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Primary Intramedullary Spinal Germ Cell Tumors
Peer-Review Short Reports
Primary Intramedullary Spinal Germ Cell Tumors Vivek A. Mehta1, Ryan M. Kretzer1, Brent Orr2, George I. Jallo1
Key words 䡲 Germ cell 䡲 Germinoma 䡲 Intramedullary 䡲 Tumor Abbreviations and Acronyms AP: Anterior-posterior b-HCG: Beta-human chorionic gonadotropin Bx: Biopsy CNS: Central nervous system GCT: Germ cell tumor GTR: Gross total resection R: Recurrence RFS: Recurrence-free survival STR: Subtotal resection From the 1Department of Neurosurgery, and 2 Division of Neuropathology, Department of Pathology, The Johns Hopkins Hospital, Baltimore, Maryland, USA To whom correspondence should be addressed: Ryan Kretzer, M.D. [E-mail: [email protected]]
䡲 BACKGROUND: Intramedullary spinal germ cell tumors are rare lesions, with germinomas being the most common variant. 䡲 METHODS: To date, there have been 23 reports of primary intramedullary germ cell tumors described in the literature, the vast majority occurring in Japanese patients. 䡲 RESULTS: We present a case of a nonmetastatic intramedullary germ cell tumor in a 28-year-old Caucasian woman. 䡲 CONCLUSIONS: Characteristics of intramedullary germ cell tumors are summarized, and the current role for surgery and adjuvant radiation and chemotherapy are discussed.
cuss the epidemiology, historical patterns of presentation, and characteristic imaging findings, and summarize the treatment strategies for all primary intramedullary GCT subtypes.
Citation: World Neurosurg. (2011) 76, 5:478.e1-478.e6. DOI: 10.1016/j.wneu.2011.01.024 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter © 2011 Elsevier Inc. All rights reserved.
INTRODUCTION Primary germ cell tumors (GCT) of the spinal cord are rare but well-recognized lesions, with germinoma being the most common variant (3). This tumor presents in young adults, affects male and female persons equally, and has a predilection for the Japanese population. To date, there have been 23 previous cases of primary intramedullary GCTs in the literature. Treatment strategies have included radiation therapy alone, combination radiation and chemotherapy, and adjuvant radiation and chemotherapy after surgical resection (3). In this report, we describe the second documented case of a primary intramedullary germinoma in a Caucasian patient, and the fourth known case in the non-Asian population. The present patient, a 28-year-old woman, was treated with a combination of gross total resection and adjuvant radiation and chemotherapy. Additionally, we dis-
CASE REPORT A 28-year-old Caucasian woman with no significant past medical history presented with 3 months of progressive back pain, bilateral lower extremity numbness, and difficulty in initiating a bowel movement. On physical examination, her lower extremity strength was 5 of 5, with the exception of 4 of 5 strength in left planar flexion and unsustained clonus at the ankle. She was able to ambulate without difficulty with toe and heel walking. Serum beta-human chorionic gonadotropin (b-hCG) was negative preoperatively. A thoracic spine magnetic resonance image (MRI) demonstrated a T1 isointense, T2 hyperintense, expansile, mixed solid-cystic, gadolinium-enhancing lesion from T11-T12 measuring 1.7 ⫻ 1.5 ⫻ 5 cm in greatest transverse, anteroposterior, and craniocaudal dimensions (Figure 1). Complete neuraxis imaging did not reveal other central nervous system lesions. The differential diagnosis based on imaging included ependymoma and astrocytoma. The patient was taken to the operating room for a T11-T12 osteoplastic
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laminotomy with neurophysiological monitoring. Using microsurgical techniques, a midline myelotomy was performed through the posterior median sulcus, and a gross total resection was accomplished using plated bayonets and microsuction. During the procedure, there was minimal diminution in the left lower extremity motor evoked potential and somatosensory evoked potential; however, the right lower extremity potentials remained intact. Postoperatively, the patient remained at her neurological baseline. Fi-
Figure 1. Sagittal T2 magnetic resonance image of the lower thoracic spine demonstrating a mixed solid and cystic intramedullary lesion at the level of T12 causing significant cord expansion.
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Figure 2. Histological examination. (A) Hematoxylin and eosin stain demonstrating large round cells with large nuclei containing prominent nucleoli and granular chromatin. The cells are arranged in monomorphous
nal pathology was consistent with a malignant GCT consistent with a germinoma. The lesion stained positive with SALL4, CKit, and weakly with OCT-4, with background lymphocytes that were CD20 and CD45 positive. Pathological staining was negative for S100, MITF, or CD30. There was focal nonspecific staining with AE1/ AE3 and CAM5.2 (Figure 2). Based on the pathological findings, a positron emission tomography scan was performed postoperatively to evaluate for potential sites of primary or metastatic disease, which was negative. Consultation was obtained from medical oncology and radiation oncology for adjuvant therapy. Given the isolated site within the spinal cord, a decision was made to proceed with adjuvant
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sheets with background lymphocytes (100⫻) . (B) Tumor cells are positive for C-KIT (100⫻). (C) Tumor cells are positive for SALL-4 (100⫻). (D) Tumor cells are weakly positive for OCT-4 (100⫻).
radiation therapy followed by chemotherapy. Six weeks after surgery, the patient underwent a course of external beam radiotherapy consisting of 180 cGy fractions over a period of 3 weeks for a total dose of 36 Gy. Her chemotherapy regimen consisted of carboplatin at 400 mg/m2 on day 1 and etoposide at 120 mg/m2 on days 1, 2, and 3, every 4 weeks for a total of 3 cycles. The patient tolerated this regimen well with mild symptoms including nausea and fatigue. This course was based on evidence from the gynecologic oncology literature, in which completely resected stage IB–III dysgerminomas of the ovaries were treated with the above regimen and showed no evidence of recurrence (39). Three months after surgery, an MRI demonstrated high T2
signal centrally within the spinal cord at the level of T12, consistent with postsurgical myelomalacia (Figure 3). At her 3-month follow-up, the patient was ambulating without difficulty and returned to her work as a school teacher. Eight months after surgery, a positron emission/computed tomography scan did not demonstrate any residual or recurrent disease.
DISCUSSION Primary GCTs account for a small fraction of all tumors of the central nervous system. The majority of these arise extra-axially from the pineal or suprasellar regions (31), and less commonly as intra-axial lesions
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PRIMARY INTRAMEDULLARY SPINAL GERM CELL TUMORS
Figure 3. Postoperative (A) sagittal T2-weighted and (B) T1-weighted postcontrast thoracic spine magnetic resonance images showing excellent surgical resection.
within the basal ganglia, thalamus, lateral ventricles, and rarely from the spinal cord (5, 9). Although metastatic GCTs are most commonly found in the cervical spine, primary GCTs are more common in the thoracic or thoracolumbar region (3). In Europe and the Unites States, intracranial germinomas make up less than 1% of all CNS tumors, but comprise greater than 3% and 12.5% in Japan and East Asia, respectively (5, 16). To date, a total of 24 primary intramedullary spinal GCTs have been reported, including the present case (1, 3, 6, 8, 11, 13-15, 17, 19, 21-23, 26, 29, 31-36, 40). The average age at presentation for intramedullary GCTs is 24 years, with a range from 5 to 43 years (3). As with intracranial germinomas, intramedullary spinal germinomas are more common in the Japanese population (16 of 24, 67%), with fewer reports in Chinese (2 of 24, 8%), Caucasian (2 of 24, 8%), Indian (1 of 24, 4%), Hispanic (1 of 24, 4%), and unknown race patients (2 of 24, 8%). The definitive cellular origin of central nervous system GCTs remains unclear. Their proclivity to occur in midline structures, however, suggests that they arise from embryonic cell nests that arrested during migration in fetal development (31). Histopathologically, primary intramedullary GCTs can be categorized into three broad subtypes: germinoma, which is associated with the most favorable response to treatment; embryonal carcinoma; and yolk sac tumors. Intracranial to intraspinal dissemination is a well-docu-
mented phenomenon of these lesions. Approximately 6% to 10% of patients with primary intracranial GCTs develop spinal masses, which are usually intradural-extramedullary in location (27), although intramedullary dissemination has also been reported (25). Of the reported cases of primary spinal GCTs, there have been five cases of dissemination, but all have been adjacent to intramedullary or intradural extramedullary spinal levels. As with other intramedullary lesions of the spinal cord, the location of GCTs will dictate the presentation. Greater than 70% of these lesions have been reported in the thoracic region or at the thoracolumbar junction, with back pain, motor and sensory deficits, and bowel/bladder dysfunction being the most common presenting complaints. Rapid neurological decline in a young patient should further raise the suspicion for an intramedullary GCT. More aggressive lesions may disseminate to other spinal levels. The majority of intramedullary germinomas have presented with elevated b-hCG, which can aid in the diagnosis. In some cases, b-hCG can be elevated to a degree that may induce precocious puberty (15). Highly elevated b-hCG levels should raise the suspicion for aggressive lesions and increase the likelihood for early recurrence and poor prognosis (18, 37, 38). The cerebrospinal fluid levels of the soluble isoform of C-kit, which GCTs stain positively for, have also been reported to be a clinical marker (30).
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Magnetic resonance imaging findings are available from the majority of the reported cases of intramedullary spinal GCTs, and some characteristic patterns can be appreciated (6). The majority of these lesions are isointense on T1-weighted MRI. On T2-weighted MRI, they are usually hyperintense and may include small, T2-hyperintense, intramedullary cystic regions. Some degree of gadolinium contrast enhancement is found in the majority of cases, although these lesions are as likely to enhance in a heterogeneous as a homogenous pattern (1, 6). Cases of T1 hyperintensity, T2 isointensity, and nonenhancement have been reported. As this same MRI pattern is also characteristic of spinal astrocytomas, imaging alone is insufficient and tissue sampling is essential for diagnosis (22). The treatment for primary intramedullary GCTs is variable, as the literature describes a variety of treatment strategies that have been used, including radiotherapy alone, radiotherapy combined with chemotherapy, and adjuvant radiation and chemotherapy after surgical resection. Recurrence-free survival has been achieved with each of these approaches, with no clear evidence of the superiority of any modality. The approaches to treatment for the more common intracranial variants offer some clues to the management of primary germinomas within the spinal cord. Intracranial germinomas are highly responsive to radiation therapy (12, 28), with 5-year survival greater than 90% with this treatment alone (4, 20). Nongerminomatous GCTs, including embryonal carcinoma or yolk sac tumors, are much less likely to respond to radiation, with a 5-year survival of less than 50%. More recently, pure intracranial germinomas have been treated with the addition of chemotherapy, which reduces the dose of radiation required to achieve similar survival rates and lessens the degree of radiation-induced functional decline (24). Chemotherapy alone was studied in a series of 71 patients with intracranial germinomas, and was found to induce a high rate of initial remission, but nearly one-half of patients experienced relapse, suggesting that radiation is needed for long-term recurrence-free survival (2). There seems to be no benefit with either partial or gross total resection of intracranial germinomas, so there is no role
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Case No.
Report
Age Sex
Race
Intramedullary Extramedullary Level Site b-hCG
Surgery
Japanese
T11–L3
At intramedullary level
⫹
Bx, amputation
Matsuoka et al., 1991 (26)
31
F
Japanese
T12–L2
⫺
⫺
STR
Nagasawa et al., 1991 (32)
31
M
Japanese
Multi focal
⫺
⫺
4
Hanafusa et al., 1993 (13)
34
F
Japanese
T10–T11
⫺
⫺
5
Slagel et al., 1995 (35)
16
F
?
T11–L4
At intramedullary level
⫺
6
Kawano et al., 1995 (21)
24
M
Japanese
L1–L3
At intramedullary level
7
Matsuyama et al., 1995 (29)
34
F
Japanese
T6–T8
8
Itoh et al., 1996 (19)
24
M
Japanese
9
Miyauchi et al., 1996 (31)
24
M
Japanese
10
Kiyuna et al., 1999 (23)
20
F
11
Ganslandt et al., 2000 (11)
29
M
12
Hata et al., 2002 (14)
33
13
Sasaki et al., 2002 (34)
32
14
Zhu et al., 2002 (40)
15
Chute et al., 2003 (8)
16
Onodera et al., 2006 (33)
16
17
Takahashi et al., 2006 (36)
22
F
Japanese
L1–L2
18
Huang et al., 2004 (17)
18
M
Caucasian
C3–C6
⫺
19
Aoyoma et al., 2007 (1)
16
F
Japanese
T9–T12
20
Aoyoma et al., 2007 (1)
34
F
Japanese
T8–T10
21
Biswas et al., 2009 (2)
28
M
Indian
22
Chen et al., 2009 (6)
22
F
Chinese
23
Kinoshita et al., 2010 (22)
21
F
Japanese
T9–T11
24
Present case
28
F
Caucasian
T11–T12
2 3
110
Follow-up (months) Outcome
Actinomycin, methotrexate, vincristine, bleomycin, cisplatin, vinblastin
6
R
50
–
15
RFS
51
–
40
RFS
GTR
45
–
24
RFS
STR
30
–
336
RFS
⫺
STR
40
–
⫺
⫺
STR
46
–
12
RFS
T11–T12
⫺
⫺
GTR
52.1
–
13
RFS
T12–L3
Conus medullaris
⫺
STR
40
–
15
RFS
Japanese
T11–L3
⫺
⫺
GTR
40
–
24
RFS
?
T12–L2
⫺
?
STR
Not reported
–
24
RFS
M
Japanese
T7–T9
⫺
⫺
STR
F
Japanese
T3–T4
⫺
⫹
7
M
Chinese
T12–L1
⫺
⫹
STR
Not reported
18
M
Hispanic
T6–T8
⫺
⫹
Bx
50
F
Japanese
T8–T12
⫺
⫹
STR
30.6
Specific drugs not reported
⫹
STR
30.6
Cisplatin, etoposide
⫺
STR
⫺
⫹
STR
⫺
⫹
Bx
L2–L4
⫺
⫹
T9–T11
⫺
⫹
Cauda equina
Cauda equina ⫺
–
–
ND
RFS
36
Carboplatin, etoposide
38
RFS
19.8
Methotrexate, etoposide
60
RFS
6
RFS
–
Not reported 18
RFS
Bleomycin, cisplatin, etoposide
6
RFS
30.6
Ifosfamide, cisplatin, etoposide
36
RFS
30.6
Ifosfamide, cisplatin, etoposide
24
RFS
GTR
20
Bleomycin, cisplatin, etoposide
11
R
STR
40
⫹
STR
25.2
⫺
GTR
36
Not reported
–
6
RFS
Carboplatin ⫹ etoposide
36
RFS
Carboplatin ⫹ etoposide
8
RFS
b-hCG, beta-human chorionic gonadotropin; Bx, biopsy; F, female; GTR, gross total resection; M, male; R, recurrence; RFS, recurrence-free survival; STR, subtotal resection. Adapted from Biswas et al. (3) and Huang et al. (17).
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M
Hisa et al., 1985 (15)
Chemotherapy
PRIMARY INTRAMEDULLARY SPINAL GERM CELL TUMORS
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5
1
Total Radiotherapy (Gy)
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Table 1. Summary of all Reported Cases of Primary Spinal Germ Cell Tumor
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for surgical resection of these lesions beyond biopsy (7, 10, 24). A variety of treatment approaches have been used for primary intramedullary spinal germinomas, with no clear consensus on the most appropriate treatment strategy. Of the 24 cases reported to date, 19 have undergone surgical resection, with 13 resulting in partial and 6 in gross total resection. Of those who have undergone surgical resection, recurrence-free survival was achieved in all but one case, with an average follow-up of 39 months. Five patients have been treated nonsurgically, with three receiving combination radiation and chemotherapy and two receiving radiation therapy alone. The most common chemotherapeutic agents used were etoposide and cisplatin, with bleomycin, carboplatin, methotrexate, and vinblastin being other commonly used agents, similar to the agents used for intracranial GCTs. The average follow-up of cases with nonsurgical management is 33 months. Recurrence has been reported in 2 of 24 cases in the literature— one in which the lesion was initially managed nonsurgically and one in which there was initial surgical resection. The first patient received only 35 Gy of local radiation with actinomycin, methotrexate, and vincristine. Five months later, there was evidence of tumor recurrence and the patient underwent amputation of the spinal cord above the level of the lesion at T7, along with an additional 75 Gy of radiation therapy and a second course of bleomycin, cisplatin, and vinblastin with no further recurrence at 1-year follow-up. The second patient underwent gross total resection and adjuvant chemotherapy with bleomycin, cisplatin, and etoposide but not radiation. Three months later he presented with acute-onset lower extremity pain and ataxia, which rapidly progressed to paraparesis. He died soon after palliative treatments, including radiation and surgery, of suspected cervical cord metastatic disease. A summary of the management of primary intramedullary GCTs with follow-up and outcomes is listed in Table 1. In our current patient, the postoperative adjuvant therapy was guided by a study from the gynecologic oncology literature (39) in which 39 women with completely resected stage IB-III dysgerminomas of the ovaries were treated with three courses of carboplatin 400 mg/m2 on day 1 plus etoposide 120
PRIMARY INTRAMEDULLARY SPINAL GERM CELL TUMORS
mg/m2 on days 1, 2, and 3, every 4 weeks for a total of three courses. The regimen was well tolerated, with no patients developing chemotherapeutic toxicity beyond grade II (transient vomiting, tolerable diarrhea, moderate infection, moderate alopecia). In the final analysis, no patient had demonstrated evidence of recurrence with an average follow-up of 7.8 years. The intent of this trial was to demonstrate the efficacy of a more gentle chemotherapy regimen, which would reduce the incidence of more severe (grade III⫹) toxicity that is often observed with the addition of bleomycin, ifosfamide, and methotrexate. These more toxic agents are commonly used to treat primary intramedullary GCTs, but evidence suggests that etoposide and bleomycin are sufficient to induce long-term, progression-free survival in patients who have undergone surgical resection. In the 23 intramedullary cases reported in the literature, radiation therapy was used in all cases with an average dose of 41 Gy. In addition, the high rate of subtotal resection in this series highlights the difficulty in delineating a border between tumor and normal spinal cord. Therefore, we recommend the use of electrophysiological monitoring, particularly motor evoked potentials, during surgical treatment of these lesions to guide the extent of resection. Motor evoked potentials rely on two monitoring modalities, the epidural (D-wave) and myogenic recordings, which have been shown to minimize the postoperative deficits after operative management of these lesions (17). Although less aggressive germinomas may be adequately managed with radiation therapy or with combined radiation and chemotherapy, tumors presenting with distant intraspinal dissemination or with high b-hCG represent a more aggressive class in which surgical management is recommended. Based on evidence from the literature in primary ovarian dysgerminomas, it is our opinion that surgical resection, followed by adjuvant radiation and chemotherapy, offers the highest probability of achieving long-term, progression-free survival.
CONCLUSIONS Primary GCTs of the spinal cord are rare, but should be considered in the differential diagnosis of an intramedullary lesion, par-
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ticularly in a patient of East Asian or Japanese ancestry. When positive, serum b-hCG can help to identify aggressive germinomas and guide the ideal treatment strategy. Although excellent results have been achieved with both partial and gross total surgical resection, nonsurgical management has also resulted in recurrence-free survival and may be appropriate for those in whom a diagnosis of a pure germinoma has been established or in poor surgical candidates. Carboplatin and etoposide have been extensively studied in the treatment of these lesions in their primary gonadal form and offer high-rates of remission with a mild toxicity profile. Radiation therapy is the cornerstone of management of primary intramedullary and intracranial GCTs and should be part of the treatment of these lesions regardless of the surgical intervention. An appreciation of the role of surgical, medical, and particularly radiation therapy is important for any neurosurgeon who encounters a primary intramedullary spinal GCT, and a multidisciplinary approach to treatment should be used.
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29. Matsuyama Y, Nagasaka T, Mimatsu K, Inoue K, Mii K, Iwata H: Intramedullary spinal cord germinoma. Spine 20:2338-2340, 1995. 30. Miyanohara O, Takeshima H, Kaji M, Hirano H, Sawamura Y, Kochi M, Kuratsu J: Diagnostic significance of soluble c-kit in the cerebrospinal fluid of patients with germ cell tumors. J Neurosurg 97:177183, 2002.
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 07 November 2010; accepted 14 January 2011 Citation: World Neurosurg. (2011) 76, 5:478.e1-478.e6. DOI: 10.1016/j.wneu.2011.01.024 Journal homepage: www.WORLDNEUROSURGERY.org
31. Miyauchi A, Matsumoto K, Kohmura E, Doi T, Hashimoto K, Kawano K: Primary intramedullary spinal cord germinoma. Case report. J Neurosurg 84:1060-1061, 1996.
Available online: www.sciencedirect.com 1878-8750/$ - see front matter © 2011 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY, DOI:10.1016/j.wneu.2011.01.024
Primary Intramedullary Spinal Germ Cell Tumors Vivek A. Mehta1, Ryan M. Kretzer1, Brent Orr2, George I. Jallo1
Key words 䡲 Germ cell 䡲 Germinoma 䡲 Intramedullary 䡲 Tumor Abbreviations and Acronyms AP: Anterior-posterior b-HCG: Beta-human chorionic gonadotropin Bx: Biopsy CNS: Central nervous system GCT: Germ cell tumor GTR: Gross total resection R: Recurrence RFS: Recurrence-free survival STR: Subtotal resection From the 1Department of Neurosurgery, and 2 Division of Neuropathology, Department of Pathology, The Johns Hopkins Hospital, Baltimore, Maryland, USA To whom correspondence should be addressed: Ryan Kretzer, M.D. [E-mail: [email protected]]
䡲 BACKGROUND: Intramedullary spinal germ cell tumors are rare lesions, with germinomas being the most common variant. 䡲 METHODS: To date, there have been 23 reports of primary intramedullary germ cell tumors described in the literature, the vast majority occurring in Japanese patients. 䡲 RESULTS: We present a case of a nonmetastatic intramedullary germ cell tumor in a 28-year-old Caucasian woman. 䡲 CONCLUSIONS: Characteristics of intramedullary germ cell tumors are summarized, and the current role for surgery and adjuvant radiation and chemotherapy are discussed.
cuss the epidemiology, historical patterns of presentation, and characteristic imaging findings, and summarize the treatment strategies for all primary intramedullary GCT subtypes.
Citation: World Neurosurg. (2011) 76, 5:478.e1-478.e6. DOI: 10.1016/j.wneu.2011.01.024 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter © 2011 Elsevier Inc. All rights reserved.
INTRODUCTION Primary germ cell tumors (GCT) of the spinal cord are rare but well-recognized lesions, with germinoma being the most common variant (3). This tumor presents in young adults, affects male and female persons equally, and has a predilection for the Japanese population. To date, there have been 23 previous cases of primary intramedullary GCTs in the literature. Treatment strategies have included radiation therapy alone, combination radiation and chemotherapy, and adjuvant radiation and chemotherapy after surgical resection (3). In this report, we describe the second documented case of a primary intramedullary germinoma in a Caucasian patient, and the fourth known case in the non-Asian population. The present patient, a 28-year-old woman, was treated with a combination of gross total resection and adjuvant radiation and chemotherapy. Additionally, we dis-
CASE REPORT A 28-year-old Caucasian woman with no significant past medical history presented with 3 months of progressive back pain, bilateral lower extremity numbness, and difficulty in initiating a bowel movement. On physical examination, her lower extremity strength was 5 of 5, with the exception of 4 of 5 strength in left planar flexion and unsustained clonus at the ankle. She was able to ambulate without difficulty with toe and heel walking. Serum beta-human chorionic gonadotropin (b-hCG) was negative preoperatively. A thoracic spine magnetic resonance image (MRI) demonstrated a T1 isointense, T2 hyperintense, expansile, mixed solid-cystic, gadolinium-enhancing lesion from T11-T12 measuring 1.7 ⫻ 1.5 ⫻ 5 cm in greatest transverse, anteroposterior, and craniocaudal dimensions (Figure 1). Complete neuraxis imaging did not reveal other central nervous system lesions. The differential diagnosis based on imaging included ependymoma and astrocytoma. The patient was taken to the operating room for a T11-T12 osteoplastic
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laminotomy with neurophysiological monitoring. Using microsurgical techniques, a midline myelotomy was performed through the posterior median sulcus, and a gross total resection was accomplished using plated bayonets and microsuction. During the procedure, there was minimal diminution in the left lower extremity motor evoked potential and somatosensory evoked potential; however, the right lower extremity potentials remained intact. Postoperatively, the patient remained at her neurological baseline. Fi-
Figure 1. Sagittal T2 magnetic resonance image of the lower thoracic spine demonstrating a mixed solid and cystic intramedullary lesion at the level of T12 causing significant cord expansion.
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Figure 2. Histological examination. (A) Hematoxylin and eosin stain demonstrating large round cells with large nuclei containing prominent nucleoli and granular chromatin. The cells are arranged in monomorphous
nal pathology was consistent with a malignant GCT consistent with a germinoma. The lesion stained positive with SALL4, CKit, and weakly with OCT-4, with background lymphocytes that were CD20 and CD45 positive. Pathological staining was negative for S100, MITF, or CD30. There was focal nonspecific staining with AE1/ AE3 and CAM5.2 (Figure 2). Based on the pathological findings, a positron emission tomography scan was performed postoperatively to evaluate for potential sites of primary or metastatic disease, which was negative. Consultation was obtained from medical oncology and radiation oncology for adjuvant therapy. Given the isolated site within the spinal cord, a decision was made to proceed with adjuvant
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sheets with background lymphocytes (100⫻) . (B) Tumor cells are positive for C-KIT (100⫻). (C) Tumor cells are positive for SALL-4 (100⫻). (D) Tumor cells are weakly positive for OCT-4 (100⫻).
radiation therapy followed by chemotherapy. Six weeks after surgery, the patient underwent a course of external beam radiotherapy consisting of 180 cGy fractions over a period of 3 weeks for a total dose of 36 Gy. Her chemotherapy regimen consisted of carboplatin at 400 mg/m2 on day 1 and etoposide at 120 mg/m2 on days 1, 2, and 3, every 4 weeks for a total of 3 cycles. The patient tolerated this regimen well with mild symptoms including nausea and fatigue. This course was based on evidence from the gynecologic oncology literature, in which completely resected stage IB–III dysgerminomas of the ovaries were treated with the above regimen and showed no evidence of recurrence (39). Three months after surgery, an MRI demonstrated high T2
signal centrally within the spinal cord at the level of T12, consistent with postsurgical myelomalacia (Figure 3). At her 3-month follow-up, the patient was ambulating without difficulty and returned to her work as a school teacher. Eight months after surgery, a positron emission/computed tomography scan did not demonstrate any residual or recurrent disease.
DISCUSSION Primary GCTs account for a small fraction of all tumors of the central nervous system. The majority of these arise extra-axially from the pineal or suprasellar regions (31), and less commonly as intra-axial lesions
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PRIMARY INTRAMEDULLARY SPINAL GERM CELL TUMORS
Figure 3. Postoperative (A) sagittal T2-weighted and (B) T1-weighted postcontrast thoracic spine magnetic resonance images showing excellent surgical resection.
within the basal ganglia, thalamus, lateral ventricles, and rarely from the spinal cord (5, 9). Although metastatic GCTs are most commonly found in the cervical spine, primary GCTs are more common in the thoracic or thoracolumbar region (3). In Europe and the Unites States, intracranial germinomas make up less than 1% of all CNS tumors, but comprise greater than 3% and 12.5% in Japan and East Asia, respectively (5, 16). To date, a total of 24 primary intramedullary spinal GCTs have been reported, including the present case (1, 3, 6, 8, 11, 13-15, 17, 19, 21-23, 26, 29, 31-36, 40). The average age at presentation for intramedullary GCTs is 24 years, with a range from 5 to 43 years (3). As with intracranial germinomas, intramedullary spinal germinomas are more common in the Japanese population (16 of 24, 67%), with fewer reports in Chinese (2 of 24, 8%), Caucasian (2 of 24, 8%), Indian (1 of 24, 4%), Hispanic (1 of 24, 4%), and unknown race patients (2 of 24, 8%). The definitive cellular origin of central nervous system GCTs remains unclear. Their proclivity to occur in midline structures, however, suggests that they arise from embryonic cell nests that arrested during migration in fetal development (31). Histopathologically, primary intramedullary GCTs can be categorized into three broad subtypes: germinoma, which is associated with the most favorable response to treatment; embryonal carcinoma; and yolk sac tumors. Intracranial to intraspinal dissemination is a well-docu-
mented phenomenon of these lesions. Approximately 6% to 10% of patients with primary intracranial GCTs develop spinal masses, which are usually intradural-extramedullary in location (27), although intramedullary dissemination has also been reported (25). Of the reported cases of primary spinal GCTs, there have been five cases of dissemination, but all have been adjacent to intramedullary or intradural extramedullary spinal levels. As with other intramedullary lesions of the spinal cord, the location of GCTs will dictate the presentation. Greater than 70% of these lesions have been reported in the thoracic region or at the thoracolumbar junction, with back pain, motor and sensory deficits, and bowel/bladder dysfunction being the most common presenting complaints. Rapid neurological decline in a young patient should further raise the suspicion for an intramedullary GCT. More aggressive lesions may disseminate to other spinal levels. The majority of intramedullary germinomas have presented with elevated b-hCG, which can aid in the diagnosis. In some cases, b-hCG can be elevated to a degree that may induce precocious puberty (15). Highly elevated b-hCG levels should raise the suspicion for aggressive lesions and increase the likelihood for early recurrence and poor prognosis (18, 37, 38). The cerebrospinal fluid levels of the soluble isoform of C-kit, which GCTs stain positively for, have also been reported to be a clinical marker (30).
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Magnetic resonance imaging findings are available from the majority of the reported cases of intramedullary spinal GCTs, and some characteristic patterns can be appreciated (6). The majority of these lesions are isointense on T1-weighted MRI. On T2-weighted MRI, they are usually hyperintense and may include small, T2-hyperintense, intramedullary cystic regions. Some degree of gadolinium contrast enhancement is found in the majority of cases, although these lesions are as likely to enhance in a heterogeneous as a homogenous pattern (1, 6). Cases of T1 hyperintensity, T2 isointensity, and nonenhancement have been reported. As this same MRI pattern is also characteristic of spinal astrocytomas, imaging alone is insufficient and tissue sampling is essential for diagnosis (22). The treatment for primary intramedullary GCTs is variable, as the literature describes a variety of treatment strategies that have been used, including radiotherapy alone, radiotherapy combined with chemotherapy, and adjuvant radiation and chemotherapy after surgical resection. Recurrence-free survival has been achieved with each of these approaches, with no clear evidence of the superiority of any modality. The approaches to treatment for the more common intracranial variants offer some clues to the management of primary germinomas within the spinal cord. Intracranial germinomas are highly responsive to radiation therapy (12, 28), with 5-year survival greater than 90% with this treatment alone (4, 20). Nongerminomatous GCTs, including embryonal carcinoma or yolk sac tumors, are much less likely to respond to radiation, with a 5-year survival of less than 50%. More recently, pure intracranial germinomas have been treated with the addition of chemotherapy, which reduces the dose of radiation required to achieve similar survival rates and lessens the degree of radiation-induced functional decline (24). Chemotherapy alone was studied in a series of 71 patients with intracranial germinomas, and was found to induce a high rate of initial remission, but nearly one-half of patients experienced relapse, suggesting that radiation is needed for long-term recurrence-free survival (2). There seems to be no benefit with either partial or gross total resection of intracranial germinomas, so there is no role
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Case No.
Report
Age Sex
Race
Intramedullary Extramedullary Level Site b-hCG
Surgery
Japanese
T11–L3
At intramedullary level
⫹
Bx, amputation
Matsuoka et al., 1991 (26)
31
F
Japanese
T12–L2
⫺
⫺
STR
Nagasawa et al., 1991 (32)
31
M
Japanese
Multi focal
⫺
⫺
4
Hanafusa et al., 1993 (13)
34
F
Japanese
T10–T11
⫺
⫺
5
Slagel et al., 1995 (35)
16
F
?
T11–L4
At intramedullary level
⫺
6
Kawano et al., 1995 (21)
24
M
Japanese
L1–L3
At intramedullary level
7
Matsuyama et al., 1995 (29)
34
F
Japanese
T6–T8
8
Itoh et al., 1996 (19)
24
M
Japanese
9
Miyauchi et al., 1996 (31)
24
M
Japanese
10
Kiyuna et al., 1999 (23)
20
F
11
Ganslandt et al., 2000 (11)
29
M
12
Hata et al., 2002 (14)
33
13
Sasaki et al., 2002 (34)
32
14
Zhu et al., 2002 (40)
15
Chute et al., 2003 (8)
16
Onodera et al., 2006 (33)
16
17
Takahashi et al., 2006 (36)
22
F
Japanese
L1–L2
18
Huang et al., 2004 (17)
18
M
Caucasian
C3–C6
⫺
19
Aoyoma et al., 2007 (1)
16
F
Japanese
T9–T12
20
Aoyoma et al., 2007 (1)
34
F
Japanese
T8–T10
21
Biswas et al., 2009 (2)
28
M
Indian
22
Chen et al., 2009 (6)
22
F
Chinese
23
Kinoshita et al., 2010 (22)
21
F
Japanese
T9–T11
24
Present case
28
F
Caucasian
T11–T12
2 3
110
Follow-up (months) Outcome
Actinomycin, methotrexate, vincristine, bleomycin, cisplatin, vinblastin
6
R
50
–
15
RFS
51
–
40
RFS
GTR
45
–
24
RFS
STR
30
–
336
RFS
⫺
STR
40
–
⫺
⫺
STR
46
–
12
RFS
T11–T12
⫺
⫺
GTR
52.1
–
13
RFS
T12–L3
Conus medullaris
⫺
STR
40
–
15
RFS
Japanese
T11–L3
⫺
⫺
GTR
40
–
24
RFS
?
T12–L2
⫺
?
STR
Not reported
–
24
RFS
M
Japanese
T7–T9
⫺
⫺
STR
F
Japanese
T3–T4
⫺
⫹
7
M
Chinese
T12–L1
⫺
⫹
STR
Not reported
18
M
Hispanic
T6–T8
⫺
⫹
Bx
50
F
Japanese
T8–T12
⫺
⫹
STR
30.6
Specific drugs not reported
⫹
STR
30.6
Cisplatin, etoposide
⫺
STR
⫺
⫹
STR
⫺
⫹
Bx
L2–L4
⫺
⫹
T9–T11
⫺
⫹
Cauda equina
Cauda equina ⫺
–
–
ND
RFS
36
Carboplatin, etoposide
38
RFS
19.8
Methotrexate, etoposide
60
RFS
6
RFS
–
Not reported 18
RFS
Bleomycin, cisplatin, etoposide
6
RFS
30.6
Ifosfamide, cisplatin, etoposide
36
RFS
30.6
Ifosfamide, cisplatin, etoposide
24
RFS
GTR
20
Bleomycin, cisplatin, etoposide
11
R
STR
40
⫹
STR
25.2
⫺
GTR
36
Not reported
–
6
RFS
Carboplatin ⫹ etoposide
36
RFS
Carboplatin ⫹ etoposide
8
RFS
b-hCG, beta-human chorionic gonadotropin; Bx, biopsy; F, female; GTR, gross total resection; M, male; R, recurrence; RFS, recurrence-free survival; STR, subtotal resection. Adapted from Biswas et al. (3) and Huang et al. (17).
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M
Hisa et al., 1985 (15)
Chemotherapy
PRIMARY INTRAMEDULLARY SPINAL GERM CELL TUMORS
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5
1
Total Radiotherapy (Gy)
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Table 1. Summary of all Reported Cases of Primary Spinal Germ Cell Tumor
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for surgical resection of these lesions beyond biopsy (7, 10, 24). A variety of treatment approaches have been used for primary intramedullary spinal germinomas, with no clear consensus on the most appropriate treatment strategy. Of the 24 cases reported to date, 19 have undergone surgical resection, with 13 resulting in partial and 6 in gross total resection. Of those who have undergone surgical resection, recurrence-free survival was achieved in all but one case, with an average follow-up of 39 months. Five patients have been treated nonsurgically, with three receiving combination radiation and chemotherapy and two receiving radiation therapy alone. The most common chemotherapeutic agents used were etoposide and cisplatin, with bleomycin, carboplatin, methotrexate, and vinblastin being other commonly used agents, similar to the agents used for intracranial GCTs. The average follow-up of cases with nonsurgical management is 33 months. Recurrence has been reported in 2 of 24 cases in the literature— one in which the lesion was initially managed nonsurgically and one in which there was initial surgical resection. The first patient received only 35 Gy of local radiation with actinomycin, methotrexate, and vincristine. Five months later, there was evidence of tumor recurrence and the patient underwent amputation of the spinal cord above the level of the lesion at T7, along with an additional 75 Gy of radiation therapy and a second course of bleomycin, cisplatin, and vinblastin with no further recurrence at 1-year follow-up. The second patient underwent gross total resection and adjuvant chemotherapy with bleomycin, cisplatin, and etoposide but not radiation. Three months later he presented with acute-onset lower extremity pain and ataxia, which rapidly progressed to paraparesis. He died soon after palliative treatments, including radiation and surgery, of suspected cervical cord metastatic disease. A summary of the management of primary intramedullary GCTs with follow-up and outcomes is listed in Table 1. In our current patient, the postoperative adjuvant therapy was guided by a study from the gynecologic oncology literature (39) in which 39 women with completely resected stage IB-III dysgerminomas of the ovaries were treated with three courses of carboplatin 400 mg/m2 on day 1 plus etoposide 120
PRIMARY INTRAMEDULLARY SPINAL GERM CELL TUMORS
mg/m2 on days 1, 2, and 3, every 4 weeks for a total of three courses. The regimen was well tolerated, with no patients developing chemotherapeutic toxicity beyond grade II (transient vomiting, tolerable diarrhea, moderate infection, moderate alopecia). In the final analysis, no patient had demonstrated evidence of recurrence with an average follow-up of 7.8 years. The intent of this trial was to demonstrate the efficacy of a more gentle chemotherapy regimen, which would reduce the incidence of more severe (grade III⫹) toxicity that is often observed with the addition of bleomycin, ifosfamide, and methotrexate. These more toxic agents are commonly used to treat primary intramedullary GCTs, but evidence suggests that etoposide and bleomycin are sufficient to induce long-term, progression-free survival in patients who have undergone surgical resection. In the 23 intramedullary cases reported in the literature, radiation therapy was used in all cases with an average dose of 41 Gy. In addition, the high rate of subtotal resection in this series highlights the difficulty in delineating a border between tumor and normal spinal cord. Therefore, we recommend the use of electrophysiological monitoring, particularly motor evoked potentials, during surgical treatment of these lesions to guide the extent of resection. Motor evoked potentials rely on two monitoring modalities, the epidural (D-wave) and myogenic recordings, which have been shown to minimize the postoperative deficits after operative management of these lesions (17). Although less aggressive germinomas may be adequately managed with radiation therapy or with combined radiation and chemotherapy, tumors presenting with distant intraspinal dissemination or with high b-hCG represent a more aggressive class in which surgical management is recommended. Based on evidence from the literature in primary ovarian dysgerminomas, it is our opinion that surgical resection, followed by adjuvant radiation and chemotherapy, offers the highest probability of achieving long-term, progression-free survival.
CONCLUSIONS Primary GCTs of the spinal cord are rare, but should be considered in the differential diagnosis of an intramedullary lesion, par-
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ticularly in a patient of East Asian or Japanese ancestry. When positive, serum b-hCG can help to identify aggressive germinomas and guide the ideal treatment strategy. Although excellent results have been achieved with both partial and gross total surgical resection, nonsurgical management has also resulted in recurrence-free survival and may be appropriate for those in whom a diagnosis of a pure germinoma has been established or in poor surgical candidates. Carboplatin and etoposide have been extensively studied in the treatment of these lesions in their primary gonadal form and offer high-rates of remission with a mild toxicity profile. Radiation therapy is the cornerstone of management of primary intramedullary and intracranial GCTs and should be part of the treatment of these lesions regardless of the surgical intervention. An appreciation of the role of surgical, medical, and particularly radiation therapy is important for any neurosurgeon who encounters a primary intramedullary spinal GCT, and a multidisciplinary approach to treatment should be used.
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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 07 November 2010; accepted 14 January 2011 Citation: World Neurosurg. (2011) 76, 5:478.e1-478.e6. DOI: 10.1016/j.wneu.2011.01.024 Journal homepage: www.WORLDNEUROSURGERY.org
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WORLD NEUROSURGERY, DOI:10.1016/j.wneu.2011.01.024