresis, 4/5 left hemiparesis, mild ataxia, wide-based gate, failed tandem gait, bilateral, left worse than right dysmetria and dysdiadochokinesia, bilateral clonus, more on the left, and diffuse hyperreflexia.
ACCEPTED MANUSCRIPT Imaging
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A brain MRI with and without gadolinium, demonstrated a defined intrinsic T1 weighted hypointense and T2 weighted hyperintense image lesion in the posterior medulla oblongata, measuring 2.4 cm in diameter, suspected to be focal and intrinsic, with peripheral edema and mild effacement of the 4th ventricle. Diffusion tensor imaging (DTI) showed portions of the cortciospinal tracts displaced anteriorly with portions of the medial lemniscus and smaller posterior tracts splayed postero-laterally. It also demonstrated some neural tracts inside the tumor with most tracts displaced peripherally to the mass. The imaging findings were somehow equivocal, such that the decision on the degree of tumor resection was left to be determined at surgery, when the focal or diffuse nature of the tumor would become clearer.
Management
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Microscopic surgery was performed through an occipital craniotomy with C1 laminectomy, assisted by navigation and intraoperative ultrasound guidance, electrophysiological monitoring including somatosensory and motor evoked potentials, subcortical stimulation, and apneustic center monitoring. Sub-total resection of the brain stem intramedullary tumor with a duraplasty was performed. Estimated resection of the mass was 90-95%. A more aggressive resection was not pursued based on electrophysiological monitoring, that indicated that the medullary decussation was situated within the lower part of the tumor, and changes in respirations (deep, spontaneous irregular inspiratory breaths and bradipnea) when the tumor was being removed at the apneustic center, located slightly superior and to the left from the medullary decussation.
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Prior to surgery, we planned on keeping the patient intubated for 5-7 days. However, postoperatively, on day 2, a failed extubation trial was attempted; he required to be re-intubated secondary to significant stridor. Prior to the re-intubation, a laryngoscopy performed by the pediatric otolaryngologist, demonstrated bilateral vocal cord paralysis. His postoperative neurological exam consisted of 5/5 muscle strength in all extremities, equally reactive pupils with full and coordinated extraocular movements, symmetric facial movements, right tongue weakness, spontaneous cough and present gag reflex. The preoperative abnormal Babinski reflex normalized, and deep tendon reflexes were diffusely 2+. On post-operative day 8, the patient was successfully extubated. He continued to have dysphonia, but without dysphagia. Ataxia was present with walking, which improved and normalized over time assisted by physical therapy. Pathology Intraoperative frozen section demonstrated an infiltrative glioma positive for malignancy. Microscopic findings showed an infiltrative astrocytic tumor composed of moderately pleomorphic cells with scant cytoplasm and irregular hyperchromatic nuclei. Mitoses were present. There was no vascular endothelial proliferation or necrosis. Immunostains for neurofilament protein highlighted nerve fibers consistent with infiltration. Neoplastic cells were positive for GFAP and Olig-2. Immunostains for Neu-N and synaptophysin were negative in
ACCEPTED MANUSCRIPT tumor cells but positive in entrapped neurons. Most of neoplastic nuclei were positive for p53. Immunostain for IDH1(R132H) was negative. K27M mutations were not assessed (this case took place before the WHO 2016 classification). Immunostain for MIB-1 showed an elevated labeling index of 20%. Diagnosis was consistent with a WHO-III anaplastic astrocytoma (Figures 1-3).
Follow up
Discussion:
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Following surgery, the patient was discharged from the hospital and as an outpatient, received adjuvant temozolomide with concurrent intensity modulated radiation therapy to the medulla and adjacent brainstem. Radiation therapy was initiated 26 days after surgery, and completed using 180cGy of radiation given in 31 fractions in 42 days. With the 42 days of radiation therapy, the patient received temozolomide 100mg daily. After the conclusion of the concurrent radiation and temozolomide, the patient was maintained on 200mg of temozolomide for five days every month. Eight months after the surgical resection, a brain MRI showed leptomeningeal dissemination, with an enhancing small lesion in the left frontal horn of the lateral ventricle and spinal drop metastasis. He presented emergently with hydrocephalus and an external ventricular drain was inserted initially, followed by a ventriculo-peritoneal shunt, with an integrated on/off valve for potential intrathecal chemotherapy. Proton beam craniospinal radiaiton was given along with weekly carboplatin, followed by adjuvant maintenance therapy with avastin and irinotecan. Six months later (14 months after surgery) a control MRI showed significant reduction of the enhancement, no new lesions, but persistent T2 hyperintensity and mild mass effect of the hypothalamus; family decided to discontinue all chemotherapy agents and pursued alternative approaches. At 16 months after surgery a head CT showed evidence of disease progression with new areas of enhancement in the hypothalamus, extending into the suprasellar region as well as new spots in the 4th ventricle and more leptomeningeal enhancement. No changes regarding the shunted hydrocephalus. Clinically he deteriorated with worsened slurring of speech, drooling, dysphagia an ataxia and wheelchair bound and died shortly after, 16 months following his initial diagnosis and surgery.
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Initial investigation for a brainstem glioma includes an MRI to better characterize the tumor2,3,10. Surgical management is not dependent on the histological grade of the tumor, but is dependent on the diffuse or non-diffuse nature of the tumor10,13, which is typically assessed through MRI. Due to their difficult location and high probability of neurologic sequellae following surgery, diffuse brainstem gliomas are often considered unresectable3,10,13, whereas surgery is generally successful in focal or dorsally exophytic tumors with a low surgical mortality2,3,10. Classically, diffuse intrinsic brain stem gliomas present with rapidly progressive symptoms and are located in the pons, while focal tumors are located in the midbrain, medulla or cervicomedullary junction10, 13. Tumors located exclusively in the medulla oblongata, like our case, are rare and have been reported in 0-21% of brain stem tumors series26.
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After a thorough review of the medical literature published in English, we could not find any other case like the one we described, whether adult or child, representing an intrinsic diffuse anaplastic astrocytoma confined to the medulla oblongata only. We did find though, case reports and case series of other intrinsic, non-exophytic tumors of the medulla oblongata, excluding the cervico-medullary tumors, which spanned a myriad of tumors such as glioblastomas multiforme (GBM) in adolescents and adults14-18, 25, germinomas in children and young adults19, low grade and anaplastic gangliogliomas in children and adults25, low grade astrocytomas in children25, oligodendrogliomas26, gangliocytomas, gangliogliomas, ependymomas and metastasis19-23,25.
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In one of the largest isolated medulla oblongata lesions series, 16 of 34 cases were neoplasms, 5 vascular malformations, 5 demyelinating / inflammatory lesions, 1 infection, 4 of other type and 3 unknown; seven of the 16 neoplasms had confirmatory pathology with the tumor being pilocytic strocytoma, neuroblastoma-like schwannoma, hemangioblastoma, low grade glioneuronal tumor, choroid plexus papilloma and GBM20. MRI patterns showed that all cystic lesions were neoplasms or cysts; all exophytic non-cystic lesions were neoplasms; all non-cystic nonexophytic lesions that contained T2 hypointensity were vascular malformations; the enhancing intrinsic lesion group represented a combination of various etiologies; and the expansile non-enhancing intrinsic lesions were neoplasms and hypertrophic olivary degeneration20.
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The medulla oblongata contains the cardiac, respiratory, vomiting and vasomotor centers of the human body; it is responsible for modulating the autonomic, involuntary functions, such as breathing, heart rate and blood pressure. Patients with primary lesions of the medulla oblongata commonly present, like our patients, with dysphagia, cough, and limb sensory-motor disorders, and may often complain of headache, impaired vision, and hiccups among other symptoms. Surgical risk is considerable, and dyspnea and dysphagia are common after surgery19, 25. Given that this risk is also high for a brain stem biopsy, authors have attempted to find magnetic resonance imaging characteristics that, together with the clinical features, could more precisely render a radiological, non-invasive, diagnosis20. In our case, we were alerted by the neuro-radiologist, that some neuronal axonal fibers were detected by the DTI series to be intrinsic, though most were displaced by the tumor. This information changed our approach and helped also informed parents that a gross total resection would not necessarily be attempted nor achieved, and that the tumor could be more invasive and malignant than a focal intrinsic tumor would be. During surgery, the areas that were not resected, did look and feel like tumor, but clearly contained normal eloquent neural structures, confirming the diffuse nature of the tumor. The surgery was carefully planned utilizing brain lab navigation and intraoperative ultrasound guidance as well as intraoperative somatosensory evoked potentials, subcortical stimulation, and apneustic center monitoring to guide the microscopic dissection. The somatosensory and motor evoked potentials reduced to minimal the damage to the white matter tracts traveling through the tumor. The apneustic center monitoring, which helped detect changes in respiration, resulting in
ACCEPTED MANUSCRIPT deep spontaneous irregular breaths and bradipnea, guided the resection of the tumor to avoid damaging the medullary respiratory neurons.
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After surgery, our patient was treated with standard conventional focal radiation3,4,10,12 over 41 days, and chemotherapy. During this time, he had resolution of his neurologic deficits; his dysphonia improved but persisted. Radiotherapy has been seen to prolong progression-free survival periods in diffuse intrinsic brain stem tumors, but overall survival has not been affected3,10,13. The median onset of disease progression after radiation is less than 6 months5. Because there is a transient response to radiotherapy, radiation doses with hyperfractionation have been advocated, but the results have shown similar responses3,12. In an attempt to prolong survival of diffuse brainstem gliomas, many studies have explored the addition of adjuvant chemotherapy to radiation. Many chemotherapeutic medications have been studied, such as temozolomide, cisplastin, vincristine, carboplatin, irinotecan and etoposide, among others, with no improvement in survivability1,3,4,11-13. Despite advances in treatment, the majority of children with malignant, diffuse brainstem gliomas survive an average of 10 months after diagnosis, and have a 25% survival rate at 24 mohts7,10,13. Poor prognostic indicators of brainstem gliomas include shorter duration of symptoms at presentation, which was 2.6 months in our patient, compared to 10.6 months for non-diffuse gliomas, and the presence of cranial nerve deficits7,8, not usually present in nondiffuse tumors.
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For our patient, since a biopsy would have been an open one and not stereotactically done, and given that we were unsure of the focal intrinsic or diffuse intrinsic nature of the tumor, we recommended surgery to attempt to resect the tumor, with a very conservative strategy. Interestingly, despite the fact that the tumor was diffuse and malignant, many of the white fibers were displaced, which allowed for a wide and safe resection. Never the less, we cannot ascertain that surgery had a yield in improving tumor progression survival nor overall survival, nor can we state the same for radio or chemotherapy in this case. Given the very high surgical morbidity, we believe that an open biopsy is probably a more adequate first step to take, as it can spare a larger resection. This however, may still require neurophysiological monitoring and navigation guidance; so the bottom line is that the surgery is the same as the one attempted for a broad resection, only that with a plan to obtain just a few sample pieces of the tumor. The subtotal resection on the other hand can potentially reduce the burden that the tumor causes on the brain stem and provide some better quality of life during the survival period. With the advent of better imaging modalities, such as advanced diffusion MRI fiber tractography27, it will be easier to detect the presence of white matter fibers within tumors of the brain stem, making diagnosis more accurate.
Conclusions Diffuse midline anaplastic astrocytomas confined to the medulla oblongata are extremely rare.
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Though MRI characteristics in our patient were not similar to those classically seen in diffuse intrinsic pontine gliomas, diffuse tension imaging, together with the short period of symptom development and presence of cranial nerve deficits hinted about the malignant nature of the tumor. Prognosis was poor as with other malignant diffuse brain stem tumors despite a wide subtotal surgical resection, radio and chemotherapy.
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References:
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1. Broniscer A, Iacono L, Chintagumpala M, Fouladi M, Wallack D, et al. Role of Temozolomide after radiotherapy for newly diagnosed diffuse brainstem glioma in children. Cancer 2004; 103: 133-139. 2. Dellaretti M, Reyns N, Touzet G, Duboise F, et al. Diffuse brainstem glioma: prognostic factors. Journal of Neurosurgery 2012; 117: 810-814. 3. Donaldson SS, Laningham F, Fisher PG. Advances toward an understanding of brainstem gliomas. Journal of Clinical Oncology 2006; 24:1266-1272. 4. Frazier JL, Lee J, Thomale UW, Noggle JC, Cohen K, Jallo G. Treatment of diffuse intrinsic brainstem gliomas: failed approaches and future strategies. Journal of Pediatric Neurosurgery 2009; 3:259-269. 5. Hargrave D, Bartels U, Bouffet. Diffuse brainstem glioma in children: critical review of clinical trials. Lancet Oncology 2006; 7:241-248. 6. Johnson TS, Munn DH, Maria BL. Modulation of tumor tolerance in primary central nervous system malignancies. Clinical and Developmental Immunology 2012;2012:937253. doi:10.1155/2012/937253. 7. Mauffrey C. Pediatric brainstem gliomas: prognostic factors and management. Journal of Clinical Neuroscience 2006; 13: 431-437. 8. Mostoufi-Moab S, Grimberg A. Pediatric brain tumor treatment: growth consequences and their management. Pediatric endocrinology reviews : PER 2010;8(1):6-17. 9. Qaddormi I, Sultan I, Gajjar A. Outcome and prognostic features in pediatric gliomas: A review of 6212 cases from the surveillance, Epidemiology and End Results (SEER) Database. Cancer 2009; 115(24):5761-5770. Doi:10.1002/cncr.24663.
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10. Schirmer CM, Goumnerova LC. Brainstem Gliomas. Youmans Neurological Surgery. 11th ed. Philadelphia, PA: Saunders/Elsevier, 2001. 2114-2120. Print. 11. Sharp JR, Bouffet E, Stempak D, Gammon J, Stephens D, et al. A Multi-centre Canadian pilot study of metronomic temozolomide combined with radiotherapy for newly diagnosed paediatric brainstem glioma. European Journal of Cancer 2010; 46:3271-3279. 12. Sirachainan N, Samart P, Visudithbhan A, Chiamchanya S, et al. Concurrent radiotherapy with temozolomide followed by adjuvant temozolomide and cis-retinoic acid in children with diffuse intrinsic pontine glioma. Neurologic Oncology 2008; 10: 577-582. 13. Sridhar K, Venkatprasanna G. Management of posterior fossa gliomas in children. Journal of Pediatric Neurology 2011; 6(Supple1):S72-S77. 14. Intraventricular Hemorrhage From a Glioblastoma in the Medulla Oblongata of an Adolescent: A Potential Diagnostic Pitfall, Hiroki Toda MD, PhD a,*, Mitsuaki Shirahata MD, PhDa,b, Koichi Iwasaki MD, PhDa, Pediatric Neurology 53 (2015) 545e546 15. Yoshimura J, Onda K, Tanaka R et al (2003) Clinicopathological study of diffuse type brainstem gliomas: analysis of 40 autopsy cases. Neurol Med Chir (Tokyo) 43:375–382 (discussion 382) 16. LuetjensG,MirzayanMJ,BrandisAet al (2009) Exophytic giant cell glioblastoma of the medulla oblongata. J Neurosurg 110:589–593 17 . Kyoshima K, Sakai K, Goto T et al (2004) Gross total surgical removal of malignant glioma from the medulla oblongata: report of two adult cases with reference to surgical anatomy. J Clin Neurosci 11:75–80 18. Progressive adult primary glioblastoma in the medulla oblongata with an unmethylated MGMT promoter and without an IDH mutation, Akifumi Yoshikawa • Mitsutoshi Nakada • Takuya Watanabe • Yutaka Hayashi • Hemragul Sabit • Yukinari Kato • Shioto Suzuki • Akishi Ooi • Hiroshi Sato • Jun-ichiro Hamada Brain Tumor Pathol (2013) 30:175–179 19. Primary medulla oblongata germinomas: two case reports and review of the literature Shuyu Hao1†, Da Li1†, Jie Feng2, Liang Wang1, Zhen Wu1, Junting Zhang1 and Liwei Zhang1 World Journal of Surgical Oncology 2013, 11:274 20. MRI Patterns of Isolated Lesions in the Medulla Oblongata Supada Prakkamakul, Pamela Schaefer, Gilberto Gonzalez, Otto Rapalino J Neuroimaging. 2016 May 25. doi: 10.1111/jon.12361. [Epub ahead of print] 21. Friedman WA, Vries JK, Quisling RG. Ganglioglioma of the medulla oblongata. Surg Neurol 1979;12:105-8. 22. DiLuna ML, Levy GH, Sood S, et al. Primary myxopapillary ependymoma of the medulla: case report. Neurosurgery 2010;66:E1208-9; discussion E9. 23. Awa R, Hanaya R, Hirano H, et al. Gangliocytoma of the medulla oblongata demonstrating high tracer uptake on positron emission tomography. J Neurooncol 2012;106:201-2.
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24. Epstein FJ, McCleary EL: Instrinsic brainstem tumors of childhood: Surgical indications, Journal of Neurosurgery, 1986; 64: 11-15. 25. Pediatr Neurosurg. 1991-1992;17(5):239-44. Intrinsic tumors of the medulla: surgical complications. Abbott R1, Shiminski-Maher T, Wisoff JH, Epstein FJ. 26. Front Surg. 2016 Jan 13;2:72. Surgical Application of the Suboccipital Subtonsillar Approach to Reach the Inferior Half of Medulla Oblongata Tumors in Adult Patients. Rabadán AT1, Campero A2, Hernández D1. 27. Meola, Antonio MD; Yeh, Fang-Cheng MD, PhD; Fellows-Mayle, Wendy PhD; Weed, Jared; Fernandez-Miranda, Juan C. MD, Human Connectome-Based Tractographic Atlas of the Brainstem Connections and Surgical Approaches, Neurosurgery: September 2016 - Volume 79 - Issue 3 - p 437–455
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28. David N. Louis, Arie Perry, Guido Reifenberger, Andreas von Deimling, Dominique Figarella‑ Branger, Webster K. Cavenee, Hiroko Ohgaki, Otmar D. Wiestler, Paul Kleihues, David W. Ellison. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary, Acta Neuropathologica, 2016 Jun;131(6):803-20
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Figure Legends
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Figure 1. H&E stain 200x. Photomicrograph shows moderately cellular tumor composed of cells with scant cytoplasm and atypical, angular and hyperchromatic nuclei.
Fig 2. H&E 600x. High power view of tumor showing two mitoses, white arrows.
Fig 3. Immuno-histochemical stain x200. Photomicrograph showing high Ki-67 labeling index.
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Disclosure: The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.
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Highlights: Malignant intrinsic tumor of the medulla oblongata are rare. MR Diffuse tension imaging can help determine the invasiveness of an intrinsic medullary tumor. A short period of symptoms, and presence of cranial nerve deficits are suggestive of a malignant histopathology.
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Amir Kershenovich, Amber Valeri PII: DOI: Reference:
S2214-7519(17)30188-3 doi:10.1016/j.inat.2018.02.006 INAT 291
To appear in:
Interdisciplinary Neurosurgery: Advanced Techniques and Case Management
Received date: Revised date: Accepted date:
19 May 2017 17 January 2018 11 February 2018
Please cite this article as: Amir Kershenovich, Amber Valeri , Pediatric diffuse intrinsic anaplastic astrocytoma of the medulla oblongata. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Inat(2017), doi:10.1016/j.inat.2018.02.006
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Pediatric Diffuse Intrinsic Anaplastic Astrocytoma of the Medulla Oblongata. Case report.
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Amir Kershenovicha,b*, M.D., M.H.A., and Amber Valerib, DO.
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Temple School of Medicine, 3500 N Broad St, Philadelphia, Pennsylvania, USA
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Department of Neurosurgery, Geisinger Health System. Geisinger Medical Center and Janet Weis Children’s Hospital, 100 North Academy Ave., Danville, Pennsylvania, USA.
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Amber Valeri, DO. E-mail: [email protected]
*Corresponding Author:
Director, Pediatric Neurosurgery
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Department of Neurosurgery Geisinger Health System
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M.C. 14-05, MH2 100 North Academy Avenue,
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Danville, PA (USA) 17822-1405 Phone: 570-271-6360 Option 3 Fax: 570-214-0083
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Amir Kershenovich, M.D.
E-mail: [email protected]
ACCEPTED MANUSCRIPT Abstract:
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Focal tumors of the brain stem are classically low grade astrocytomas. We present the rare case of a child with an anaplastic astrocytoma confined to the medulla oblongata. An 11-year-old male found to have an intrinsic tumor of the medulla oblongata; the initial MRI was equivocal for determining the focal or diffuse nature of the tumor. After a subtotal resection followed by aggressive adjuvant therapy, rapid deterioration and death occurred at 16 months after initial diagnosis and surgery. Diffuse intrinsic anaplastic astrocytomas confined to the medulla oblongata are extremely rare. Diffuse tension imaging, a short period of symptoms, and presence of cranial nerve deficits are suggestive of a malignant histopathology. Prognosis is poor.
ACCEPTED MANUSCRIPT Introduction: Within the United States, cancer in the pediatric population is the leading cause of death in children from ages 1-15 years old. Second only to leukemia in frequency, central nervous system tumors comprise 20% of childhood cancers. Approximately 60% of pediatric brain tumors are located infratentorially, with brain stem neoplasms, the majority of which are gliomas, comprising 25% of the posterior fossa tumors3,10.
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Brainstem gliomas (BSG) are a heterogeneous group of tumors that have been classified by location and pathology10. Arising from the midbrain, pons, medulla oblongata, or cervicomedullary junction, BSGs are characterized as diffuse, focal, dorsally exophytic, or cervicomedullary13,24.
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Diffuse intrinsic tumors comprise 80% of BSG and are typically high grade tumors2,3,10 and are located or centered in the pons10,12,13. Focal or dorsally exophytic tumors located in the midbrain, medulla or cervicomedullary junction are classically WHO-1 or 2 low grade astrocytomas2,3,10. The WHO in 2016 classified pediatric tumors located in the midline (e.g., thalamus, brain stem, and spinal cord) with a diffuse growth pattern as diffuse midline gliomas, characterized by a K27M mutation in the histone H3 gene H3F3A, or less commonly in the related HIST1H3B gene, which includes tumors previously referred to as diffuse intrinsic pontine glioma (DIPG)28.
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Here we present the rare case of a child with a diffuse intrinsic WHO-3 anaplastic astrocytoma of the medulla oblongata, thought per initial imaging to be a focal tumor.
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Case Report
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Presentation
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An 11-year-old Caucasian male presented with history of four weeks of dizziness, ataxia, epigastric pain, nausea and non-bloody, non-bilious daily intractable emesis, treated initially as viral gastritis. He then developed left arm monoparesis, had a single episode of headache, and was seen to have a hoarse voice, dysphagia, unintentional weight loss of 2.5 kilograms, and dysdiadochokinesis. A brain MRI demonstrated a brain stem tumor confined to the posterior medulla oblongata, suspected to be focal and intrinsic by the imaging characteristics. On exam, vital signs were within normal limits and stable, and the findings from the affected neurological functions were dysphonia and dysarthria, right palate and right vocal cord paresis, 4/5 left hemiparesis, mild ataxia, wide-based gate, failed tandem gait, bilateral, left worse than right dysmetria and dysdiadochokinesia, bilateral clonus, more on the left, and diffuse hyperreflexia.
ACCEPTED MANUSCRIPT Imaging
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A brain MRI with and without gadolinium, demonstrated a defined intrinsic T1 weighted hypointense and T2 weighted hyperintense image lesion in the posterior medulla oblongata, measuring 2.4 cm in diameter, suspected to be focal and intrinsic, with peripheral edema and mild effacement of the 4th ventricle. Diffusion tensor imaging (DTI) showed portions of the cortciospinal tracts displaced anteriorly with portions of the medial lemniscus and smaller posterior tracts splayed postero-laterally. It also demonstrated some neural tracts inside the tumor with most tracts displaced peripherally to the mass. The imaging findings were somehow equivocal, such that the decision on the degree of tumor resection was left to be determined at surgery, when the focal or diffuse nature of the tumor would become clearer.
Management
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Microscopic surgery was performed through an occipital craniotomy with C1 laminectomy, assisted by navigation and intraoperative ultrasound guidance, electrophysiological monitoring including somatosensory and motor evoked potentials, subcortical stimulation, and apneustic center monitoring. Sub-total resection of the brain stem intramedullary tumor with a duraplasty was performed. Estimated resection of the mass was 90-95%. A more aggressive resection was not pursued based on electrophysiological monitoring, that indicated that the medullary decussation was situated within the lower part of the tumor, and changes in respirations (deep, spontaneous irregular inspiratory breaths and bradipnea) when the tumor was being removed at the apneustic center, located slightly superior and to the left from the medullary decussation.
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Prior to surgery, we planned on keeping the patient intubated for 5-7 days. However, postoperatively, on day 2, a failed extubation trial was attempted; he required to be re-intubated secondary to significant stridor. Prior to the re-intubation, a laryngoscopy performed by the pediatric otolaryngologist, demonstrated bilateral vocal cord paralysis. His postoperative neurological exam consisted of 5/5 muscle strength in all extremities, equally reactive pupils with full and coordinated extraocular movements, symmetric facial movements, right tongue weakness, spontaneous cough and present gag reflex. The preoperative abnormal Babinski reflex normalized, and deep tendon reflexes were diffusely 2+. On post-operative day 8, the patient was successfully extubated. He continued to have dysphonia, but without dysphagia. Ataxia was present with walking, which improved and normalized over time assisted by physical therapy. Pathology Intraoperative frozen section demonstrated an infiltrative glioma positive for malignancy. Microscopic findings showed an infiltrative astrocytic tumor composed of moderately pleomorphic cells with scant cytoplasm and irregular hyperchromatic nuclei. Mitoses were present. There was no vascular endothelial proliferation or necrosis. Immunostains for neurofilament protein highlighted nerve fibers consistent with infiltration. Neoplastic cells were positive for GFAP and Olig-2. Immunostains for Neu-N and synaptophysin were negative in
ACCEPTED MANUSCRIPT tumor cells but positive in entrapped neurons. Most of neoplastic nuclei were positive for p53. Immunostain for IDH1(R132H) was negative. K27M mutations were not assessed (this case took place before the WHO 2016 classification). Immunostain for MIB-1 showed an elevated labeling index of 20%. Diagnosis was consistent with a WHO-III anaplastic astrocytoma (Figures 1-3).
Follow up
Discussion:
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Following surgery, the patient was discharged from the hospital and as an outpatient, received adjuvant temozolomide with concurrent intensity modulated radiation therapy to the medulla and adjacent brainstem. Radiation therapy was initiated 26 days after surgery, and completed using 180cGy of radiation given in 31 fractions in 42 days. With the 42 days of radiation therapy, the patient received temozolomide 100mg daily. After the conclusion of the concurrent radiation and temozolomide, the patient was maintained on 200mg of temozolomide for five days every month. Eight months after the surgical resection, a brain MRI showed leptomeningeal dissemination, with an enhancing small lesion in the left frontal horn of the lateral ventricle and spinal drop metastasis. He presented emergently with hydrocephalus and an external ventricular drain was inserted initially, followed by a ventriculo-peritoneal shunt, with an integrated on/off valve for potential intrathecal chemotherapy. Proton beam craniospinal radiaiton was given along with weekly carboplatin, followed by adjuvant maintenance therapy with avastin and irinotecan. Six months later (14 months after surgery) a control MRI showed significant reduction of the enhancement, no new lesions, but persistent T2 hyperintensity and mild mass effect of the hypothalamus; family decided to discontinue all chemotherapy agents and pursued alternative approaches. At 16 months after surgery a head CT showed evidence of disease progression with new areas of enhancement in the hypothalamus, extending into the suprasellar region as well as new spots in the 4th ventricle and more leptomeningeal enhancement. No changes regarding the shunted hydrocephalus. Clinically he deteriorated with worsened slurring of speech, drooling, dysphagia an ataxia and wheelchair bound and died shortly after, 16 months following his initial diagnosis and surgery.
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Initial investigation for a brainstem glioma includes an MRI to better characterize the tumor2,3,10. Surgical management is not dependent on the histological grade of the tumor, but is dependent on the diffuse or non-diffuse nature of the tumor10,13, which is typically assessed through MRI. Due to their difficult location and high probability of neurologic sequellae following surgery, diffuse brainstem gliomas are often considered unresectable3,10,13, whereas surgery is generally successful in focal or dorsally exophytic tumors with a low surgical mortality2,3,10. Classically, diffuse intrinsic brain stem gliomas present with rapidly progressive symptoms and are located in the pons, while focal tumors are located in the midbrain, medulla or cervicomedullary junction10, 13. Tumors located exclusively in the medulla oblongata, like our case, are rare and have been reported in 0-21% of brain stem tumors series26.
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After a thorough review of the medical literature published in English, we could not find any other case like the one we described, whether adult or child, representing an intrinsic diffuse anaplastic astrocytoma confined to the medulla oblongata only. We did find though, case reports and case series of other intrinsic, non-exophytic tumors of the medulla oblongata, excluding the cervico-medullary tumors, which spanned a myriad of tumors such as glioblastomas multiforme (GBM) in adolescents and adults14-18, 25, germinomas in children and young adults19, low grade and anaplastic gangliogliomas in children and adults25, low grade astrocytomas in children25, oligodendrogliomas26, gangliocytomas, gangliogliomas, ependymomas and metastasis19-23,25.
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In one of the largest isolated medulla oblongata lesions series, 16 of 34 cases were neoplasms, 5 vascular malformations, 5 demyelinating / inflammatory lesions, 1 infection, 4 of other type and 3 unknown; seven of the 16 neoplasms had confirmatory pathology with the tumor being pilocytic strocytoma, neuroblastoma-like schwannoma, hemangioblastoma, low grade glioneuronal tumor, choroid plexus papilloma and GBM20. MRI patterns showed that all cystic lesions were neoplasms or cysts; all exophytic non-cystic lesions were neoplasms; all non-cystic nonexophytic lesions that contained T2 hypointensity were vascular malformations; the enhancing intrinsic lesion group represented a combination of various etiologies; and the expansile non-enhancing intrinsic lesions were neoplasms and hypertrophic olivary degeneration20.
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The medulla oblongata contains the cardiac, respiratory, vomiting and vasomotor centers of the human body; it is responsible for modulating the autonomic, involuntary functions, such as breathing, heart rate and blood pressure. Patients with primary lesions of the medulla oblongata commonly present, like our patients, with dysphagia, cough, and limb sensory-motor disorders, and may often complain of headache, impaired vision, and hiccups among other symptoms. Surgical risk is considerable, and dyspnea and dysphagia are common after surgery19, 25. Given that this risk is also high for a brain stem biopsy, authors have attempted to find magnetic resonance imaging characteristics that, together with the clinical features, could more precisely render a radiological, non-invasive, diagnosis20. In our case, we were alerted by the neuro-radiologist, that some neuronal axonal fibers were detected by the DTI series to be intrinsic, though most were displaced by the tumor. This information changed our approach and helped also informed parents that a gross total resection would not necessarily be attempted nor achieved, and that the tumor could be more invasive and malignant than a focal intrinsic tumor would be. During surgery, the areas that were not resected, did look and feel like tumor, but clearly contained normal eloquent neural structures, confirming the diffuse nature of the tumor. The surgery was carefully planned utilizing brain lab navigation and intraoperative ultrasound guidance as well as intraoperative somatosensory evoked potentials, subcortical stimulation, and apneustic center monitoring to guide the microscopic dissection. The somatosensory and motor evoked potentials reduced to minimal the damage to the white matter tracts traveling through the tumor. The apneustic center monitoring, which helped detect changes in respiration, resulting in
ACCEPTED MANUSCRIPT deep spontaneous irregular breaths and bradipnea, guided the resection of the tumor to avoid damaging the medullary respiratory neurons.
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After surgery, our patient was treated with standard conventional focal radiation3,4,10,12 over 41 days, and chemotherapy. During this time, he had resolution of his neurologic deficits; his dysphonia improved but persisted. Radiotherapy has been seen to prolong progression-free survival periods in diffuse intrinsic brain stem tumors, but overall survival has not been affected3,10,13. The median onset of disease progression after radiation is less than 6 months5. Because there is a transient response to radiotherapy, radiation doses with hyperfractionation have been advocated, but the results have shown similar responses3,12. In an attempt to prolong survival of diffuse brainstem gliomas, many studies have explored the addition of adjuvant chemotherapy to radiation. Many chemotherapeutic medications have been studied, such as temozolomide, cisplastin, vincristine, carboplatin, irinotecan and etoposide, among others, with no improvement in survivability1,3,4,11-13. Despite advances in treatment, the majority of children with malignant, diffuse brainstem gliomas survive an average of 10 months after diagnosis, and have a 25% survival rate at 24 mohts7,10,13. Poor prognostic indicators of brainstem gliomas include shorter duration of symptoms at presentation, which was 2.6 months in our patient, compared to 10.6 months for non-diffuse gliomas, and the presence of cranial nerve deficits7,8, not usually present in nondiffuse tumors.
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For our patient, since a biopsy would have been an open one and not stereotactically done, and given that we were unsure of the focal intrinsic or diffuse intrinsic nature of the tumor, we recommended surgery to attempt to resect the tumor, with a very conservative strategy. Interestingly, despite the fact that the tumor was diffuse and malignant, many of the white fibers were displaced, which allowed for a wide and safe resection. Never the less, we cannot ascertain that surgery had a yield in improving tumor progression survival nor overall survival, nor can we state the same for radio or chemotherapy in this case. Given the very high surgical morbidity, we believe that an open biopsy is probably a more adequate first step to take, as it can spare a larger resection. This however, may still require neurophysiological monitoring and navigation guidance; so the bottom line is that the surgery is the same as the one attempted for a broad resection, only that with a plan to obtain just a few sample pieces of the tumor. The subtotal resection on the other hand can potentially reduce the burden that the tumor causes on the brain stem and provide some better quality of life during the survival period. With the advent of better imaging modalities, such as advanced diffusion MRI fiber tractography27, it will be easier to detect the presence of white matter fibers within tumors of the brain stem, making diagnosis more accurate.
Conclusions Diffuse midline anaplastic astrocytomas confined to the medulla oblongata are extremely rare.
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Though MRI characteristics in our patient were not similar to those classically seen in diffuse intrinsic pontine gliomas, diffuse tension imaging, together with the short period of symptom development and presence of cranial nerve deficits hinted about the malignant nature of the tumor. Prognosis was poor as with other malignant diffuse brain stem tumors despite a wide subtotal surgical resection, radio and chemotherapy.
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References:
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1. Broniscer A, Iacono L, Chintagumpala M, Fouladi M, Wallack D, et al. Role of Temozolomide after radiotherapy for newly diagnosed diffuse brainstem glioma in children. Cancer 2004; 103: 133-139. 2. Dellaretti M, Reyns N, Touzet G, Duboise F, et al. Diffuse brainstem glioma: prognostic factors. Journal of Neurosurgery 2012; 117: 810-814. 3. Donaldson SS, Laningham F, Fisher PG. Advances toward an understanding of brainstem gliomas. Journal of Clinical Oncology 2006; 24:1266-1272. 4. Frazier JL, Lee J, Thomale UW, Noggle JC, Cohen K, Jallo G. Treatment of diffuse intrinsic brainstem gliomas: failed approaches and future strategies. Journal of Pediatric Neurosurgery 2009; 3:259-269. 5. Hargrave D, Bartels U, Bouffet. Diffuse brainstem glioma in children: critical review of clinical trials. Lancet Oncology 2006; 7:241-248. 6. Johnson TS, Munn DH, Maria BL. Modulation of tumor tolerance in primary central nervous system malignancies. Clinical and Developmental Immunology 2012;2012:937253. doi:10.1155/2012/937253. 7. Mauffrey C. Pediatric brainstem gliomas: prognostic factors and management. Journal of Clinical Neuroscience 2006; 13: 431-437. 8. Mostoufi-Moab S, Grimberg A. Pediatric brain tumor treatment: growth consequences and their management. Pediatric endocrinology reviews : PER 2010;8(1):6-17. 9. Qaddormi I, Sultan I, Gajjar A. Outcome and prognostic features in pediatric gliomas: A review of 6212 cases from the surveillance, Epidemiology and End Results (SEER) Database. Cancer 2009; 115(24):5761-5770. Doi:10.1002/cncr.24663.
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28. David N. Louis, Arie Perry, Guido Reifenberger, Andreas von Deimling, Dominique Figarella‑ Branger, Webster K. Cavenee, Hiroko Ohgaki, Otmar D. Wiestler, Paul Kleihues, David W. Ellison. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary, Acta Neuropathologica, 2016 Jun;131(6):803-20
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Figure Legends
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Figure 1. H&E stain 200x. Photomicrograph shows moderately cellular tumor composed of cells with scant cytoplasm and atypical, angular and hyperchromatic nuclei.
Fig 2. H&E 600x. High power view of tumor showing two mitoses, white arrows.
Fig 3. Immuno-histochemical stain x200. Photomicrograph showing high Ki-67 labeling index.
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Disclosure: The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.
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Highlights: Malignant intrinsic tumor of the medulla oblongata are rare. MR Diffuse tension imaging can help determine the invasiveness of an intrinsic medullary tumor. A short period of symptoms, and presence of cranial nerve deficits are suggestive of a malignant histopathology.
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