Intramedullary spinal cord germinoma—2 case reports

Surgical Neurology 67 (2007) 177 – 183 www.surgicalneurology-online.com

Neoplasm-Spine

Intramedullary spinal cord germinoma—2 case reports Takeshi Aoyama, MD4, Kazutoshi Hida, MD, Nobuaki Ishii, MD, Toshitaka Seki, MD, Jun Ikeda, MD, Yoshinobu Iwasaki, MD Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan Received 18 April 2006; accepted 23 May 2006

Abstract

Background: Primary intramedullary spinal cord germinoma is very rare. We encountered 2 patients with primary intramedullary spinal cord germinoma. We describe herein our comprehensive management system for CNS germinoma, including intramedullary spinal cord germinoma, along with a review of the literature. This is the first report to describe successful application of ICE chemotherapy for intramedullary germinoma. Case Descriptions: A 16-year-old adolescent girl (case 1) experienced lumbago and subsequently noticed gait disturbance that aggravated gradually. On admission, paraparesis and urinary retention were noted. Magnetic resonance imaging demonstrated marked cord swelling between T9 and T12, with slight enhancement in the spinal cord. Astrocytic tumor was initially suspected, and partial removal was performed. However, pathologic examination identified germinoma. Successful treatment with ICE chemotherapy and radiotherapy was implemented, with no evidence of recurrence apparent at 48 months postoperatively. A 34-year-old woman (case 2) presented with paraparesis and sensory disturbance. Magnetic resonance imaging demonstrated cord swelling between T8 and T10, with slight Gd-DTPA enhancement. Because the lesion did not respond to steroid pulse therapy, spinal cord tumor was suspected and biopsy was performed. Pathologic examination verified primary germinoma of the spine. Successful treatment with ICE chemotherapy and radiotherapy was implemented with no exacerbation of neurologic deficits. No evidence of recurrence was apparent at 36 months postoperatively. Conclusion: Correct diagnosis of very rare primary intramedullary spinal cord germinoma is important, because these patients can be treated successfully using chemo- and radiotherapy without neurologic deterioration. D 2007 Elsevier Inc. All rights reserved.

Keywords:

Chemotherapy; Germinoma; Intramedullary; Radiotherapy; Spinal cord

1. Introduction Histologically, the cells that comprise germ cell tumors are similar to germinal cells originating in genital or extragenital organs. These cells sometimes arise in the CNS and Abbreviations: ACD, dactinomycin; BLM, bleomycin; b-HCG, b-subunit of human chorionic gonadotropin; CDDP, cisplatin; CNS, central nervous system; CSF, cerebrospinal fluid; CT, computed tomography; EP therapy, etoposide cisplatin therapy; Gd-DTPA, gadopentetate dimeglumine; ICE, ifosfamide cisplatin etoposide; IFOS, ifosfamide; MMT, manual muscle testing; MRI, magnetic resonance imaging; MTX, methotrexate; PLAP, placental alkaline phosphatase; STGC, syncytiotrophoblastic giant cell; TS, tumor site; VBL, vinblastine; VCR, vincristine; VP16, etoposide; WN, whole neuroaxis. 4 Corresponding author. Tel.: +81 11 716 1161; fax: +81 11 708 7737. E-mail address: [email protected] (T. Aoyama). 0090-3019/$ – see front matter D 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.surneu.2006.05.062

frequencies differ among geographic areas. Central nervous system germ cell tumors account for 1% of all CNS tumors in Europe and the United States, compared with 3% in Japan and 12.5% in East Asia [2]. These tumors arise on midline structures, and in the CNS, they usually originate near the third ventricle, in the pineal body, or in the suprasellar region and are easily diagnosed in these regions. However, extremely rare cases are found in the spinal cord [3,5-7, 9-11,13-16,20,21], and preoperative radiologic diagnosis is very difficult because of this rarity. If these tumors are correctly identified, patients can be spared radical surgery, because germ cell tumors are readily cured using radio and chemotherapy. We encountered 2 patients with intramedullary spinal cord germinoma. We review the literature and describe our

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Fig. 1. Patient 1. Thoracic MRI on admission shows an intramedullary mass between T9 and T12. A: T1-weighted imaging. B: T2-weighted imaging. C: Gadolinium-enhanced imaging.

adaptation of the therapeutic strategy for CNS germinoma to treat intramedullary spinal cord germinoma. 2. Case reports

normal tissue (Fig. 2A). Intraoperative frozen section suggested astrocytic tumor; and piece-by-piece removal and dissection at the tumor margin resulted in partial removal. Postoperatively, paraparesis worsened.

2.1. Patient 1 This 16-year-old adolescent girl experienced onset of lumbago in March 2002. She subsequently suffered bilateral leg pain and started to notice gait disturbance. Lumbar disk hernia was diagnosed at another hospital and treated conservatively. In July, she suddenly experienced urinary retention. Magnetic resonance imaging identified a thoracic cord lesion and she was transferred to our department. Neither past medical nor family history was informative. Examination revealed bilateral leg weakness (MMT 4/5), hypalgesia, and hypesthesia below the T12 level, and disturbance of vibration sense in both legs. No hyperreflexia or pathologic reflexes were identified. Magnetic resonance imaging demonstrated cord swelling between T9 and T12, with a homogeneous hypointense mass on T1-weighted MRI (Fig. 1A) and a slightly hyperintense mass with spotty strong hyperintensity on T2-weighted imaging (Fig. 1B). No clear margin was apparent. Gadopentetate dimeglumine MRI revealed slight enhancement (Fig. 1C). Based on clinical course and radiologic findings, highgrade astrocytic tumor was initially suspected. In August 2002, laminectomy was performed between T8 and T12. After opening the dura, enlargement of the spinal cord was noted, with a significant shift of the posterior median sulcus to the left. Myelotomy from the posterior median sulcus and dissection disclosed a soft gray tumor that bled easily, was invasive, and displayed no clear border between tumor and

Fig. 2. Patient 1. A: Intraoperative finding of a gray, soft, and easily bleeding tumor with infiltration into normal tissue. B: Large cells with large nucleoli and infiltration of lymphocytes in the so-called 2-cell pattern (hematoxylin and eosin, original magnification 400).

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in serum and CSF were 0.9 and 7.3 mIU/mL, respectively; both levels were thus slightly elevated. Cerebrospinal fluid dissemination was noted on postoperative thoracic MRI (Fig. 3A), but no obvious lesion was found on brain MRI or abdominal or pelvic CT. The tumor was diagnosed as primary intramedullary germinoma producing b-HCG. According to our protocol for treating intracranial germinoma, the patient received 4 courses of the ICE regimen (IFOS 900 mg/m2 for days 1-5, cisplatin 20 mg/m2 for days 1-5, etoposide 60 mg/m2 for days 1-5). Tumor size decreased and dissemination disappeared after the second course of chemotherapy (Fig. 3B). In January 2003, local radiotherapy was performed with 30.6 Gy/17 fr. The patient remains in good condition as of the time of writing, and no evidence of recurrence has been seen as of 45 months after surgery. 2.2. Patient 2

Fig. 3. Patient 1. A: Thoracic MRI (Gd-enhanced) immediately after surgery. Dissemination at the cauda equina was suspected. B: Thoracic MRI (Gd-enhanced) obtained after the fourth course of ICE chemotherapy. Primary tumor and dissemination have disappeared.

Tumor cells contained large nuclei with clear sphenoid nucleoli proliferation in a sheetlike pattern. Lymphocytes and macrophages had infiltrated both interstitial tissue and normal tissue in the so-called 2-cell pattern. Histopathologic examination verified germ cell tumor (Fig. 2B). No STGCs were present, and immunohistologic staining identified some PLAP-positive cells. Because pathologic study disclosed germinoma, the patient underwent whole-body investigation. Levels of b-HCG

This 34-year-old woman noticed unstable gait in April 2003, and shortly thereafter developed paraparesis. Magnetic resonance imaging performed at another hospital detected a thoracic cord lesion. Multiple sclerosis was suspected, so steroid pulse therapy was initiated (methylprednisolone 1000 mg/d). Although the patient was subsequently able to stand unassisted, MRI revealed no obvious changes. Because steroid therapy was tapered, the symptoms exacerbated and steroid pulse therapy was repeated, but this time, it resulted in no response. She was subsequently referred to us for further investigation. On admission, paraparesis, hyperreflexia, pathologic reflexes of both legs, sensory disturbance below the T11 level, gait disturbance, and bladder dysfunction were noted. Magnetic resonance imaging demonstrated cord swelling below the T8 through T10 level. An isointense mass was apparent on T1-weighted imaging (Fig. 4A), with slight

Fig. 4. Patient 2. Thoracic MRI on admission reveals an intramedullary tumor between T8 and T10. A: T1-weighted imaging; B: T2-weighted imaging; C: Gdenhanced imaging.

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Fig. 5. Patient 2. The 2-cell pattern is apparent, as seen in patient 1 (hematoxylin and eosin staining, original magnification 400).

hyperintensity on T2-weighted imaging (Fig. 4B) and slight Gd-DTPA enhancement (Fig. 4C). No other lesions in the brain or other levels of the spinal cord were identified. Clinical course was considered too rapid for astrocytic tumor. Based on our experience with the first patient, germinoma was suspected and biopsy performed. In June 2003, the patient underwent laminectomy between T8 and T12. Upon opening the dura, the spinal cord was enlarged and many tumor nodules were present at the bilateral posterior root, which measured approximately 5 mm in diameter. Incision of the posterior median sulcus of the spinal cord revealed a translucent purple tumor. A small portion of this tumor was removed for pathologic examination of the biopsy specimen, which confirmed the presence of large cells with large nuclei and clear nucleoli. Because the 2-cell pattern was clearly present, typical germinoma was diagnosed. No STGCs were found (Fig. 5). Although the patient experienced slight bilateral leg pain, motor function did not deteriorate. The b-HCG levels in serum and CSF were 0.5 and 24.7 mIU/mL, respectively, with slight elevation at both levels. A diagnosis of b-HCG– producing germinoma was made, and, as in case 1, 4 courses of ICE chemotherapy were administered and followed by 30.6 Gy/17 fr radiotherapy. No tumor recurrence has been identified over the past 34 months. 3. Discussion 3.1. Primary spinal germinoma Primary intramedullary spinal cord germ cell tumors are very rare, and only 13 other cases have been reported previously (Table 1) [3,5-7,9-11,13-16,20,21]. The frequency of germ cell tumor appears to be higher in East Asia than in Western countries [12], with 11 of the reported 15 germinomas, including our cases, occurring in ethnically Japanese patients [5-7,10,11,13-16] and 1 case in a Chinese patient

[21]. The median age of the 15 reported cases was 23.8 years (range, 5-34 years). As with intracranial germinoma, this tumor tends to occur in younger individuals. The 15 patients comprised 8 males and 7 females, indicating no apparent sex difference. Intracranial germinoma, however, appears to display higher prevalence in males. Of the 15 intramedullary spinal cord germ cell tumors, 3 involved the cervical and upper thoracic spine, whereas the other 12 involved the lower thoracic spine and conus medullaris. Surgery was performed in 13 patients, comprising 2 gross total removals, 8 partial removals, and 3 biopsies. The difference in surgical treatment is probably attributable to the difficulty of obtaining correct diagnosis for these tumors. One patient who did not undergo tumor removal was diagnosed by CSF cytology, whereas diagnosis in the other patient was based on a highly elevated serum b-HCG level. Histopathologically, 12 tumors were judged to be germinoma, and 3 were germinomas with STGC. Follow-up period ranged from 6 months to 28 years, and 1 patient suffered tumor recurrence. 3.2. Neuroradiologic findings We initially suspected that the lesion in case 1 represented a high-grade astrocytic tumor. Although the rapid progression of neurologic symptoms suggested a malignant astrocytic tumor, Gd-DTPA MRI in case 1 showed relatively good enhancement, whereas case 2 showed only slight enhancement. Spinal germ cell tumors appear as isoor hypointense masses in the enlarged spinal cord on T1-weighted MRI, and hypo- or hyperintense masses on T2weighted imaging. Many variations are seen for Gd-DTPA enhancement (Table 1). Of the 13 previously reported cases, MRI was performed on only 10 cases, with 5 of the 10 cases showing good enhancement, 3 cases showing slight enhancement, 1 case showing no enhancement, and no findings described for 1 case. Characteristic MRI findings are thus difficult to define in primary spinal germinoma. Symptoms of intramedullary spinal cord tumor are typically rapidly progressive, with the exception of 2 cases [3,5]. Germinoma should be considered as 1 differential diagnosis in cases of rapid deterioration in young patients with intramedullary lesion. Based on our experience with case 1, we performed biopsy alone in case 2. In case 2, the patient was able to be treated using combined chemoradiotherapy without subsequent exacerbation of neurologic deficits. 3.3. Treatment of intracranial germinoma Intracranial germinomas have been considered to be curable using radiotherapy alone. Some authors have recommended delivery of 40 to 60 Gy to the primary intracranial site and approximately 30 Gy directed at the remainder of the uninvolved brain [8,18]. However, endocrine disorders and neurocognitive impairments can develop after the delivery of curative irradiation [1]. Lowering the dose and field size of the initial irradiation may enable a reduction of these adverse effects and allow

Table 1 Clinical summary of 15 cases of primary intramedullary spinal cord germinoma reported in the literature Age/sex

Location

Enhancement by Gd-DTPA

Level of serum or CSF HCG

Operation

Radiation TS (Gy)

Hisa et al [7]

5/M

T11-L3

Not performed

High

Biopsy, amputation

110

Matsuoka et al [11] Nagasawa et al [15] Hanafusa et al [5] Slagel et al [20] Matsuyama et al [13] Miyauchi et al [14] Itoh et al [10] Sasaki et al [16] Hata et al [6]

31/F

T12-L2

Normal

Partial

31/M

Midcervical

Slight, homogeneous Not performed

Not described

34/F

T10-T11

Not enhanced

16/F

L1-L4

34/F

Radiation WN

Chemotherapy

Histology

Course

Germinoma with STGC

Alive ( N 2 y)

50

ACD + MTX + VCR BLM + CDDP + VBL –

Germinoma

Alive ( N 2 y)

–

51

–

Germinoma

Alive ( N 4 y)

Normal

Gross total

45

–

Germinoma

Alive ( N 5 y)

Not performed

Not described

Partial

30

–

Germinoma

Alive ( N 28 y)

T6-T8

Moderate, homogeneous

Normal

Partial

46

–

Germinoma

Alive ( N 2 y)

24/M

T12-L3

Moderate, homogeneous

Negative

Partial

40

15 Gy

–

Germinoma

Alive ( N 15 mo)

24/M

T11-T12

Moderate, homogeneous

Negative

Gross total

28

24.1 Gy

–

Germinoma

Alive ( N 2 y)

32/F

T3-T4

Moderate, heterogeneous

High

–

19.8

27.5 Gy

MTX + VP16

Alive ( N 5 y)

33/M

T7-T9

Slight, heterogeneous

Negative

Partial

36

Zhu et al [21]

7/M

T12-L1

Homogeneous

High

Partial

Not described

Not described

Carboplatine + VP16 Not described

Germinoma with STGC Germinoma

Chute et al [3] Huang et al [9]

18/M 18/M

T6-T8 C3-C6

Slight, homogeneous Intense, homogeneous

High Negative

Biopsy Partial

50 Unknown dose

Present case 1

16/F

T9-T12

Moderate, homogeneous

High

Partial

30.6

Present case 2

34/F

T8-T10

Slight, homogeneous

High

Biopsy

30.6

30 Gy

– BLM + CDDP + VP16 IFOS + CDDP + VP16 IFOS + CDDP + VP16

Alive ( N 4 y)

Germinoma with STGC Germinoma Germinoma

Not described Alive ( N 6 mo) Alive ( N 6 mo)

Germinoma

Alive ( N 3 y)

Germinoma

Alive ( N 2 y)

T. Aoyama et al. / Surgical Neurology 67 (2007) 177 – 183

Series

M indicates male; F, female.

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Table 2 Classification of intracranial germ cell tumors for appropriate treatment selection [17] Good prognosis group Solitary pure germinoma Mature teratoma Intermediate prognosis group Germinoma with elevated serum b-HCG Extensive or multifocal germinoma Disseminated germinoma Immature teratoma Mixed GCT consisting of germinoma with either mature or immature teratoma Poor prognosis group Teratoma with malignant transformation Embryonal carcinoma Yolk Sac tumor Choriocarcinoma Mixed GCT including a component of embryonal carcinoma, yolk sac tumor, choriocarcinoma, or teratoma with malignant transformation

for the delivery of additional radiotherapy in cases of recurrence, although rate of recurrence may be increased in such cases. Shirato et al [19] suggested that no improvement in tumor control rate is achieved by increasing dose to the primary tumor to greater than 40 Gy, but the dose used for whole-ventricle irradiation should not be dropped to less than 30 Gy in 20 fractions to avoid recurrence. Sawamura [17] classified germ cell tumors based on appropriate selection of treatment (Table 2). They reported that patients with elevated serum b-HCG levels display high rates of recurrence even in the absence of histologically confirmed STGC. After irradiation therapy alone [1], 10-year survival rate is 90% in patients with pure germinoma and 60% in patients with b-HCG–secreting germinoma. We therefore developed a strategy for treating intracranial germinoma. Patients with solitary pure germinoma receive 4 cycles of EP therapy (etoposide, 100 mg/m2; cisplatin, 20 mg/m2) for 5 consecutive days every 4 weeks followed by 24 Gy/12 fr local irradiation. Patients with multifocal or disseminated pure germinoma or b-HCG–secreting germinoma are treated with a combination of IFOS (900 mg/m2), cisplatin (20 mg/m2), and etoposide (60 mg/m2) (ICE therapy) for 5 consecutive days every 4 weeks for 4 to 6 cycles, followed by 6 Gy/3 fr delivered to the neurohypophysis and 16 Gy/8 fr to the pineal region after wholeventricle irradiation with 24 Gy/12 fr. This treatment strategy has allowed excellent tumor control [1]. 3.4. Treatment of primary intramedullary germinoma Because primary spinal cord germinoma is extremely rare, development of a treatment protocol is difficult. Radiotherapy alone was performed in 8 cases. Combined radio- and chemotherapy was used in 4 previously reported cases (Table 1). Irradiation dose of part of the tumor ranged between 30 and 110 Gy. (For the combination of TS and WN, the dose was calculated as TS + WN.) In 7 cases, the dose was 50 Gy or greater. Maximum radiation tolerance of

the spinal cord has been reported as 50 Gy using a conventional fraction schedule [4]. Reducing radiation dose is thus important. To achieve this aim, we have adopted combination therapy with radio- and chemotherapy. For chemotherapy, various agents have been used. Combination chemo- and radiotherapy has been reported for 4 patients with spinal cord germinoma [6,7,9,16]. Hata et al [6] followed the administration of carboplatin and VP16 with the delivery of a reduced radiation dose (36 Gy), and observed no tumor recurrence over a 4-year follow-up period. Sasaki et al [16] used MTX and VP16. Huang et al [9] used BLM, CDDP, and VP16. We treated our patients using IFOS, CDDP, and VP16 in accordance with the protocol applied to intracranial germinoma. Both patients remain in complete remission as of the time of writing. However, careful follow-up is required to evaluate the longterm therapeutic results of our combination treatment. References [1] Aoyama H, Shirato H, Ikeda J, et al. Induction chemotherapy followed by low-dose involved-field radiotherapy for intracranial germ cell tumors. J Clin Oncol 2002;20:857 - 65. [2] Borg M. Germ cell tumours of the central nervous system in children—controversies in radiotherapy. Med Pediatr Oncol 2003; 40:367 - 74. [3] Chute DJ, Burton BC, Klement LA, et al. Primary intramedullary spinal cord germinoma: case report. J Neurooncol 2003;63:69 - 73. [4] Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 1991;21:109 - 22. [5] Hanafusa K, Shibuya H, Abe M, et al. Intramedullary spinal cord germinoma: case report and review of the literature. Rofo 1993; 159:203 - 4. [6] Hata M, Ogino I, Sakata K, et al. Intramedullary spinal cord germinoma: case report and review of the literature. Radiology 2002;223:379 - 83. [7] Hisa S, Morinaga S, Kobayashi Y, et al. Intramedullary spinal cord germinoma producing HCG and precocious puberty in a boy. Cancer 1985;55:2845 - 9. [8] Horowitz MB, Hall WA. Central nervous system germinomas. A reviewArch Neurol 1991;48:652 - 7. [9] Huang JH, Tsui I, Judkins AR, et al. Intramedullary cervical spine germinoma: case report. Neurosurgery 2004;55:E1440 - 4. [10] Itoh Y, Mineura K, Sasajima H, et al. Intramedullary spinal cord germinoma: case report and review of the literature. Neurosurgery 1996;38:187 - 91. [11] Matsuoka S, Itoh M, Shinonome T, et al. Intramedullary spinal cord germinoma: case report. Surg Neurol 1991;35:122 - 6. [12] Matsutani M. Germ cell tumor. In: Tamura A, Matsutani M, Shimizu T, editors. Basic treatment indicator of neurosurgical disease based on EBM (in Japanese). Tokyo7 Medicalview; 2002. p. 81 - 5. [13] Matsuyama Y, Nagasaka T, Mimatsu K, et al. Intramedullary spinal cord germinoma. Spine 1995;20:2338 - 40. [14] Miyauchi A, Matsumoto K, Kohmura E, et al. Primary intramedullary spinal cord germinoma: case report. J Neurosurg 1996;84:1060 - 1. [15] Nagasawa S, Kikuchi H, Yamashita J, et al. Intramedullary spinal cord germinomas occurring four years after spinal cord germinoma: case report. Neurol Med Chir (Tokyo) 1991;31:729 - 31. [16] Sasaki T, Amano T, Takao M, et al. A case of intramedullary spinal cord tumor producing human chorionic gonadotropin. J Neuro-Oncol 2002;56:247 - 50. [17] Sawamura Y. Current diagnosis and treatment of central nervous system germ cell tumours. Curr Opin Neurol 1996;9:419 - 23.

T. Aoyama et al. / Surgical Neurology 67 (2007) 177 – 183 [18] Sawamura Y, Shirato H, Ikeda J, et al. Induction chemotherapy followed by reduced-volume radiation therapy for newly diagnosed central nervous system germinoma. J Neurosurg 1998;88:66 - 72. [19] Shirato H, Nishio M, Sawamura Y, et al. Analysis of long-term treatment of intracranial germinoma. Int J Radiat Oncol Biol Phys 1997;37:511 - 5. [20] Slagel DD, Goeken JA, Platz CA, et al. Primary germinoma of the spinal cord: a case report with 28-year follow-up and review of the literature. Acta Neuropathol, Suppl 1995;90:657 - 9. [21] Zhu J, Gao Y, Zheng W, Yang J. Intramedullary spinal cord germinoma: a case report. Chin Med J (Engl) 2002;115:1418 - 9.

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and immigration process, every neurosurgeon should be aware of that rare entity, even if it is 3 times more frequent in Japan and 12.5 more frequent in East Asia than in Europe and America. Diagnosis is impossible without histology, which emphasizes what we have said for more than 10 years, that histology is mandatory before starting any complementary treatment in spinal cord tumors. In the 2 cases reported by the Japanese authors, correct diagnosis was made upon biopsy with a spectacular good answer by chemotherapy followed by radiation therapy. The authors should be commended for their excellent presentation.

Commentary The authors report 2 very rare cases of great interest. Intramedullary germinoma is very rare, almost primary germinoma. But because of the increase of expatriate people

Jacques Brotchi, MD, PhD Department of Neurosurgery Erasme Hospital University Brussels B-1070 Brussels, Belgium