- Email: [email protected]
H3K27M-Positive Primary Spinal Glioblastoma Presenting with Hemorrhage—A Rare Clinical Entity
Accepted Manuscript H3k27m- Positive Primary Spinal Gliobastoma Presenting With Haemorrhage- A Rare Clinical Entity Alok Uppar, MCh, Subhas K. Konar, MCh, B.N. Nandeesh, M. D, Dhaval Shukla, MCh PII:
S1878-8750(19)30651-5
DOI:
https://doi.org/10.1016/j.wneu.2019.03.025
Reference:
WNEU 11703
To appear in:
World Neurosurgery
Received Date: 20 December 2018 Revised Date:
1 March 2019
Accepted Date: 2 March 2019
Please cite this article as: Uppar A, Konar SK, Nandeesh BN, Shukla D, H3k27m- Positive Primary Spinal Gliobastoma Presenting With Haemorrhage- A Rare Clinical Entity, World Neurosurgery (2019), doi: https://doi.org/10.1016/j.wneu.2019.03.025. 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
Title page: Case Report
RI PT
Title: H3K27M- POSITIVE PRIMARY SPINAL GLIOBASTOMA PRESENTING WITH HAEMORRHAGE- A RARE CLINICAL ENTITY.
Alok Uppar, MCh1, Subhas K. Konar, MCh1, Nandeesh B. N, M. D2, Dhaval Shukla, MCh1 1: Department of Neurosurgery, National Institute of Mental Health and Neurosciences, Bangalore, India.
M AN U
SC
2: Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore, India.
Correspondence: Dr. Subhas K. Konar, MCh
TE D
Assistant Professor, Department of Neurosurgery
National Institute of Mental Health and Neurosciences (NIMHANS)
EP
Bangalore 560029 Mobile: 09986438181
AC C
Email: [email protected]
Conflict of Interest: Nil
Inform Consent: Taken from patient. Page: Manuscript:8.
ACCEPTED MANUSCRIPT
H3K27M- POSITIVE PRIMARY SPINAL GLIOBASTOMA PRESENTING
RI PT
WITH HAEMORRHAGE- A RARE CLINICAL ENTITY.
ABSTRACT
Primary Spinal GBM (sGBM) is a rare and aggressive spinal tumor with dismal outcomes. The authors present an unusual case- the first of its kind, with intra-tumoral hemorrhage and sudden
SC
onset quadriplegia in a case of primary sGBM. Patient was managed with emergency surgical decompression. Eventually the patient succumbed after a prolonged ICU stay. The tumor was
M AN U
positive for histone molecular alteration- ‘H3K27M’.
KEYWORDS: Primary Spinal Glioblastoma, Hemorrhage, H3K27M, Surgery. INTRODUCTION
Primary glial tumors account for a majority of intramedullary tumors which include
TE D
astrocytomas (nearly1%)[1], ependymomas, and less commonly glial neoplasms such as gangliogliomas. Primary spinal GBMs are rare with an incidence of nearly 7.5% of all intramedullary gliomas which account for nearly 1 to 3% of all spinal cord tumors [2, 3]. The
EP
cervical and dorsal spine are the commonly involved areas followed by cervico-thoracic junction[1, 4]. There have been reports of GBM in the conus medullaris also[5, 6]. Treatment options available are surgical decompression and adjuvant chemoradiation. The prognosis,
AC C
however, remains dismal; with patients after treatment having a mean average survival of nearly 14 months with a median of 16 months[7].Also, a few authors have reported cordectomy for lower spinal cord GBMs with prolonged survival[8, 9]. Intratumoral hemorrhage with sudden clinical deterioration is described in ependymomas(11 cases) and few hemangioblastomas but not in other intramedullary tumors[10].
ACCEPTED MANUSCRIPT
CASE REPORT 28- year -old lady was referred with complaints of numbness of right hand and mild weakness of right handgrip for 1 month. This was followed by numbness in the right lower limb and mild
RI PT
stiffness in both lower limbs for 15 days. This was followed by a sudden onset weakness of both upper limbs and lower limbs. She had transient urgency in urination which had gradually
improved over a month. On examination, she had flaccid weakness of right upper limb (0/5 power), left upper limb had normal tone and power of 2/5(MRC grade). Bilateral lower limb
SC
power was 4/5 with increased tone and exaggerated deep tendon reflexes with upgoing planters. She had a graded sensory loss below C5 dermatome. MRI Cervical spine revealed an enlarged cord from C3 to C7 level with T1 isointense, T2 hyperintense signals with multiple foci of
M AN U
blooming seen on gradient images which suggested a lesion with bleed. The lesion was heterogeneously enhancing on contrast and had significant perilesional edema extending up to D5 level. (FIGURE 1, 2) She was admitted, and surgery was planned under SSEP and MEP monitoring the next day. However, she had another episode of a sudden deterioration in the ward; became quadriplegic and developed shallow respiration for which she was intubated and taken up for surgery on an emergency basis. She underwent C3-C7 laminectomy, gross total
TE D
decompression of tumor. The lesion had areas of reddish discoloration- suggestive of an acute hemorrhagic event. There was a good plane all around the lesion and surrounding cord looked edematous. Post-operatively, she did not show any improvement in motor power and remained quadriplegic. She received mechanical ventilation and had a prolonged ICU stay of 15 days.
EP
After 15 days of ICU admission and multiple attempts at weaning- which was unsuccessful, she developed CSF leak through surgical wound site for which lumbar drain was placed
AC C
immediately. CT brain was done, and hydrocephalus was ruled out. CSF showed plenty of pus cells and grew Acinetobacter baumanii and appropriate antibiotics were started. However, she deteriorated in sensorium on post-op day 20 and succumbed to infection three days later. The histopathological examination (FIGURE 3) performed on the tissue revealed a cellular tumor composed of cells with clear cytoplasm which were arranged in sheets and possessing cytoplasmic processes resembling glial cells (Figure A). The neoplasm was highly vascular with intervening vessels being dilated and congested along with proliferating vasculature (Figure B, Inset). Mitosis was increased in cellular areas. Areas of necrosis were observed (Figure B) seen. On immunohistochemical analysis, the tumor cells were diffusely positive for GFAP
ACCEPTED MANUSCRIPT
(Figure D) and H3K27M was positive in tumor cells (Figure C) with H3Me3 showing a global reduction of expression in tumor cells. Isocitrate dehydrogenase staining (Figure:4, A&B) was
RI PT
done and it was negative. The neoplasm showed increased MIB-1 labeling (15%).
DISCUSSION
The total number of primary sGBMs reported till date stands at less than 200. The survival and overall prognosis remain dismal which can be attributed to the malignant nature of the disease
SC
itself and to the decreased scope of achieving a gross total decompression in view of surrounding spinal cord damage. Various factors are described which predict the survival in patients with
M AN U
primary spinal GBM [11].
Although there have been a handful of case reports and a few series describing this disease, the present case, to the best of our knowledge is the first of its kind to be reported which has presented with a tumor bleed associated with acute clinical deterioration as well as H3K27M positivity. Our patient had two episodes of clinical deterioration, the first – which resulted in
TE D
sudden lower limb stiffness, worsening of upper limb power and the second instance, a bleed of greater magnitude resulted in sudden quadriplegia and respiratory failure. This was also corroborating with our MRI and intra-op findings. Primary spinal GBM lesions appear as infiltrative, expansile masses with high T2 signal and heterogeneous enhancement on
EP
postcontrast T1-weighted sequences[12-14]. The MRI showed features of multiple foci of acute bleed (T1-ISO, T2 HYPER) and foci of blooming on gradient images. The intra-operative
AC C
findings also revealed lesion with blood and clots. These tumors are also known to show variable MRI characteristics which may give rise to diagnostic ambiguity. The presence of acute bleedlike findings on MRI may further complicate the issue with respect to radiological diagnosis. However, it necessitates prompt surgical action as conditions like demyelination/ transverse myelitis do not bleed.
The possible explanation for such bleed could be the association of tumor with proangiogenic factors like VEGF. Also, small vascular malformations associated with gliomas in general(cavernous angioma, venous malformation) could be another possibility, which has been
ACCEPTED MANUSCRIPT
described by a few authors[15, 16]; although it was not seen on the detailed histopathological analysis in our case. Spinal ependymoma is known to present with bleed[10]. One case report of sGBM presenting with a secondary cerebral vascular malformation is described[17]. But there are no such reports of malformation or hemorrhage associated with sGBM. It is proposed that the
RI PT
hyper-angiogenic environment of high-grade tumors induces abnormal arteriovenous
connections which might have given rise to abnormal primitive vessels which might have resulted in bleed[18].
SC
Only a few dedicated studies describe molecular alterations in spinal gliomas[19-21]. Diffuse leptomeningeal glioneuronal tumor with H3K27M mutation has also been described[22]. Another case report describing a 25-year-old lady succumbing to leptomeningeal gliomatosis
M AN U
which was H3K27M mutant was recently published[23]. The H3K27M mutation is the most common mutation among genes encoding histone protein H3 viz H3.1 AND H3.3. Also, the K27M mutation is proven and well known to be one of the early hallmark events during glioma genesis [24]. Molecular alterations were studied in our present which revealed positive TP53 expression, H3K27M mutation. The presence of H3K27M mutation confers a poor prognosis and is usually associated with midline GBMs and has been well validated in the pediatric age
TE D
group by various authors[25]. However, to the best of our knowledge, the present report is one of the first of its kind describing a positive H3K27M mutant primary sGBM presenting with an acute bleed. Future studies directed towards understanding the incidence, clinicopathological correlations associated with such novel markers like H3K27M mutation would be of great help
EP
towards using specific targeted therapy. A new molecule EZH2 has recently been published to be of specific help targeting the H3K27M mutations in pediatric gliomas[26]. This has paved the
AC C
way for further enthusiasm and research to find out novel therapeutic molecules for further treatment in such clinical conditions which are known to carry a poor prognosis. Our patient had a stormy post-operative period – had a poor neurological recovery in terms of motor power/ sensory improvement and had prolonged ventilator dependency and could not be weaned off the ventilator even after multiple attempts for nearly 3 weeks. Also, the overall morbid condition of our patient was further complicated by CSF leak from the wound site. We attribute this to poor wound healing to prolonged post-surgical stress, dependent position of the wound and poor nutrition. Hydrocephalus is known to complicate spinal malignant
ACCEPTED MANUSCRIPT
astrocytoma’s as they are known to be associated with increased protein concentration in the CSF, occlusion of the CSF channel in the subarachnoid space at the skull base and brain surface[1, 27]. We excluded hydrocephalus by performing a CT scan and lumbar drain was
RI PT
placed. She had a deterioration in sensorium on post-op day 21 after which she progressively
deteriorated, landed in multiple organ dysfunction and finally succumbed on post-op day 23. CONCLUSION
SC
Primary spinal GBM is a rare entity with dismal outcomes. Rarer is - presentation with an acute catastrophic event like tumor bleed which is associated with sudden worsening, poor
M AN U
neurological recovery and prolonged ventilator dependency and CNS infections. Histone protein mutation H3K27M in spinal GBM can be associated with such tumors and is to be considered, which throws open futuristic opportunities to study/develop therapeutic molecules which may be helpful in the treatment of these patients. DISCLOSURE- Nil
TE D
CONFLICT OF INTEREST: Authors do not have any conflict of interest. INFORM CONSENT: Consent was taken from the patient’s relative for publication.
EP
REFERENCES:
AC C
[1] Cohen AR, Wisoff JH, Allen JC, Epstein FJJon. Malignant astrocytomas of the spinal cord. 1989;70:504. [2] Medhkour A, Chan MJSn. Extremely rare glioblastoma multiforme of the conus medullaris with holocord and brain stem metastases, leading to cranial nerve deficit and respiratory failure: a case report and review of the literature. 2005;63:576-82. [3] Ciappetta P, Salvati M, Capoccia G, Artico M, Raco A, Fortuna AJN. Spinal glioblastomas: report of seven cases and review of the literature. 1991;28:302-6. [4] Guidetti B, Mercuri S, Vagnozzi RJJon. Long-term results of the surgical treatment of 129 intramedullary spinal gliomas. 1981;54:323-30. [5] Mori K, Imai S, Shimizu J, Taga T, Ishida M, Matsusue YJTSJ. Spinal glioblastoma multiforme of the conus medullaris with holocordal and intracranial spread in a child: a case report and review of the literature. 2012;12:e1-e6. [6] Cacchione A, Mastronuzzi A, Cefalo MG, Colafati GS, Diomedi-Camassei F, Rizzi M, et al. Pediatric spinal glioblastoma of the conus medullaris: a case report of long survival. 2016;35:44.
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
[7] Shen C-X, Wu J-F, Zhao W, Cai Z-W, Cai R-Z, Chen C-MJM. Primary spinal glioblastoma multiforme: a case report and review of the literature. 2017;96. [8] Viljoen S, Hitchon PW, Ahmed R, Kirby PAJSni. Cordectomy for intramedullary spinal cord glioblastoma with a 12-year survival. 2014;5. [9] Marchan EM, Sekula RF, Jannetta PJ, Quigley MRJJoNS. Long-term survival enhanced by cordectomy in a patient with a spinal glioblastoma multiforme and paraplegia: Case report. 2007;7:656-9. [10] Lee S-H, Park DJ, Jeun S-SJBtr, treatment. Acute Paraplegia as a Result of Hemorrhagic Spinal Ependymoma Masked by Spinal Anesthesia: Case Report and Review of Literature. 2016;4:30-4. [11] Konar SK, Maiti TK, Bir SC, Kalakoti P, Bollam P, Nanda A. Predictive Factors Determining the Overall Outcome of Primary Spinal Glioblastoma Multiforme: An Integrative Survival Analysis. World neurosurgery. 2016;86:341-8.e1-3. [12] Wong AP, Dahdaleh NS, Fessler RG, Melkonian SC, Lin Y, Smith ZA, et al. Risk factors and long-term survival in adult patients with primary malignant spinal cord astrocytomas. 2013;115:493-503. [13] Kim W-H, Yoon SH, Kim C-Y, Kim K-j, Lee MM, Choe G, et al. Temozolomide for malignant primary spinal cord glioma: an experience of six cases and a literature review. 2011;101:247-54. [14] Choi W-C, Lee JH, Lee S-HJSn. Spinal cord glioblastoma multiforme of conus medullaris masquerading as high lumbar disk herniation. 2009;71:234-7. [15] Gmeiner M, Sonnberger M, Wurm G, Weis SJCn, neurosurgery. Glioblastoma with the appearance of arteriovenous malformation: pitfalls in diagnosis. 2013;115:501-6. [16] Aucourt J, Jissendi P, Kerdraon O, Baroncini MJJoN. Neuroimaging features and pathology of mixed glioblastoma–AVM complex: a case report. 2012;39:258-62. [17] Linsenmann T, Westermaier T, Vince GH, Monoranu CM, Löhr M, Ernestus R-I, et al. Primary spinal glioblastoma multiforme with secondary manifestation as a cerebral “angioglioma.” Literature review and case report. 2015;76:e128-e34. [18] Harris OA, Chang SD, Harris BT, Adler JRJNr. Acquired cerebral arteriovenous malformation induced by an anaplastic astrocytoma: an interesting case. 2000;22:473-7. [19] Shankar GM, Lelic N, Gill CM, Thorner AR, Van Hummelen P, Wisoff JH, et al. BRAF alteration status and the histone H3F3A gene K27M mutation segregate spinal cord astrocytoma histology. 2016;131:147-50. [20] Nagaishi M, Nobusawa S, Yokoo H, Sugiura Y, Tsuda K, Tanaka Y, et al. Genetic mutations in high grade gliomas of the adult spinal cord. 2016;33:267-9. [21] Gessi M, Gielen GH, Dreschmann V, Waha A, Pietsch TJAn. High frequency of H3F3A K27M mutations characterizes pediatric and adult high-grade gliomas of the spinal cord. 2015;130:435-7. [22] Gao Y, Feng YY, Yu JH, Li QC, Qiu XS, Wang EHJN. Diffuse midline gliomas with histone H3-K27M mutation: A rare case with PNET-like appearance and neuropil-like islands. 2018;38:165-70. [23] Velz J, Christoph Neidert M, Struckmann K, Hackius M, Germans M, Bozinov O, et al. A Rare Case of Diffuse Midline Glioma, H3 K27M Mutant, of the Spinal Cord Mimicking Meningitis2018. [24] Sturm D, Witt H, Hovestadt V, Khuong-quang D, Jones D, Korshunov A, et al. Lb. 01 Hotspot mutations in H3f3a and Idh1 define distinct epigenetic and biological subgroups of glioblastoma. 2012;14:iii1–iii94. [25] Chan K-M, Fang D, Gan H, Hashizume R, Yu C, Schroeder M, et al. The histone H3. 3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression. 2013;27:985-90. [26] Mohammad F, Weissmann S, Leblanc B, Pandey DP, Højfeldt JW, Comet I, et al. EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas. 2017;23:483. [27] ASANO N, KITAMURA K, SEO Y, MUKAI K, SOGA T, HONDO H, et al. Spinal cord glioblastoma multiforme with intracranial dissemination. 1990;30:489-94.
ACCEPTED MANUSCRIPT
LEGENDS: FIGURE 1: Pre-operative images showing lesion characteristics on MRI.
SC
FIGURE 2: Images highlighting features of hemorrhage.
RI PT
A) Sagittal T1W image, B) Sagittal T2W image, C) Sagittal T1W Contrast image - Note the intramedullary lesion extending from C3 to C7 level with expansion of the cord, isointense on T1, heterointense on T2 and mild heterogeneously enhancing on contrast with significant perilesional edema extending up to medulla superiorly and dorsal spinal cord inferiorly. D)Axial T1W contrast image shows the intramedullary location more clearly and a good plane present all around (indicated by solid white arrow).
FIGURE 3: Histopathological details:
M AN U
A) Serial T2W axial images showing the hyperintense foci at multiple levels. (solid white arrows indicating foci of bleed) B) Serial sagittal T2W images showing multiple foci of hyperintensities suggestive of acute hemorrhage (solid white arrows indicating foci of bleed). C)Gradient axial image showing foci of intense blooming (solid white arrow showing focus of bleed). D)Postoperative T1W contrast image showing decompression.
EP
TE D
A: Microphotograph showing a cellular glial neoplasm with undifferentiated cells possessing hyperchromatic nucleus in a glial interstitium. H & E x 400, B. Microphotograph showing the glial neoplasm with necrosis and a glomeruloid vasculature(inset). H & E x 400, C. Microphotograph showing a cellular glial neoplasm which are GFAP positive. GFAP (IHC) x 400, D. Microphotograph showing a cellular glial neoplasm which are positive for H3K27M. H3K27M (IHC) x 400.
AC C
FIGURE 4: A & B: Shows Isocitrate dehydrogenase immunohistochemistry finding and it was negative for the stain.
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT
Abbreviations sGBM: Spinal glioblastoma multiforme.
RI PT
CT: Computer Tomography MRI: Magnetic Resonance Imaging
AC C
EP
TE D
M AN U
SC
CNS: Central nervous system
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
Disclosure-Conflict of Interest: Authors do not have any conflict of interest or anything to disclose.
S1878-8750(19)30651-5
DOI:
https://doi.org/10.1016/j.wneu.2019.03.025
Reference:
WNEU 11703
To appear in:
World Neurosurgery
Received Date: 20 December 2018 Revised Date:
1 March 2019
Accepted Date: 2 March 2019
Please cite this article as: Uppar A, Konar SK, Nandeesh BN, Shukla D, H3k27m- Positive Primary Spinal Gliobastoma Presenting With Haemorrhage- A Rare Clinical Entity, World Neurosurgery (2019), doi: https://doi.org/10.1016/j.wneu.2019.03.025. 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
Title page: Case Report
RI PT
Title: H3K27M- POSITIVE PRIMARY SPINAL GLIOBASTOMA PRESENTING WITH HAEMORRHAGE- A RARE CLINICAL ENTITY.
Alok Uppar, MCh1, Subhas K. Konar, MCh1, Nandeesh B. N, M. D2, Dhaval Shukla, MCh1 1: Department of Neurosurgery, National Institute of Mental Health and Neurosciences, Bangalore, India.
M AN U
SC
2: Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore, India.
Correspondence: Dr. Subhas K. Konar, MCh
TE D
Assistant Professor, Department of Neurosurgery
National Institute of Mental Health and Neurosciences (NIMHANS)
EP
Bangalore 560029 Mobile: 09986438181
AC C
Email: [email protected]
Conflict of Interest: Nil
Inform Consent: Taken from patient. Page: Manuscript:8.
ACCEPTED MANUSCRIPT
H3K27M- POSITIVE PRIMARY SPINAL GLIOBASTOMA PRESENTING
RI PT
WITH HAEMORRHAGE- A RARE CLINICAL ENTITY.
ABSTRACT
Primary Spinal GBM (sGBM) is a rare and aggressive spinal tumor with dismal outcomes. The authors present an unusual case- the first of its kind, with intra-tumoral hemorrhage and sudden
SC
onset quadriplegia in a case of primary sGBM. Patient was managed with emergency surgical decompression. Eventually the patient succumbed after a prolonged ICU stay. The tumor was
M AN U
positive for histone molecular alteration- ‘H3K27M’.
KEYWORDS: Primary Spinal Glioblastoma, Hemorrhage, H3K27M, Surgery. INTRODUCTION
Primary glial tumors account for a majority of intramedullary tumors which include
TE D
astrocytomas (nearly1%)[1], ependymomas, and less commonly glial neoplasms such as gangliogliomas. Primary spinal GBMs are rare with an incidence of nearly 7.5% of all intramedullary gliomas which account for nearly 1 to 3% of all spinal cord tumors [2, 3]. The
EP
cervical and dorsal spine are the commonly involved areas followed by cervico-thoracic junction[1, 4]. There have been reports of GBM in the conus medullaris also[5, 6]. Treatment options available are surgical decompression and adjuvant chemoradiation. The prognosis,
AC C
however, remains dismal; with patients after treatment having a mean average survival of nearly 14 months with a median of 16 months[7].Also, a few authors have reported cordectomy for lower spinal cord GBMs with prolonged survival[8, 9]. Intratumoral hemorrhage with sudden clinical deterioration is described in ependymomas(11 cases) and few hemangioblastomas but not in other intramedullary tumors[10].
ACCEPTED MANUSCRIPT
CASE REPORT 28- year -old lady was referred with complaints of numbness of right hand and mild weakness of right handgrip for 1 month. This was followed by numbness in the right lower limb and mild
RI PT
stiffness in both lower limbs for 15 days. This was followed by a sudden onset weakness of both upper limbs and lower limbs. She had transient urgency in urination which had gradually
improved over a month. On examination, she had flaccid weakness of right upper limb (0/5 power), left upper limb had normal tone and power of 2/5(MRC grade). Bilateral lower limb
SC
power was 4/5 with increased tone and exaggerated deep tendon reflexes with upgoing planters. She had a graded sensory loss below C5 dermatome. MRI Cervical spine revealed an enlarged cord from C3 to C7 level with T1 isointense, T2 hyperintense signals with multiple foci of
M AN U
blooming seen on gradient images which suggested a lesion with bleed. The lesion was heterogeneously enhancing on contrast and had significant perilesional edema extending up to D5 level. (FIGURE 1, 2) She was admitted, and surgery was planned under SSEP and MEP monitoring the next day. However, she had another episode of a sudden deterioration in the ward; became quadriplegic and developed shallow respiration for which she was intubated and taken up for surgery on an emergency basis. She underwent C3-C7 laminectomy, gross total
TE D
decompression of tumor. The lesion had areas of reddish discoloration- suggestive of an acute hemorrhagic event. There was a good plane all around the lesion and surrounding cord looked edematous. Post-operatively, she did not show any improvement in motor power and remained quadriplegic. She received mechanical ventilation and had a prolonged ICU stay of 15 days.
EP
After 15 days of ICU admission and multiple attempts at weaning- which was unsuccessful, she developed CSF leak through surgical wound site for which lumbar drain was placed
AC C
immediately. CT brain was done, and hydrocephalus was ruled out. CSF showed plenty of pus cells and grew Acinetobacter baumanii and appropriate antibiotics were started. However, she deteriorated in sensorium on post-op day 20 and succumbed to infection three days later. The histopathological examination (FIGURE 3) performed on the tissue revealed a cellular tumor composed of cells with clear cytoplasm which were arranged in sheets and possessing cytoplasmic processes resembling glial cells (Figure A). The neoplasm was highly vascular with intervening vessels being dilated and congested along with proliferating vasculature (Figure B, Inset). Mitosis was increased in cellular areas. Areas of necrosis were observed (Figure B) seen. On immunohistochemical analysis, the tumor cells were diffusely positive for GFAP
ACCEPTED MANUSCRIPT
(Figure D) and H3K27M was positive in tumor cells (Figure C) with H3Me3 showing a global reduction of expression in tumor cells. Isocitrate dehydrogenase staining (Figure:4, A&B) was
RI PT
done and it was negative. The neoplasm showed increased MIB-1 labeling (15%).
DISCUSSION
The total number of primary sGBMs reported till date stands at less than 200. The survival and overall prognosis remain dismal which can be attributed to the malignant nature of the disease
SC
itself and to the decreased scope of achieving a gross total decompression in view of surrounding spinal cord damage. Various factors are described which predict the survival in patients with
M AN U
primary spinal GBM [11].
Although there have been a handful of case reports and a few series describing this disease, the present case, to the best of our knowledge is the first of its kind to be reported which has presented with a tumor bleed associated with acute clinical deterioration as well as H3K27M positivity. Our patient had two episodes of clinical deterioration, the first – which resulted in
TE D
sudden lower limb stiffness, worsening of upper limb power and the second instance, a bleed of greater magnitude resulted in sudden quadriplegia and respiratory failure. This was also corroborating with our MRI and intra-op findings. Primary spinal GBM lesions appear as infiltrative, expansile masses with high T2 signal and heterogeneous enhancement on
EP
postcontrast T1-weighted sequences[12-14]. The MRI showed features of multiple foci of acute bleed (T1-ISO, T2 HYPER) and foci of blooming on gradient images. The intra-operative
AC C
findings also revealed lesion with blood and clots. These tumors are also known to show variable MRI characteristics which may give rise to diagnostic ambiguity. The presence of acute bleedlike findings on MRI may further complicate the issue with respect to radiological diagnosis. However, it necessitates prompt surgical action as conditions like demyelination/ transverse myelitis do not bleed.
The possible explanation for such bleed could be the association of tumor with proangiogenic factors like VEGF. Also, small vascular malformations associated with gliomas in general(cavernous angioma, venous malformation) could be another possibility, which has been
ACCEPTED MANUSCRIPT
described by a few authors[15, 16]; although it was not seen on the detailed histopathological analysis in our case. Spinal ependymoma is known to present with bleed[10]. One case report of sGBM presenting with a secondary cerebral vascular malformation is described[17]. But there are no such reports of malformation or hemorrhage associated with sGBM. It is proposed that the
RI PT
hyper-angiogenic environment of high-grade tumors induces abnormal arteriovenous
connections which might have given rise to abnormal primitive vessels which might have resulted in bleed[18].
SC
Only a few dedicated studies describe molecular alterations in spinal gliomas[19-21]. Diffuse leptomeningeal glioneuronal tumor with H3K27M mutation has also been described[22]. Another case report describing a 25-year-old lady succumbing to leptomeningeal gliomatosis
M AN U
which was H3K27M mutant was recently published[23]. The H3K27M mutation is the most common mutation among genes encoding histone protein H3 viz H3.1 AND H3.3. Also, the K27M mutation is proven and well known to be one of the early hallmark events during glioma genesis [24]. Molecular alterations were studied in our present which revealed positive TP53 expression, H3K27M mutation. The presence of H3K27M mutation confers a poor prognosis and is usually associated with midline GBMs and has been well validated in the pediatric age
TE D
group by various authors[25]. However, to the best of our knowledge, the present report is one of the first of its kind describing a positive H3K27M mutant primary sGBM presenting with an acute bleed. Future studies directed towards understanding the incidence, clinicopathological correlations associated with such novel markers like H3K27M mutation would be of great help
EP
towards using specific targeted therapy. A new molecule EZH2 has recently been published to be of specific help targeting the H3K27M mutations in pediatric gliomas[26]. This has paved the
AC C
way for further enthusiasm and research to find out novel therapeutic molecules for further treatment in such clinical conditions which are known to carry a poor prognosis. Our patient had a stormy post-operative period – had a poor neurological recovery in terms of motor power/ sensory improvement and had prolonged ventilator dependency and could not be weaned off the ventilator even after multiple attempts for nearly 3 weeks. Also, the overall morbid condition of our patient was further complicated by CSF leak from the wound site. We attribute this to poor wound healing to prolonged post-surgical stress, dependent position of the wound and poor nutrition. Hydrocephalus is known to complicate spinal malignant
ACCEPTED MANUSCRIPT
astrocytoma’s as they are known to be associated with increased protein concentration in the CSF, occlusion of the CSF channel in the subarachnoid space at the skull base and brain surface[1, 27]. We excluded hydrocephalus by performing a CT scan and lumbar drain was
RI PT
placed. She had a deterioration in sensorium on post-op day 21 after which she progressively
deteriorated, landed in multiple organ dysfunction and finally succumbed on post-op day 23. CONCLUSION
SC
Primary spinal GBM is a rare entity with dismal outcomes. Rarer is - presentation with an acute catastrophic event like tumor bleed which is associated with sudden worsening, poor
M AN U
neurological recovery and prolonged ventilator dependency and CNS infections. Histone protein mutation H3K27M in spinal GBM can be associated with such tumors and is to be considered, which throws open futuristic opportunities to study/develop therapeutic molecules which may be helpful in the treatment of these patients. DISCLOSURE- Nil
TE D
CONFLICT OF INTEREST: Authors do not have any conflict of interest. INFORM CONSENT: Consent was taken from the patient’s relative for publication.
EP
REFERENCES:
AC C
[1] Cohen AR, Wisoff JH, Allen JC, Epstein FJJon. Malignant astrocytomas of the spinal cord. 1989;70:504. [2] Medhkour A, Chan MJSn. Extremely rare glioblastoma multiforme of the conus medullaris with holocord and brain stem metastases, leading to cranial nerve deficit and respiratory failure: a case report and review of the literature. 2005;63:576-82. [3] Ciappetta P, Salvati M, Capoccia G, Artico M, Raco A, Fortuna AJN. Spinal glioblastomas: report of seven cases and review of the literature. 1991;28:302-6. [4] Guidetti B, Mercuri S, Vagnozzi RJJon. Long-term results of the surgical treatment of 129 intramedullary spinal gliomas. 1981;54:323-30. [5] Mori K, Imai S, Shimizu J, Taga T, Ishida M, Matsusue YJTSJ. Spinal glioblastoma multiforme of the conus medullaris with holocordal and intracranial spread in a child: a case report and review of the literature. 2012;12:e1-e6. [6] Cacchione A, Mastronuzzi A, Cefalo MG, Colafati GS, Diomedi-Camassei F, Rizzi M, et al. Pediatric spinal glioblastoma of the conus medullaris: a case report of long survival. 2016;35:44.
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
[7] Shen C-X, Wu J-F, Zhao W, Cai Z-W, Cai R-Z, Chen C-MJM. Primary spinal glioblastoma multiforme: a case report and review of the literature. 2017;96. [8] Viljoen S, Hitchon PW, Ahmed R, Kirby PAJSni. Cordectomy for intramedullary spinal cord glioblastoma with a 12-year survival. 2014;5. [9] Marchan EM, Sekula RF, Jannetta PJ, Quigley MRJJoNS. Long-term survival enhanced by cordectomy in a patient with a spinal glioblastoma multiforme and paraplegia: Case report. 2007;7:656-9. [10] Lee S-H, Park DJ, Jeun S-SJBtr, treatment. Acute Paraplegia as a Result of Hemorrhagic Spinal Ependymoma Masked by Spinal Anesthesia: Case Report and Review of Literature. 2016;4:30-4. [11] Konar SK, Maiti TK, Bir SC, Kalakoti P, Bollam P, Nanda A. Predictive Factors Determining the Overall Outcome of Primary Spinal Glioblastoma Multiforme: An Integrative Survival Analysis. World neurosurgery. 2016;86:341-8.e1-3. [12] Wong AP, Dahdaleh NS, Fessler RG, Melkonian SC, Lin Y, Smith ZA, et al. Risk factors and long-term survival in adult patients with primary malignant spinal cord astrocytomas. 2013;115:493-503. [13] Kim W-H, Yoon SH, Kim C-Y, Kim K-j, Lee MM, Choe G, et al. Temozolomide for malignant primary spinal cord glioma: an experience of six cases and a literature review. 2011;101:247-54. [14] Choi W-C, Lee JH, Lee S-HJSn. Spinal cord glioblastoma multiforme of conus medullaris masquerading as high lumbar disk herniation. 2009;71:234-7. [15] Gmeiner M, Sonnberger M, Wurm G, Weis SJCn, neurosurgery. Glioblastoma with the appearance of arteriovenous malformation: pitfalls in diagnosis. 2013;115:501-6. [16] Aucourt J, Jissendi P, Kerdraon O, Baroncini MJJoN. Neuroimaging features and pathology of mixed glioblastoma–AVM complex: a case report. 2012;39:258-62. [17] Linsenmann T, Westermaier T, Vince GH, Monoranu CM, Löhr M, Ernestus R-I, et al. Primary spinal glioblastoma multiforme with secondary manifestation as a cerebral “angioglioma.” Literature review and case report. 2015;76:e128-e34. [18] Harris OA, Chang SD, Harris BT, Adler JRJNr. Acquired cerebral arteriovenous malformation induced by an anaplastic astrocytoma: an interesting case. 2000;22:473-7. [19] Shankar GM, Lelic N, Gill CM, Thorner AR, Van Hummelen P, Wisoff JH, et al. BRAF alteration status and the histone H3F3A gene K27M mutation segregate spinal cord astrocytoma histology. 2016;131:147-50. [20] Nagaishi M, Nobusawa S, Yokoo H, Sugiura Y, Tsuda K, Tanaka Y, et al. Genetic mutations in high grade gliomas of the adult spinal cord. 2016;33:267-9. [21] Gessi M, Gielen GH, Dreschmann V, Waha A, Pietsch TJAn. High frequency of H3F3A K27M mutations characterizes pediatric and adult high-grade gliomas of the spinal cord. 2015;130:435-7. [22] Gao Y, Feng YY, Yu JH, Li QC, Qiu XS, Wang EHJN. Diffuse midline gliomas with histone H3-K27M mutation: A rare case with PNET-like appearance and neuropil-like islands. 2018;38:165-70. [23] Velz J, Christoph Neidert M, Struckmann K, Hackius M, Germans M, Bozinov O, et al. A Rare Case of Diffuse Midline Glioma, H3 K27M Mutant, of the Spinal Cord Mimicking Meningitis2018. [24] Sturm D, Witt H, Hovestadt V, Khuong-quang D, Jones D, Korshunov A, et al. Lb. 01 Hotspot mutations in H3f3a and Idh1 define distinct epigenetic and biological subgroups of glioblastoma. 2012;14:iii1–iii94. [25] Chan K-M, Fang D, Gan H, Hashizume R, Yu C, Schroeder M, et al. The histone H3. 3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression. 2013;27:985-90. [26] Mohammad F, Weissmann S, Leblanc B, Pandey DP, Højfeldt JW, Comet I, et al. EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas. 2017;23:483. [27] ASANO N, KITAMURA K, SEO Y, MUKAI K, SOGA T, HONDO H, et al. Spinal cord glioblastoma multiforme with intracranial dissemination. 1990;30:489-94.
ACCEPTED MANUSCRIPT
LEGENDS: FIGURE 1: Pre-operative images showing lesion characteristics on MRI.
SC
FIGURE 2: Images highlighting features of hemorrhage.
RI PT
A) Sagittal T1W image, B) Sagittal T2W image, C) Sagittal T1W Contrast image - Note the intramedullary lesion extending from C3 to C7 level with expansion of the cord, isointense on T1, heterointense on T2 and mild heterogeneously enhancing on contrast with significant perilesional edema extending up to medulla superiorly and dorsal spinal cord inferiorly. D)Axial T1W contrast image shows the intramedullary location more clearly and a good plane present all around (indicated by solid white arrow).
FIGURE 3: Histopathological details:
M AN U
A) Serial T2W axial images showing the hyperintense foci at multiple levels. (solid white arrows indicating foci of bleed) B) Serial sagittal T2W images showing multiple foci of hyperintensities suggestive of acute hemorrhage (solid white arrows indicating foci of bleed). C)Gradient axial image showing foci of intense blooming (solid white arrow showing focus of bleed). D)Postoperative T1W contrast image showing decompression.
EP
TE D
A: Microphotograph showing a cellular glial neoplasm with undifferentiated cells possessing hyperchromatic nucleus in a glial interstitium. H & E x 400, B. Microphotograph showing the glial neoplasm with necrosis and a glomeruloid vasculature(inset). H & E x 400, C. Microphotograph showing a cellular glial neoplasm which are GFAP positive. GFAP (IHC) x 400, D. Microphotograph showing a cellular glial neoplasm which are positive for H3K27M. H3K27M (IHC) x 400.
AC C
FIGURE 4: A & B: Shows Isocitrate dehydrogenase immunohistochemistry finding and it was negative for the stain.
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT
Abbreviations sGBM: Spinal glioblastoma multiforme.
RI PT
CT: Computer Tomography MRI: Magnetic Resonance Imaging
AC C
EP
TE D
M AN U
SC
CNS: Central nervous system
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
Disclosure-Conflict of Interest: Authors do not have any conflict of interest or anything to disclose.