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Germinoma Involving the Retina: An Unusual Presentation of Recurrent Intracranial Mixed Germ Cell Tumor
Case report
Germinoma Involving the Retina: An Unusual Presentation of Recurrent Intracranial Mixed Germ Cell Tumor Mohammad H. Abu Arja1, Melissa Stalling2,3, Lance S. Governale4, Christopher R. Pierson2,3,5, Jerome A. Rusin6, Joshua D. Palmer7, Jonathan L. Finlay1, Randal Olshefski1, Daniel R. Boue´2,3
Key words Central nervous system tumors - Germ cell tumor - Germinoma - Mixed malignant germ cell tumor - Optic pathway - Relapse - Retinal infiltration -
Abbreviations and Acronyms AFP: Alpha-fetoprotein bHCG: Beta-human chorionic gonadotropin CNS: Central nervous system CSF: Cerebrospinal fluid GCT: Germ cell tumors MRI: Magnetic resonance imaging RION: Radiation-induced optic neuropathy From the 1Department of Pediatrics, Division of Hematology, Oncology and Blood and Marrow Transplant, and 2Department of Pathology & Laboratory Medicine, Nationwide Children’s Hospital, Columbus, Ohio; 3Department of Pathology, James Cancer Hospital, Ohio State University, Columbus, Ohio; 4 Department of Neurosurgery, University of Florida, Gainesville, Florida; 5Department of Biomedical Education and Anatomy, James Cancer Hospital, Ohio State University, Columbus, Ohio; 6Department of Radiology, Nationwide Children’s Hospital, Columbus, Ohio; and 7Department of Radiation Oncology, James Cancer Hospital, Ohio State University, Columbus, Ohio, USA To whom correspondence should be addressed: Mohammad H. Abu Arja, M.D., M.Sc. [E-mail: [email protected]] Citation: World Neurosurg. (2019) 124:116-120. https://doi.org/10.1016/j.wneu.2018.12.143 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
- BACKGROUND:
We report a patient with primary central nervous system mixed malignant germ cell tumor (GCT) who presented with recurrent malignant germinomatous infiltration of the retina.
- CASE
DESCRIPTION: A 10-year-old girl initially presented with a large suprasellar mixed malignant GCT with a near-complete response after initial induction of chemotherapy and irradiation. Three and a half years after initial therapy, she presented with progressively worsening vision in her left eye. Magnetic resonance imaging showed infiltrative changes within the left optic nerve but no discrete mass. Serum and cerebrospinal fluid tumor markers were not elevated and cerebrospinal fluid cytology was negative. Left optic nerve biopsy confirmed the presence of mature teratoma and pure germinoma components. She was treated with gross-total resection of the left eye and optic nerve and chemotherapy. Histopathologic evaluation of the optic nerve showed only mature teratoma elements, but with pure germinoma cells infiltrating the inner layers of the retina.
- CONCLUSIONS:
Loco-regional extension of suprasellar GCT to the optic nerve is not uncommon; however, to the best of our knowledge, infiltration of the tumor into the retina is not reported in the literature. Early detection of optic pathway involvement and proper delineation of the irradiation field may prevent GCT infiltration of the retina with subsequent vision loss.
Histologically, CNS GCT are divided into germinomatous and non-germinomatous tumors. Non-germinomatous GCT include yolk sac tumor, embryonal carcinoma, choriocarcinoma, and teratoma occurring alone or as mixed malignant GCT that commonly also include germinoma.2,3 To the best of our knowledge, we report the first documented case of primary CNS mixed malignant GCT to recur within the retina.
INTRODUCTION Central nervous system (CNS) germ cell tumors (GCT) are a group of neoplasms that have a predilection for midline structures including the suprasellar and pineal regions.1-3 The clinical presentation is dependent on the tumor location and size. Patients with suprasellar lesions most commonly present with visual field deficits, hypopituitarism, and endocrine abnormalities.1-3
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CASE DESCRIPTION A retrospective review of the patient’s medical records was conducted in February 2018. A 10-year-old girl presented with headaches, polydipsia, and polyuria. A brain magnetic resonance imaging (MRI) scan limited by dental brace artifact revealed a uniformly enhancing mass in the suprasellar cistern (Figure 1A and B).
The baseline serum alpha-fetoprotein (AFP) was equivocally elevated at 10 ng/mL (lab normal range <8.5 ng/mL) and serum beta-human chorionic gonadotropin (bHCG) was 35.5 IU/L. On hospital day 5, while waiting for a planned surgical resection, the patient complained of worsening headache and became unarousable to voice and stimulation. Computed tomography scan revealed hemorrhage within the tumor with evidence of brain stem herniation. She was transferred to the pediatric intensive care unit and an external ventricular drain was placed emergently. After the patient was stabilized, the decision was made to forgo tumor resection and proceed with upfront chemotherapy, which was started within 24 hours of the documented hemorrhage. The patient was treated with alternating cycles of carboplatin/etoposide and ifosfamide/etoposide according to the published Société Française d’Oncologie
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CASE MOHAMMAD H. ABU ARJA ET AL.
Figure 1. (A) Contrast-enhanced mid-sagittal T1 brain MRI from the time of initial presentation showing homogeneously enhanced suprasellar mass. (B) Contrast-enhanced axial T2 brain magnetic resonance imaging (MRI) from the time of initial presentation. The region of the optic nerves appears normal. Metallic artifact is present from the patient’s dental braces. (C)
Pédiatrique protocol for intracranial GCT4 modified by reducing the daily etoposide dose by 40% and extending the number of cycles from 4 to 6. The patient’s neurologic status slowly improved and the external ventricular drain was removed on hospital day 14. She was discharged on hospital day 21. After 6 cycles of chemotherapy, a near complete response of the suprasellar mass was achieved; however, there were 2 stable enhancing lesions in the floor and the anterior wall of the third ventricle (Figure 1C and D). Whole ventricular irradiation (3600 cGy) with a boost to the primary tumor using intensity modulated radiation therapy (1800 cGy in 180 cGy fractions) followed. The patient recovered to her prepresentation baseline and
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Contrast-enhanced mid-sagittal T1 brain MRI after induction chemotherapy showing small areas of residual tumor in the floor of the third ventricle (arrow). (D) Contrast-enhanced axial T1 brain MRI after induction therapy showing a residual enhancing nodule along the anterior wall of the third ventricle in the region of the lamina terminalis (arrow).
continued to be asymptomatic with stable signal abnormality in the third ventricle during follow-up MRIs. Three and a half years following the end of treatment, at the age of 14, the patient presented with dysconjugate gaze and blurry vision in her left eye. Ophthalmologic examination revealed an afferent pupillary defect and pale optic nerve. Vision was limited to hand motion only. Retinal infiltration by tumor was not observed. Orbital MRI showed new thickening and enhancement of the intraorbital and cisternal left optic nerve, suspicious for tumor relapse or radiationinduced optic neuropathy (RION) (Figure 2A and B). Spine MRI, lumbar cerebrospinal fluid (CSF) cytology, and tumor markers were all within normal
Figure 2. (A) Contrast-enhanced coronal T1 orbit magnetic resonance imaging (MRI) 3.5 years after initial presentation showing new mild diffuse contrast enhancement of the left optic nerve (arrow). (B) Contrast-enhanced axial T1 orbit MRI 3.5 years after initial presentation showing thickening and enhancement of the intraorbital and cisternal left optic nerve (arrow). (C) Contrast-enhanced coronal T1 brain MRI 17 months after the initial appearance of left optic nerve enhancement showing more
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limits. The patient was observed with MRI over the next several months with no change in the enhancement of the left optic nerve. Serum AFP and bHCG were monitored every 4e6 months and remained normal. Seventeen months later, vision in the left eye deteriorated to minimal light perception. MRI revealed increased nodular enhancement of the left optic nerve with cystic peripherally enhancing components, and restricted diffusion (Figure 2CeE). Serum and CSF bHCG were 8.7 and 11 IU/L respectively, whereas serum and CSF AFP and CSF cytology were normal. Accordingly, a left optic nerve biopsy was performed. Via an endoscopic endonasal transsphenoidal approach; the anatomy of the posterior
pronounced enhancement in the left optic nerve and a superiorly projecting cyst (arrow). (D and E) Contrast-enhanced coronal T1 MRI (D), contrast-enhanced axial T1 MRI (E) 17 months after the initial appearance of left optic nerve enhancement showing the extension of the enhancement anteriorly to the junction of the left optic nerve and the left globe (arrow).
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Figure 3. Intraoperative images from endoscopic endonasal transsphenoidal surgery. The biopsy site is just superior to the sellar prominence, paramedian to the left. Magnified view shows the abnormal, firm, grayish-white tissue in the location of the left optic nerve.
sphenoid wall was identified (Figure 3). A biopsy site was localized along the optic prominence, just superior to the sellar prominence, paramedian to the left. Computerized navigation confirmed the location. The overlying bone was removed with a diamond burr drill and the dura opened. Abnormal, firm, graywhite tissue in the location of the left optic nerve was encountered (Figure 3). It was so firm that the biopsy tissue needed to be removed sharply with endoscopic scissors. Although there was only a small CSF leak, the biopsy site was repaired with a pedicled naso-septal flap in anticipation of likely future craniotomy. Pathology revealed mature teratoma and pure germinoma. The patient
Figure 4. Intraoperative image from left frontotemporal craniotomy (upper in image is anterior, right in image is lateral). The tumor-infiltrated left optic nerve is seen, including the superiorly projecting cyst. The vascular clip on the left ophthalmic artery origin between the tumor and the carotid can be seen.
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received a single course of high-dose cyclophosphamide with peripheral blood hematopoietic cell collection. Because of the predominantly mature teratoma component and continued abnormal left optic nerve imaging, from the chiasm to the globe, the patient underwent a gross total resection with enucleation (Figure 4). Via a left frontotemporal craniotomy with extradural resection of the anterior clinoid process and optic canal roof as well as a Sylvian fissure dissection, the left optic nerve tumor was identified. With arachnoid microdissection, the frontal lobe was gently elevated from the left optic nerve tumor, the optic chiasm, the right optic nerve, the left optic tract, and the left carotid artery. The dura of the posterior optic canal was opened, and the left ophthalmic artery isolated at its origin. Although there was a risk to contralateral vision due to Wilbrand knee, the tumor location and possible cure necessitated transection of the left optic nerve at its junction with the chiasm. A vascular clip was then placed on the left ophthalmic artery at its carotid origin. Just distal to the clip, the artery was coagulated and sectioned. The oculoplastic surgeons then enucleated the left globe. From the orbital side, the optic nerve and sheath were isolated. Microdissection around the nerve in the sheath ensued. Eventually, the nerve released and was removed en bloc from the orbit. The cranial side was explored to ensure no hemorrhage or disruption
of normal structures. There was no opening into the sphenoid air sinus. Craniotomy closure then proceeded in standard fashion. Orbital reconstruction was performed with a dermal fat graft. Histopathologic evaluation of the globe/ retina showed scattered deposits of mitotically active, large atypical cells subjacent to the inner limiting membrane and infiltrating inner retinal layers (Figures 5 and 6). The cells showed strong OCT4 nuclear immunoreactivity and strong CD117 (c-kit) cytoplasmic immunoreactivity, whereas CD30, AFP, and glypican-3 immunohistochemistry were all negative, confirming a diagnosis of pure germinoma (Figure 6). The left optic nerve showed pronounced axonal loss and mature teratomatous elements including epithelial-lined cysts and mature cartilage surrounded by fibroconnective tissue (Figure 5B and C). The patient was consolidated with 2 cycles of marrow-ablative carboplatin and thiotepa followed by autologous hematopoietic cell rescue, without any irradiation. She continues to survive without evidence of relapse by MRI and tumor marker surveillance 21 months postconsolidation therapy. DISCUSSION Loco-regional extension of CNS GCT at diagnosis is common, and usually occurs in the third ventricular region.5 Moreover, localized CNS germinoma tends to relapse in the periventricular wall outside the irradiation field.6-9 CNS GCT extension to the optic pathway at diagnosis is not uncommon. One retrospective study reported 19 out of 100 patients with primary CNS GCT had optic chiasm, nerve, or tract extension.5 Of the 19 patients, 16 presented initially with single or bifocal suprasellar primary tumor.5 However, to the best of our knowledge, few relapsed CNS GCT in the optic pathway have been reported in the literature,7,10-12 moreover, retinal invasion has not been reported previously. Decreased visual acuity in patients with a history of suprasellar GCT may indicate progression or tumor relapse in the optic pathway; therefore, orbital MRI is essential for the evaluation of these patients. The finding of a thickened enhancing
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CASE MOHAMMAD H. ABU ARJA ET AL.
Figure 5. (A) Left eye enucleation specimen: yellow arrows show irregular retinal thickening by infiltrating tumor (1x objective magnification; Hematoxylin and Eosin-stained section). (B and C) Left optic nerve specimen showing pronounced axonal loss and mature teratomatous
optic system on imaging is not solely attributable to tumor progression, as it may arise secondarily to RION.13 RION is a late radiation toxicity that usually occurs >6 months following irradiation, with an average of 18 months postirradiation, following doses of 5400 cGy or higher.13-15 RION is usually associated with a unilateral slow painless decrease in visual acuity, visual fields, and decreased afferent papillary reflex.13 Vision loss secondary to tumor progression may be associated with endocrinopathies and/or increased intracranial pressure. However, patients with suprasellar GCT may experience decreased visual acuity due to optic system tumor invasion without signs of raised intracranial pressure.16 Pursuing a biopsy of the optic pathway enhancement earlier in the course of the disease may
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elements including benign mature hyaline cartilage (B ¼ 40x objective magnification) and benign epithelial-lined cyst (C ¼ 20x objective magnification) surrounded by hypocellular fibroconnective scar tissue fibrosis (Hematoxylin and Eosin-stained sections).
be necessary to differentiate between RION and tumor progression. However, the status of the patient’s vision when optic nerve enhancement develops would need to be considered when deciding on the risk-benefit ratio of a biopsy. Optic nerve and intra-orbital eye involvement by CNS GCT have important implications for diagnosis, radiotherapy, follow-up and prognosis. At initial presentation, brain MRI protocols need to include coronal fluid-attenuated inversion recovery T2 and postgadolinium T1 sequences to allow for proper evaluation of the intraorbital optic nerves. Brain MRI that does not include coronal fluidattenuated inversion recovery T2 may not be optimal to diagnose early infiltration of the optic nerves. Patients with visual changes by history or ocular findings by physical examination will need a
Figure 6. (A) Routine Hematoxylin and Eosin section of the retina showing scattered deposits of large malignant, mitotically-active cells with atypical nuclei and prominent nucleoli in the optic nerve and ganglion cell layers (arrows). These cells infiltrate the inner retina. These tumor (germinoma) cells appear to be mostly subjacent to the inner limiting membrane,
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complete orbital MRI. Early identification of optic nerve involvement is essential to modify the irradiation field as the optic nerve region is not included in the whole ventricular irradiation field. The comprehensive inclusion of the optic pathway in the irradiation field may reduce the risk of future relapse, especially from germinomatous elements. In our patient, the dental brace artifact and rapid clinical deterioration limited our ability to perform a comprehensive initial disease evaluation. CONCLUSIONS Early detection of optic pathway involvement and appropriate adjustment of the irradiation field may prevent future vision loss that can result in poor functional status among survivors of CNS GCT.
evidence that the tumor spread down the optic nerve to reach the retina (20x objective magnification). (B) OCT4 is strongly positive in essentially all tumor cell nuclei (arrow) (20x objective magnification). (C) CD117 (c-kit) shows strong cytoplasmic reactivity in essentially all tumor cells (arrow) (20x objective magnification).
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REFERENCES 1. Loius D, Ohgaki H, Wiestler O, et al. WHO Classification of Tumours of the Central Nervous System. 4th ed. Lyon, France: International Agency for Research on Cancer; 2016. 2. Jennings MT, Gelman R, Hochberg F. Intracranial germ-cell tumors: natural history and pathogenesis. J Neurosurg. 1985;63:155-167. 3. Matsutani M, Sano K, Takakura K, et al. Primary intracranial germ cell tumors: a clinical analysis of 153 histologically verified cases. J Neurosurg. 1997; 86:446-455. 4. Bouffet E, Baranzelli MC, Patte C, et al. Combined treatment modality for intracranial germinomas: results of a multicentre SFOP experience. Br J Cancer. 1999;79:1199-1204. 5. Duron L, Sadones F, Thiesse P, et al. Locoregional extensions of central nervous system germ cell tumors: a retrospective radiological analysis of 100 patients. Neuroradiology. 2018;60: 27-34. 6. Calaminus G, Kortmann R, Worch J, et al. SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site
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irradiation for patients with localized disease. Neuro Oncol. 2013;15:788-796. 7. Alapetite C, Brisse H, Patte C, et al. Pattern of relapse and outcome of non-metastatic germinoma patients treated with chemotherapy and limited field radiation: the SFOP experience. Neuro Oncol. 2010;12:1318-1325. 8. Khatua S, Dhall G, O’Neil S, et al. Treatment of primary CNS germinomatous germ cell tumors with chemotherapy prior to reduced dose whole ventricular and local boost irradiation. Pediatr Blood Cancer. 2010;55:42-46.
14. Ferguson I, Huecker J, Huang J, McClelland C, Van Stavern G. Risk factors for radiation-induced optic neuropathy: a case-control study. Clin Exp Ophthalmol. 2017;45:592-597. 15. Parsons JT, Bova FJ, Fitzgerald CR, Mendenhall WM, Million RR. Radiation optic neuropathy after megavoltage external-beam irradiation: analysis of time-dose factors. Int J Radiat Oncol Biol Phys. 1994;30:755-763. 16. Frappaz D, Pedone C, Thiesse P, et al. Visual complaints in intracranial germinomas. Pediatr Blood Cancer. 2017;64:e26543.
9. Kenjo M, Yamasaki F, Takayasu T, et al. Results of sequential chemoradiotherapy for intracranial germinoma. Jpn J Radiol. 2015;33:336-343. 10. Nakajima T, Kumabe T, Jokura H, Yoshimoto T. Recurrent germinoma in the optic nerve: report of two cases. Neurosurgery. 2001;48:214-217. 11. Sonoda Y, Kumabe T, Sugiyama S, et al. Germ cell tumors in the basal ganglia: problems of early diagnosis and treatment. J Neurosurg Pediatr. 2008; 2:118-124.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 25 September 2018; accepted 26 December 2018 Citation: World Neurosurg. (2019) 124:116-120. https://doi.org/10.1016/j.wneu.2018.12.143
12. Pereira LS, Green AJ, Hwang TN, McCulley TJ. Suprasellar germinoma and late perioptic seeding. Eur J Ophthalmol. 2008;18:159-161.
Journal homepage: www.journals.elsevier.com/worldneurosurgery
13. Danesh-Meyer HV. Radiation-induced optic neuropathy. J Clin Neurosci. 2008;15:95-100.
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Germinoma Involving the Retina: An Unusual Presentation of Recurrent Intracranial Mixed Germ Cell Tumor Mohammad H. Abu Arja1, Melissa Stalling2,3, Lance S. Governale4, Christopher R. Pierson2,3,5, Jerome A. Rusin6, Joshua D. Palmer7, Jonathan L. Finlay1, Randal Olshefski1, Daniel R. Boue´2,3
Key words Central nervous system tumors - Germ cell tumor - Germinoma - Mixed malignant germ cell tumor - Optic pathway - Relapse - Retinal infiltration -
Abbreviations and Acronyms AFP: Alpha-fetoprotein bHCG: Beta-human chorionic gonadotropin CNS: Central nervous system CSF: Cerebrospinal fluid GCT: Germ cell tumors MRI: Magnetic resonance imaging RION: Radiation-induced optic neuropathy From the 1Department of Pediatrics, Division of Hematology, Oncology and Blood and Marrow Transplant, and 2Department of Pathology & Laboratory Medicine, Nationwide Children’s Hospital, Columbus, Ohio; 3Department of Pathology, James Cancer Hospital, Ohio State University, Columbus, Ohio; 4 Department of Neurosurgery, University of Florida, Gainesville, Florida; 5Department of Biomedical Education and Anatomy, James Cancer Hospital, Ohio State University, Columbus, Ohio; 6Department of Radiology, Nationwide Children’s Hospital, Columbus, Ohio; and 7Department of Radiation Oncology, James Cancer Hospital, Ohio State University, Columbus, Ohio, USA To whom correspondence should be addressed: Mohammad H. Abu Arja, M.D., M.Sc. [E-mail: [email protected]] Citation: World Neurosurg. (2019) 124:116-120. https://doi.org/10.1016/j.wneu.2018.12.143 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
- BACKGROUND:
We report a patient with primary central nervous system mixed malignant germ cell tumor (GCT) who presented with recurrent malignant germinomatous infiltration of the retina.
- CASE
DESCRIPTION: A 10-year-old girl initially presented with a large suprasellar mixed malignant GCT with a near-complete response after initial induction of chemotherapy and irradiation. Three and a half years after initial therapy, she presented with progressively worsening vision in her left eye. Magnetic resonance imaging showed infiltrative changes within the left optic nerve but no discrete mass. Serum and cerebrospinal fluid tumor markers were not elevated and cerebrospinal fluid cytology was negative. Left optic nerve biopsy confirmed the presence of mature teratoma and pure germinoma components. She was treated with gross-total resection of the left eye and optic nerve and chemotherapy. Histopathologic evaluation of the optic nerve showed only mature teratoma elements, but with pure germinoma cells infiltrating the inner layers of the retina.
- CONCLUSIONS:
Loco-regional extension of suprasellar GCT to the optic nerve is not uncommon; however, to the best of our knowledge, infiltration of the tumor into the retina is not reported in the literature. Early detection of optic pathway involvement and proper delineation of the irradiation field may prevent GCT infiltration of the retina with subsequent vision loss.
Histologically, CNS GCT are divided into germinomatous and non-germinomatous tumors. Non-germinomatous GCT include yolk sac tumor, embryonal carcinoma, choriocarcinoma, and teratoma occurring alone or as mixed malignant GCT that commonly also include germinoma.2,3 To the best of our knowledge, we report the first documented case of primary CNS mixed malignant GCT to recur within the retina.
INTRODUCTION Central nervous system (CNS) germ cell tumors (GCT) are a group of neoplasms that have a predilection for midline structures including the suprasellar and pineal regions.1-3 The clinical presentation is dependent on the tumor location and size. Patients with suprasellar lesions most commonly present with visual field deficits, hypopituitarism, and endocrine abnormalities.1-3
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CASE DESCRIPTION A retrospective review of the patient’s medical records was conducted in February 2018. A 10-year-old girl presented with headaches, polydipsia, and polyuria. A brain magnetic resonance imaging (MRI) scan limited by dental brace artifact revealed a uniformly enhancing mass in the suprasellar cistern (Figure 1A and B).
The baseline serum alpha-fetoprotein (AFP) was equivocally elevated at 10 ng/mL (lab normal range <8.5 ng/mL) and serum beta-human chorionic gonadotropin (bHCG) was 35.5 IU/L. On hospital day 5, while waiting for a planned surgical resection, the patient complained of worsening headache and became unarousable to voice and stimulation. Computed tomography scan revealed hemorrhage within the tumor with evidence of brain stem herniation. She was transferred to the pediatric intensive care unit and an external ventricular drain was placed emergently. After the patient was stabilized, the decision was made to forgo tumor resection and proceed with upfront chemotherapy, which was started within 24 hours of the documented hemorrhage. The patient was treated with alternating cycles of carboplatin/etoposide and ifosfamide/etoposide according to the published Société Française d’Oncologie
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CASE MOHAMMAD H. ABU ARJA ET AL.
Figure 1. (A) Contrast-enhanced mid-sagittal T1 brain MRI from the time of initial presentation showing homogeneously enhanced suprasellar mass. (B) Contrast-enhanced axial T2 brain magnetic resonance imaging (MRI) from the time of initial presentation. The region of the optic nerves appears normal. Metallic artifact is present from the patient’s dental braces. (C)
Pédiatrique protocol for intracranial GCT4 modified by reducing the daily etoposide dose by 40% and extending the number of cycles from 4 to 6. The patient’s neurologic status slowly improved and the external ventricular drain was removed on hospital day 14. She was discharged on hospital day 21. After 6 cycles of chemotherapy, a near complete response of the suprasellar mass was achieved; however, there were 2 stable enhancing lesions in the floor and the anterior wall of the third ventricle (Figure 1C and D). Whole ventricular irradiation (3600 cGy) with a boost to the primary tumor using intensity modulated radiation therapy (1800 cGy in 180 cGy fractions) followed. The patient recovered to her prepresentation baseline and
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Contrast-enhanced mid-sagittal T1 brain MRI after induction chemotherapy showing small areas of residual tumor in the floor of the third ventricle (arrow). (D) Contrast-enhanced axial T1 brain MRI after induction therapy showing a residual enhancing nodule along the anterior wall of the third ventricle in the region of the lamina terminalis (arrow).
continued to be asymptomatic with stable signal abnormality in the third ventricle during follow-up MRIs. Three and a half years following the end of treatment, at the age of 14, the patient presented with dysconjugate gaze and blurry vision in her left eye. Ophthalmologic examination revealed an afferent pupillary defect and pale optic nerve. Vision was limited to hand motion only. Retinal infiltration by tumor was not observed. Orbital MRI showed new thickening and enhancement of the intraorbital and cisternal left optic nerve, suspicious for tumor relapse or radiationinduced optic neuropathy (RION) (Figure 2A and B). Spine MRI, lumbar cerebrospinal fluid (CSF) cytology, and tumor markers were all within normal
Figure 2. (A) Contrast-enhanced coronal T1 orbit magnetic resonance imaging (MRI) 3.5 years after initial presentation showing new mild diffuse contrast enhancement of the left optic nerve (arrow). (B) Contrast-enhanced axial T1 orbit MRI 3.5 years after initial presentation showing thickening and enhancement of the intraorbital and cisternal left optic nerve (arrow). (C) Contrast-enhanced coronal T1 brain MRI 17 months after the initial appearance of left optic nerve enhancement showing more
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limits. The patient was observed with MRI over the next several months with no change in the enhancement of the left optic nerve. Serum AFP and bHCG were monitored every 4e6 months and remained normal. Seventeen months later, vision in the left eye deteriorated to minimal light perception. MRI revealed increased nodular enhancement of the left optic nerve with cystic peripherally enhancing components, and restricted diffusion (Figure 2CeE). Serum and CSF bHCG were 8.7 and 11 IU/L respectively, whereas serum and CSF AFP and CSF cytology were normal. Accordingly, a left optic nerve biopsy was performed. Via an endoscopic endonasal transsphenoidal approach; the anatomy of the posterior
pronounced enhancement in the left optic nerve and a superiorly projecting cyst (arrow). (D and E) Contrast-enhanced coronal T1 MRI (D), contrast-enhanced axial T1 MRI (E) 17 months after the initial appearance of left optic nerve enhancement showing the extension of the enhancement anteriorly to the junction of the left optic nerve and the left globe (arrow).
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Figure 3. Intraoperative images from endoscopic endonasal transsphenoidal surgery. The biopsy site is just superior to the sellar prominence, paramedian to the left. Magnified view shows the abnormal, firm, grayish-white tissue in the location of the left optic nerve.
sphenoid wall was identified (Figure 3). A biopsy site was localized along the optic prominence, just superior to the sellar prominence, paramedian to the left. Computerized navigation confirmed the location. The overlying bone was removed with a diamond burr drill and the dura opened. Abnormal, firm, graywhite tissue in the location of the left optic nerve was encountered (Figure 3). It was so firm that the biopsy tissue needed to be removed sharply with endoscopic scissors. Although there was only a small CSF leak, the biopsy site was repaired with a pedicled naso-septal flap in anticipation of likely future craniotomy. Pathology revealed mature teratoma and pure germinoma. The patient
Figure 4. Intraoperative image from left frontotemporal craniotomy (upper in image is anterior, right in image is lateral). The tumor-infiltrated left optic nerve is seen, including the superiorly projecting cyst. The vascular clip on the left ophthalmic artery origin between the tumor and the carotid can be seen.
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received a single course of high-dose cyclophosphamide with peripheral blood hematopoietic cell collection. Because of the predominantly mature teratoma component and continued abnormal left optic nerve imaging, from the chiasm to the globe, the patient underwent a gross total resection with enucleation (Figure 4). Via a left frontotemporal craniotomy with extradural resection of the anterior clinoid process and optic canal roof as well as a Sylvian fissure dissection, the left optic nerve tumor was identified. With arachnoid microdissection, the frontal lobe was gently elevated from the left optic nerve tumor, the optic chiasm, the right optic nerve, the left optic tract, and the left carotid artery. The dura of the posterior optic canal was opened, and the left ophthalmic artery isolated at its origin. Although there was a risk to contralateral vision due to Wilbrand knee, the tumor location and possible cure necessitated transection of the left optic nerve at its junction with the chiasm. A vascular clip was then placed on the left ophthalmic artery at its carotid origin. Just distal to the clip, the artery was coagulated and sectioned. The oculoplastic surgeons then enucleated the left globe. From the orbital side, the optic nerve and sheath were isolated. Microdissection around the nerve in the sheath ensued. Eventually, the nerve released and was removed en bloc from the orbit. The cranial side was explored to ensure no hemorrhage or disruption
of normal structures. There was no opening into the sphenoid air sinus. Craniotomy closure then proceeded in standard fashion. Orbital reconstruction was performed with a dermal fat graft. Histopathologic evaluation of the globe/ retina showed scattered deposits of mitotically active, large atypical cells subjacent to the inner limiting membrane and infiltrating inner retinal layers (Figures 5 and 6). The cells showed strong OCT4 nuclear immunoreactivity and strong CD117 (c-kit) cytoplasmic immunoreactivity, whereas CD30, AFP, and glypican-3 immunohistochemistry were all negative, confirming a diagnosis of pure germinoma (Figure 6). The left optic nerve showed pronounced axonal loss and mature teratomatous elements including epithelial-lined cysts and mature cartilage surrounded by fibroconnective tissue (Figure 5B and C). The patient was consolidated with 2 cycles of marrow-ablative carboplatin and thiotepa followed by autologous hematopoietic cell rescue, without any irradiation. She continues to survive without evidence of relapse by MRI and tumor marker surveillance 21 months postconsolidation therapy. DISCUSSION Loco-regional extension of CNS GCT at diagnosis is common, and usually occurs in the third ventricular region.5 Moreover, localized CNS germinoma tends to relapse in the periventricular wall outside the irradiation field.6-9 CNS GCT extension to the optic pathway at diagnosis is not uncommon. One retrospective study reported 19 out of 100 patients with primary CNS GCT had optic chiasm, nerve, or tract extension.5 Of the 19 patients, 16 presented initially with single or bifocal suprasellar primary tumor.5 However, to the best of our knowledge, few relapsed CNS GCT in the optic pathway have been reported in the literature,7,10-12 moreover, retinal invasion has not been reported previously. Decreased visual acuity in patients with a history of suprasellar GCT may indicate progression or tumor relapse in the optic pathway; therefore, orbital MRI is essential for the evaluation of these patients. The finding of a thickened enhancing
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CASE MOHAMMAD H. ABU ARJA ET AL.
Figure 5. (A) Left eye enucleation specimen: yellow arrows show irregular retinal thickening by infiltrating tumor (1x objective magnification; Hematoxylin and Eosin-stained section). (B and C) Left optic nerve specimen showing pronounced axonal loss and mature teratomatous
optic system on imaging is not solely attributable to tumor progression, as it may arise secondarily to RION.13 RION is a late radiation toxicity that usually occurs >6 months following irradiation, with an average of 18 months postirradiation, following doses of 5400 cGy or higher.13-15 RION is usually associated with a unilateral slow painless decrease in visual acuity, visual fields, and decreased afferent papillary reflex.13 Vision loss secondary to tumor progression may be associated with endocrinopathies and/or increased intracranial pressure. However, patients with suprasellar GCT may experience decreased visual acuity due to optic system tumor invasion without signs of raised intracranial pressure.16 Pursuing a biopsy of the optic pathway enhancement earlier in the course of the disease may
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elements including benign mature hyaline cartilage (B ¼ 40x objective magnification) and benign epithelial-lined cyst (C ¼ 20x objective magnification) surrounded by hypocellular fibroconnective scar tissue fibrosis (Hematoxylin and Eosin-stained sections).
be necessary to differentiate between RION and tumor progression. However, the status of the patient’s vision when optic nerve enhancement develops would need to be considered when deciding on the risk-benefit ratio of a biopsy. Optic nerve and intra-orbital eye involvement by CNS GCT have important implications for diagnosis, radiotherapy, follow-up and prognosis. At initial presentation, brain MRI protocols need to include coronal fluid-attenuated inversion recovery T2 and postgadolinium T1 sequences to allow for proper evaluation of the intraorbital optic nerves. Brain MRI that does not include coronal fluidattenuated inversion recovery T2 may not be optimal to diagnose early infiltration of the optic nerves. Patients with visual changes by history or ocular findings by physical examination will need a
Figure 6. (A) Routine Hematoxylin and Eosin section of the retina showing scattered deposits of large malignant, mitotically-active cells with atypical nuclei and prominent nucleoli in the optic nerve and ganglion cell layers (arrows). These cells infiltrate the inner retina. These tumor (germinoma) cells appear to be mostly subjacent to the inner limiting membrane,
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complete orbital MRI. Early identification of optic nerve involvement is essential to modify the irradiation field as the optic nerve region is not included in the whole ventricular irradiation field. The comprehensive inclusion of the optic pathway in the irradiation field may reduce the risk of future relapse, especially from germinomatous elements. In our patient, the dental brace artifact and rapid clinical deterioration limited our ability to perform a comprehensive initial disease evaluation. CONCLUSIONS Early detection of optic pathway involvement and appropriate adjustment of the irradiation field may prevent future vision loss that can result in poor functional status among survivors of CNS GCT.
evidence that the tumor spread down the optic nerve to reach the retina (20x objective magnification). (B) OCT4 is strongly positive in essentially all tumor cell nuclei (arrow) (20x objective magnification). (C) CD117 (c-kit) shows strong cytoplasmic reactivity in essentially all tumor cells (arrow) (20x objective magnification).
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Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 25 September 2018; accepted 26 December 2018 Citation: World Neurosurg. (2019) 124:116-120. https://doi.org/10.1016/j.wneu.2018.12.143
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