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Diagnosis of germinal neoplasm in the thalamus and basal ganglia
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Surg Neurol 1986;26:24-28
Diagnosis of Germinal Neoplasm in the Thalamus and Basal Ganglia Nobuo Ono, M.D., Hiroshi K. Inoue, M.D., D.M.Sc., Hirofumi Naganuma, M.D., Hideo Kunimine, M.D., Akira Zama, M.D., and Masaru Tamura, M.D., D.M.Sc. Department of Neurosurgery, Gunma University School of Medicine, Gunma, Japan
Ono N, lnoue HK, Naganuma H, Kunimine H, Zama A, Tamura M. Diagnosis of germinal neoplasm in the thalamus and basal ganglia. Surg Neurol 1986;26:24-28.
Germinal neoplasms originating in the thalamus and basal ganglia were histologically verified by stereotactic biopsies in five cases and by other methods in three cases. Immunoperoxidase staining was performed on the tumors using antibodies against human chorionic gonadotropin and placental alkaline phosphatase. The presence of human chorionic gonadotropin was demonstrated in one germinoma and two mixed tumors, but not in three germinomas. Placental alkaline phosphatase was demonstrated to be present in four germinomas and one mixed tumor. Stereotactic biopsy specimens can be studied immunohistochemically, and the placental isoenzyme of alkaline phosphatase appears to be a new tumor marker for germinoma. KEY WORDS: Thalamus; Basal ganglia; Germinoma; Stereotactic biopsy; Immunohistochemistry; Placental alkaline phosphatase
T u m o r s of germ cell origin usually arise in the pineal and suprasellar regions [24,27,28,31,32]. Neoplasms involving the thalamus and basal ganglia are mostly ofglial origin [2], but in some cases are of germinal origin [9,10,13,16,22,23,29,34]. The accurate histological differentiation between the glial and germinal origin of those tumors is essential, because germinomas are commonly thought to be radiocurable. This paper deals with the diagnosis of germinal neoplasms in the thalamus and basal ganglia. Special reference is made to immunohistochemical investigations of tumor markers: human chorionic gonadotropin and placental alkaline phosphatase.
Presented at the Annual Meeting of the Japan Neurosurgical Society, Chiba, Japan, October 24-26, 1984. Address reprint requests to." Hiroshi K. Inoue, M.D., Department of Neurosurgery, Gunma University School of Medicine, 3-39-22, Showa-machi, Maebashi, Gunma 371, Japan. © 1986 by Elsevier Science Publishing Co., Inc.
Clinical Material Between 1955 and 1985, 43 cases of primary intracranial germinal neoplasms have been referred to the Department of Neurosurgery, G u n m a University School of Medicine. These were classified into four groups according to tumor localization. Twenty-six (23 males and 3 females) were in the pineal region, eight (4 males and 4 females) in the suprasellar region, eight in the thalamus and basal ganglia, and one in the ventricles. Eight patients with germ cell tumors in the thalamus and basal ganglia were investigated in detail.
Patient Characteristics and Diagnosis There were seven males and one female, ranging in age from 7 to 16 years at the time of initial diagnosis. T h e r e were six germinomas, one mixed choriocarcinoma and germinoma, and one embryonal carcinoma with germinoma and teratomatous components. The histologic diagnosis was confirmed by stereotactic biopsies in five cases, at operation (subtotal resection) in one patient, at autopsy in one patient, and in the remaining patient (case 2) the diagnosis was probable because of the clinical course and radiologic findings. Cytologic examination of cerebrospinal fluid disclosed no tumor cells. The most common symptom among these patients was hemiparesis, present in all cases. Mental disturbance occurred in five cases. In contrast to the pineal tumors, signs and symptoms of increased intracranial pressure were found in only three cases in the later stages of the disease. N o paralysis of upward gaze was seen. In two patients an initial symptom was progressive dystonia (cases 3 and 5). In case 5, it was associated with intolerable muscle pain. The resultant involuntary m o v e m e n t s indicated lesions in the thalamus and basal ganglia [ 1,12]. One germinoma was found in both basal ganglia (case 5); others were found on the left side. Both the thalamus and basal ganglia were affected in four cases (cases 2, 3, 7, and 8). The region of the corpus striatum and globus pallidus was mainly involved in three cases (cases 4, 5, 0090-31)19/86/$3.50
Germinal Neoplasm
and 6). In case 1, the tumor was found in the thalamus and hypothalamic region at autopsy [ 17]. Plain x-ray films of the skull were not contributory. Six patients underwent a computed tomography (CT) examination prior to receiving correct diagnoses. Five out of the six tumors showed slightly high-density masses with marked homogeneous contrast enhancement (Figure 1, upper left and right). One germinoma (case 4) showed a round low-density mass with ring enhancement (Figure 2, left). Angiographical tumor stains were demonstrated in only two cases, those of choriocarcinoma (case 1) and embryonal carcinoma (case 6), and not in germinomas. Treatment and Outcome As germinomas have been known to be radiosensitive, radiotherapy is often preferred to extensive removal. Of our eight cases, seven were primarily treated by radiation following the operations (five biopsies, one craniotomy, and one ventriculoperitoneal shunt) (Table 1). Case I of choriocarcinoma (previously documented) was autopsied without any treatment [17]. The embryonal
Figure 1. Case 3: computed tomography (CT) scan before treatment, without contrast enhancement, showing a mass of slightly high density in the left basal ganglia and thalamus (upper left), which is markedly enhanced with contrast medium (uPper right); unenhanced (lower left) and enhanced (lower right) CT scans after treatment showing no residual tumor.
Surg Neurol 1986;26:24-28
25
Figure 2. Case 4: (left) computed tomography (CT] scan &fore treatment, with contrast enhancement, showing a mass of low density surrounded by ring enhancement in the left basal ganglia; (right) CT scan after treatment, with contrast enhancement, showing no residual tumor.
carcinoma (case 6) will be reported in detail elsewhere [23]. As for the radiation, the first 30 Gy were given to the whole brain and the remaining 20-30 Gy only to the tumor site. When the patient's condition permitted, 20-30 Gy to the spinal axis was added. The efficacy of the treatment was confirmed by improvement of both clinical and radiologic findings in all cases. Repeated CT scans after the treatments showed no residual tumor (Figure 1, lower left and right; Figure 2, right). The longest survival period to date has been 13 years. In case 5 only, the tumor recurred 2 years after the radiation. He died of pulmonary fibrosis complicated with adult respiratory distress syndrome and disseminated intravascular coagulation following four courses of combined chemotherapy of cisplatin, vinblastine, and bleomycin (Einhorn's regimen) [4, 24]. Immunohistochemistry The immunoperoxidase method was performed on the four germinomas and two mixed tumors as described [ 17,18,25,30]. Rabbit antisera against human chorionic gonadotropin, c~-fetoprotein, carcinoembryonic antigen (Dako immunoglobulins, Denmark), and human placental alkaline phosphatase (Green Cross Corporation, Japan) were obtained commercially. For the negative control, tissue sections were treated with normal rabbit serum in place of the primary antibody. A section of healthy full-term placenta was used as the positive control for placental alkaline phosphatase. As summarized in Table 2, one germinoma and two mixed tumors (cases 1, 3, and 6) revealed localization of human chorionic gonadotropin antigen in syncytiotrophoblastic giant cells (Figure 3, left). None of the germinomas was positive for c,-fetoprotein or carcinoembryonic antigen. Definite
26
Surg Neurol 1986;26:24-28
Ono et al
Table 1. Clinical Data on Eight Patients with Germinal Neoplasms in the Thalamus and Basal Ganglia Case No.
A g e (yr)
Sex
Operation
Radiation
Outcome
1 2 3 4 5 6 7 8
7 9 10 8 10 16 10 12
F M M M M M M M
VP Shunt Stereo biopsy Stereo biopsy Stereo biopsy Total removal Stereo biopsy Stereo biopsy
+ + + + + + +
Autopsied A l i v e a n d well (13 yr) A l i v e a n d well (6 yr) A l i v e a n d well (5 yr) Died of chemotherapy A l i v e a n d well (2 yr) A l i v e a n d well ( 1 8 m o ) A l i v e a n d well (17 m o )
Abbreviations: VP, ventriculoperitoneal; stereo, stereotactic.
regions [9,27,29,31]. No sex predominance in suprasellar lesions has been noted [24,28]. Increased concentrations of tumor markers (human chorionic gonadotropin, ~-fetoprotein, and carcinoembryonic antigen) in the serum and cerebrospinal fluid, and angiographically marked tumor stains, imply nonseminomatous germ cell tumors [17,18,24,26,27]. Besides the autopsied case with choriocarcinomas (case 1) and the case in which embryonal carcinoma was totally removed (case 6), the correct pathological diagnoses of germinomas were made mainly by stereotactic biopsies. We believe that a tentative radiotherapy often obscures the pathological diagnosis and sometimes results in inadequate treatment. Recent advances in stereotactic CT scans have provided enough anatomic information so that deep brain biopsies may be performed safely and accurately. The bioptic method in the deeply situated tumors was previously documented in detail [20,21]. Even if the biopsies of the tumors are safely performed, exact verification of germinoma is sometimes difficult, because of the small size of the specimens. Immunohistochemical studies of the biopsy specimens greatly help to make correct pathological diagnoses. The localization of human chorionic gonadotropin antigen in the syncytiotrophoblastic giant cells is definitely indicative of germinal origin, not of glial or malignant lymphoma origin [16,17]. The incidence of positive staining of human chorionic gonad-
reactions for placental alkaline phosphatase were obtained in the cytoplasm of the large polygonal cells of the two-cell pattern in four germinomas (cases 3-5 and 7) and one mixed tumor (Figure 3, right). No definite reaction for placental alkaline phosphatase was obtained in intracranial gliomas, malignant lymphomas, or adjacent brain tissues.
Discussion The incidence of germinomas in the thalamus and basal ganglia was previously estimated at 4% to 10% of intracranial germinomas [9,13,27,29,31]. These regions are the third most common, next to the pineal and suprasellar regions. The ratio 8:43 (19%) in our series of intracranial germinal tumors is a relatively higher incidence than in other institutions. This may be because the patients are referred to our hospital from distant areas for histological verification on the basis of stereotactic biopsy. It is desirable that the pathological diagnosis be performed as early, safely, and correctly as possible. Gliomas and malignant lymphomas are common in the thalamus and basal ganglia [2,9]; however, they differ from germinomas in many respects. The male predominance (7: 1) and sex distribution between 7 and 16 years of age are similar to those of previously reported germinomas in the pineal, thalamic, and basal ganglia
Table 2. Results of lmmunohistochemical Study Case No.
HCG
PLAP
AFP
CEA
1
+
-
-
-
3 4 5 6
+ +
+ + + +
+
+
7
-
+
-
-
H i s t o l o g i c diagnosis Choriocarcinoma and germinoma Germinoma Germinoma Germinoma Embryonal carcinoma with germinoma and teratoma Germinoma
Abbreviations: H C G , human chorionic gonadotropin; PLAP, placental alkaline phosphatase; AFP, a-fetoprotein; CEA, carcinoembryonic antigen.
Germinal Neoplasm
Figure 3. Immunoperoxidasestudy of germinomas. Case3 (left): a positive reaction for human chorionic gonadotropin is seen in syncytiotrophoblastic giant cells (counterstained with hematoxylin, × 250). Case 4 (right): positive localization of placental alkaline phosphatase is demonstrated in the cytoplasm of the largepolygonal cells (counterstained with hematoxylin. × 62.5).
otropin in germinomas is rather low, however, especially in the biopsy specimens (only case 3; Figure 3, left). Uchida et al [30] described immunohistochemical staining of placental alkaline phosphatase in testicular tumors. The very high incidence of seminoma (approximately 90%) revealed a positive staining of placental alkaline phosphatase, mainly on the cell membrane of tumor cells and often in the cytoplasm of large polygonal cells. We obtained similar results in intracranial germ cell tumors to those described by Uchida et al and Paiva et al [25,30]. Placental alkaline phosphatase is an oncodevelopmental protein that is expressed by placental syncytiotroptloblastic cells by the twelfth week of pregnancy, but is also produced ectopically by a variety of malignant tumors, including germinomas in particular [5,6,11,19,30,33]. The elevated levels of serum placental alkaline phosphatase in testicular seminoma patients have been evaluated by several investigators [7,8,11,14,15,33]. Serologic and cerebrospinal diagnoses of intracranial germinomas producing placental alkaline phosphatase are now under investigation in our laboratories. The results o f treatments, mainly by radiation, in the cases with germ cell tumors in the thalamus and basal ganglia have been excellent in six cases (cases 2 - 4 and 6-8), although the prognosis without proper treatment is p o o r (case 1). Combined chemotherapy must be carefully used, as long as the tumor can be treated by radiation (case 5).
Surg Neurol 1986;26:24-28
27
Conclusions The management and outcome of germinal neoplasms in the thalamus and basal ganglia are summarized. The incidence of intracranial germinal neoplasms is 4 % to 19%. Knowledge of the clinical features, male predominance, and age distribution of the patients, combined with tumor markers and neuroradiologic findings, allows for increased accuracy in indicating the pathological diagnosis. Stereotactic biopsies in conjunction with immunohistochemical studies of tumor markers further establish the tissue diagnosis. H u m a n chorionic gonadotropin has been used as a tumor marker for choriocarcinomas, a-fetoprotein for embryonal carcinomas or endodermal sinus tumors, and carcinoembryonic antigen for teratomas [3,17,18,23,27]. It now appears that the placental isoenzyme of alkaline phosphatase may be a useful tumor marker for germinomas.
The authors thank Professor Chihiro Ohye, Department of Neurosurgery, for reviewing the manuscript; Professor Yoichi Ishida, First Department of Pathology, for histological diagnosis; and Toshikazu Ushida, M.D., Department of Pathology,Nihon University Schoolof Medicine, for supplying antibodies to placental alkaline phosphatase.
References 1. Arseni C, Horvath L, Dumitrescu L. Extrapyramidalsyndromes in intracranial space-occupyingprocesses in children. Eur Neurol 1972;7:169-88. 2. Bernstein M, Hoffman HJ, HaUiday WC, Hendrick EB, Humphreys gP. Thalamic tumors in children. Long-term follow-up and treatment guidelines. J Neurosurg 1984;61:649-56. 3. BoninJM, Rubinstein LJ. Immunohistochemistryof central nervous system tumors. Its contributions to neurological diagnosis. J Neurosurg 1984;60:1121-33. 4. Einhorn LH. Combination chemotherapy with cis-dichlorodiammineplatinum (II) in disseminated testicularcancer. Cancer Treat Rep 1979;63:1659-62.
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Surg N e u r o l 1986;26:24-28
5. Fishman WH, Inglis NR, Stolbach LL, Krant MJ. A serum alkaline phosphatase isoenzyme of human neoplastic cell origin. Cancer Res 1968;28:150-4. 6. Holmgren PA, Stigbrand T, Damber MG, Von Schoultz B, Wahren B. Determination of placental alkaline phosphatase-Regan isoenzyme in cancer sera by a sensitive radioimmunoassay. Scand J Immunol (Suppl) 1978;8:515-8. 7. Japadpour N. Multiple biochemical tumor markers in seminoma. A double-blind study. Cancer 1983;52:887-9. 8. Jeppsson A, Wahren B, Stigbrand T, Edsmyr F, Andersson L. A clinical evaluation of serum placental alkaline phosphatase in seminoma patients. Br J Urol 1983;55:73-8. 9. Kobayashi T, Kageyama N, Kida Y, YoshidaJ, Shibuya N, Okamura K. Unilateral germinomas involving the basal ganglia and thalamus. J Neurosurg 1981;55:55-62. 10. Kwak R, Saso S, Suzuki J. Ipsilateral cerebral atrophy with thalamic tumor of childhood. J Neurosurg 1978;48:443-9. 11. Lange PH, Millan JL, Stigbrand T, Vessella RL, Ruoslahti E, Fishman WH. Placental alkaline phosphatase as a tumor marker for seminoma. Cancer Res 1982;42:3244-7. 12. Lins MM, McDonnell DE, Aschenbrener CA, Cancilla PA. Extrapyramidal disorder with pineal germinoma. Case report. J Neurosurg 1978;48:108-16. 13. Mabushi S, Abe H, Nakagawa Y, Aida T, Tashiro K, Tsuru M. Germinoma originating in the basal ganglia. Report of 2 cases (in Japanese). No Shinkei Geka 1982;10:977-82. 14. Millan JL. Usefulness of PLAP as a tumor marker in germ-cell testicular tumors. Placental and placental-like alkaline phosphatase. Umea University Medical Dissertations 107. Umea, Sweden, 1983;19-22. 15. Millan JL, Stigbrand T. "Sandwich" enzyme immunoassay for placental alkaline phosphatase. Clin Chem 1981;27:2014-8. 16. Moriyama T, Teramoto S, Kitajima H, Yonekura M, Nakamura M, Matsumura H. Primary intracranial germ cell tumor in the right basal ganglia and its vicinity area. A report of the case with germinoma and choriocarcinoma histologically. (In Japanese.) No Shinkei Geka 1983;11:73-80. 17. Naganuma H, Inoue H, Misumi S, Nakamura M, Tamura M. lntracranial germ-cell tumors, lmmunohistochemical study of three autopsy cases. J Neurosurg 1984;6 1:931-7. 18. Naganuma H, Inoue H, Nakamura M, Koizumi H. Localization of carcinoembryonic antigen in intracranial mature teratomas. J Neurosurg 1985;62:870-3. 19. Nathanson L, Fishman WH. New observation of the Regan isoenzyme of alkaline phosphatase in cancer patients. Cancer 1971;27:1388-97. 20. Ohye C, Kawashima Y, Hirato M, Wada H, Nakajima H. Ste-
O n o et al
reotactic CT scan applied to stereotactic thalamotomy and biopsy. Acta Neurochir 1984;71:55-68. 21. Ohye C, Nakajima H, Matsushima T, Komatsu T, Hirato M, Kawashima Y. CT assisted stereotactic biopsy of deep cerebral lesions and the results. Acta Neurochir (Suppl) 1984;33:257-9. 22. Okada K, Kawano N, Takagi H, Ohwada T, Yada K, Atari E. Teratocarcinoma in the basal ganglia. A case report of total removal. (In Japanese.) Shoni No Noshinkei 1980;5:243-8. 23~ Ono N, Inoue HK, Naganuma H, Misumi S, Tamura M. Germ cell tumor in the basal ganglia: immunohistochemical demonstration of a-fetoprotein, human chorionic gonadotropin, and carcinoembryonic antigen. Surg Neurol 1986;25:495-500. 24. Ono N, Takeda F, Uki J, Zama A, Hayashi Y, Sampi K. A suprasellar embryonal carcinoma producing alpha-fetoprotein and human chorionic gonadotropin; treated with combined chemotherapy followed by radiotherapy. Surg Neurol 1982; 18:435-43. 25. PaivaJ, Damjanov I, Lange PH, Harris H. Immunohistochemical localization of placental-like alkaline phosphatase in testis and germ-cell tumors using monoclonal antibodies. Am J Pathol 1983;111:156-65. 26. Saitoh Y, Arita N, Ushio Y, Koshino K, Ikeda T, Mogami H. Germ cell tumor in the basal ganglia with elevated serum and CSF alpha-fetoprotein levels. (In Japanese.) No To Shinkei 1983;35:935-9. 27. Sano K. Pineal tumors. (In Japanese.) Neurol Med Chir 1984;23:4 l 1-9. 28. Takeuchi J, Handa H, Nagata I. Suprasellar germinoma. J Neurosurg 1978;49:41-8. 29. Tanaka R, Ueki K. Germinomas in the cerebral hemisphere. Surg Neurol 1979;12:239-41. 30. Uchida T, Shimoda T, Miyata H, Shikata T, Iino S, Suzuki H, Oda T, Hirano K, Sugiura M. Immunoperoxidase study of alkaline phosphatase in testicular tumor. Cancer 1981;48:1455-62. 31. Ueki K, Tanaka R. Treatments and prognosis of pineal tumors. Experiences of 110 cases. Neurol Med Chir (Tokyo) 1980;20:1-26. 32. Waga S, Handa H, Yamashita J. Intracranial germinomas; treatment and results. Surg Neurol 1979; 11:167-72. 33. Wahren B, Holmgren PA, Stigbrand T. Placental alkaline phosphatase, alpha-fetoprotein and carcinoembryonic antigen in testicular tumors: tissue typing by means of cytologic smears. Int J Cancer 1979;24:749-53. 34. Yamada H, lnamura K, Sakai N, Ando T, Hirata T, Misao H, Sakata K, Shimokawa K. Intracranial germinoma developing in the right basal ganglia. Report of a case followed up by CT scan and review of the literature. (In Japanese.) No To Shinkei 1980;32:387-92.
Surg Neurol 1986;26:24-28
Diagnosis of Germinal Neoplasm in the Thalamus and Basal Ganglia Nobuo Ono, M.D., Hiroshi K. Inoue, M.D., D.M.Sc., Hirofumi Naganuma, M.D., Hideo Kunimine, M.D., Akira Zama, M.D., and Masaru Tamura, M.D., D.M.Sc. Department of Neurosurgery, Gunma University School of Medicine, Gunma, Japan
Ono N, lnoue HK, Naganuma H, Kunimine H, Zama A, Tamura M. Diagnosis of germinal neoplasm in the thalamus and basal ganglia. Surg Neurol 1986;26:24-28.
Germinal neoplasms originating in the thalamus and basal ganglia were histologically verified by stereotactic biopsies in five cases and by other methods in three cases. Immunoperoxidase staining was performed on the tumors using antibodies against human chorionic gonadotropin and placental alkaline phosphatase. The presence of human chorionic gonadotropin was demonstrated in one germinoma and two mixed tumors, but not in three germinomas. Placental alkaline phosphatase was demonstrated to be present in four germinomas and one mixed tumor. Stereotactic biopsy specimens can be studied immunohistochemically, and the placental isoenzyme of alkaline phosphatase appears to be a new tumor marker for germinoma. KEY WORDS: Thalamus; Basal ganglia; Germinoma; Stereotactic biopsy; Immunohistochemistry; Placental alkaline phosphatase
T u m o r s of germ cell origin usually arise in the pineal and suprasellar regions [24,27,28,31,32]. Neoplasms involving the thalamus and basal ganglia are mostly ofglial origin [2], but in some cases are of germinal origin [9,10,13,16,22,23,29,34]. The accurate histological differentiation between the glial and germinal origin of those tumors is essential, because germinomas are commonly thought to be radiocurable. This paper deals with the diagnosis of germinal neoplasms in the thalamus and basal ganglia. Special reference is made to immunohistochemical investigations of tumor markers: human chorionic gonadotropin and placental alkaline phosphatase.
Presented at the Annual Meeting of the Japan Neurosurgical Society, Chiba, Japan, October 24-26, 1984. Address reprint requests to." Hiroshi K. Inoue, M.D., Department of Neurosurgery, Gunma University School of Medicine, 3-39-22, Showa-machi, Maebashi, Gunma 371, Japan. © 1986 by Elsevier Science Publishing Co., Inc.
Clinical Material Between 1955 and 1985, 43 cases of primary intracranial germinal neoplasms have been referred to the Department of Neurosurgery, G u n m a University School of Medicine. These were classified into four groups according to tumor localization. Twenty-six (23 males and 3 females) were in the pineal region, eight (4 males and 4 females) in the suprasellar region, eight in the thalamus and basal ganglia, and one in the ventricles. Eight patients with germ cell tumors in the thalamus and basal ganglia were investigated in detail.
Patient Characteristics and Diagnosis There were seven males and one female, ranging in age from 7 to 16 years at the time of initial diagnosis. T h e r e were six germinomas, one mixed choriocarcinoma and germinoma, and one embryonal carcinoma with germinoma and teratomatous components. The histologic diagnosis was confirmed by stereotactic biopsies in five cases, at operation (subtotal resection) in one patient, at autopsy in one patient, and in the remaining patient (case 2) the diagnosis was probable because of the clinical course and radiologic findings. Cytologic examination of cerebrospinal fluid disclosed no tumor cells. The most common symptom among these patients was hemiparesis, present in all cases. Mental disturbance occurred in five cases. In contrast to the pineal tumors, signs and symptoms of increased intracranial pressure were found in only three cases in the later stages of the disease. N o paralysis of upward gaze was seen. In two patients an initial symptom was progressive dystonia (cases 3 and 5). In case 5, it was associated with intolerable muscle pain. The resultant involuntary m o v e m e n t s indicated lesions in the thalamus and basal ganglia [ 1,12]. One germinoma was found in both basal ganglia (case 5); others were found on the left side. Both the thalamus and basal ganglia were affected in four cases (cases 2, 3, 7, and 8). The region of the corpus striatum and globus pallidus was mainly involved in three cases (cases 4, 5, 0090-31)19/86/$3.50
Germinal Neoplasm
and 6). In case 1, the tumor was found in the thalamus and hypothalamic region at autopsy [ 17]. Plain x-ray films of the skull were not contributory. Six patients underwent a computed tomography (CT) examination prior to receiving correct diagnoses. Five out of the six tumors showed slightly high-density masses with marked homogeneous contrast enhancement (Figure 1, upper left and right). One germinoma (case 4) showed a round low-density mass with ring enhancement (Figure 2, left). Angiographical tumor stains were demonstrated in only two cases, those of choriocarcinoma (case 1) and embryonal carcinoma (case 6), and not in germinomas. Treatment and Outcome As germinomas have been known to be radiosensitive, radiotherapy is often preferred to extensive removal. Of our eight cases, seven were primarily treated by radiation following the operations (five biopsies, one craniotomy, and one ventriculoperitoneal shunt) (Table 1). Case I of choriocarcinoma (previously documented) was autopsied without any treatment [17]. The embryonal
Figure 1. Case 3: computed tomography (CT) scan before treatment, without contrast enhancement, showing a mass of slightly high density in the left basal ganglia and thalamus (upper left), which is markedly enhanced with contrast medium (uPper right); unenhanced (lower left) and enhanced (lower right) CT scans after treatment showing no residual tumor.
Surg Neurol 1986;26:24-28
25
Figure 2. Case 4: (left) computed tomography (CT] scan &fore treatment, with contrast enhancement, showing a mass of low density surrounded by ring enhancement in the left basal ganglia; (right) CT scan after treatment, with contrast enhancement, showing no residual tumor.
carcinoma (case 6) will be reported in detail elsewhere [23]. As for the radiation, the first 30 Gy were given to the whole brain and the remaining 20-30 Gy only to the tumor site. When the patient's condition permitted, 20-30 Gy to the spinal axis was added. The efficacy of the treatment was confirmed by improvement of both clinical and radiologic findings in all cases. Repeated CT scans after the treatments showed no residual tumor (Figure 1, lower left and right; Figure 2, right). The longest survival period to date has been 13 years. In case 5 only, the tumor recurred 2 years after the radiation. He died of pulmonary fibrosis complicated with adult respiratory distress syndrome and disseminated intravascular coagulation following four courses of combined chemotherapy of cisplatin, vinblastine, and bleomycin (Einhorn's regimen) [4, 24]. Immunohistochemistry The immunoperoxidase method was performed on the four germinomas and two mixed tumors as described [ 17,18,25,30]. Rabbit antisera against human chorionic gonadotropin, c~-fetoprotein, carcinoembryonic antigen (Dako immunoglobulins, Denmark), and human placental alkaline phosphatase (Green Cross Corporation, Japan) were obtained commercially. For the negative control, tissue sections were treated with normal rabbit serum in place of the primary antibody. A section of healthy full-term placenta was used as the positive control for placental alkaline phosphatase. As summarized in Table 2, one germinoma and two mixed tumors (cases 1, 3, and 6) revealed localization of human chorionic gonadotropin antigen in syncytiotrophoblastic giant cells (Figure 3, left). None of the germinomas was positive for c,-fetoprotein or carcinoembryonic antigen. Definite
26
Surg Neurol 1986;26:24-28
Ono et al
Table 1. Clinical Data on Eight Patients with Germinal Neoplasms in the Thalamus and Basal Ganglia Case No.
A g e (yr)
Sex
Operation
Radiation
Outcome
1 2 3 4 5 6 7 8
7 9 10 8 10 16 10 12
F M M M M M M M
VP Shunt Stereo biopsy Stereo biopsy Stereo biopsy Total removal Stereo biopsy Stereo biopsy
+ + + + + + +
Autopsied A l i v e a n d well (13 yr) A l i v e a n d well (6 yr) A l i v e a n d well (5 yr) Died of chemotherapy A l i v e a n d well (2 yr) A l i v e a n d well ( 1 8 m o ) A l i v e a n d well (17 m o )
Abbreviations: VP, ventriculoperitoneal; stereo, stereotactic.
regions [9,27,29,31]. No sex predominance in suprasellar lesions has been noted [24,28]. Increased concentrations of tumor markers (human chorionic gonadotropin, ~-fetoprotein, and carcinoembryonic antigen) in the serum and cerebrospinal fluid, and angiographically marked tumor stains, imply nonseminomatous germ cell tumors [17,18,24,26,27]. Besides the autopsied case with choriocarcinomas (case 1) and the case in which embryonal carcinoma was totally removed (case 6), the correct pathological diagnoses of germinomas were made mainly by stereotactic biopsies. We believe that a tentative radiotherapy often obscures the pathological diagnosis and sometimes results in inadequate treatment. Recent advances in stereotactic CT scans have provided enough anatomic information so that deep brain biopsies may be performed safely and accurately. The bioptic method in the deeply situated tumors was previously documented in detail [20,21]. Even if the biopsies of the tumors are safely performed, exact verification of germinoma is sometimes difficult, because of the small size of the specimens. Immunohistochemical studies of the biopsy specimens greatly help to make correct pathological diagnoses. The localization of human chorionic gonadotropin antigen in the syncytiotrophoblastic giant cells is definitely indicative of germinal origin, not of glial or malignant lymphoma origin [16,17]. The incidence of positive staining of human chorionic gonad-
reactions for placental alkaline phosphatase were obtained in the cytoplasm of the large polygonal cells of the two-cell pattern in four germinomas (cases 3-5 and 7) and one mixed tumor (Figure 3, right). No definite reaction for placental alkaline phosphatase was obtained in intracranial gliomas, malignant lymphomas, or adjacent brain tissues.
Discussion The incidence of germinomas in the thalamus and basal ganglia was previously estimated at 4% to 10% of intracranial germinomas [9,13,27,29,31]. These regions are the third most common, next to the pineal and suprasellar regions. The ratio 8:43 (19%) in our series of intracranial germinal tumors is a relatively higher incidence than in other institutions. This may be because the patients are referred to our hospital from distant areas for histological verification on the basis of stereotactic biopsy. It is desirable that the pathological diagnosis be performed as early, safely, and correctly as possible. Gliomas and malignant lymphomas are common in the thalamus and basal ganglia [2,9]; however, they differ from germinomas in many respects. The male predominance (7: 1) and sex distribution between 7 and 16 years of age are similar to those of previously reported germinomas in the pineal, thalamic, and basal ganglia
Table 2. Results of lmmunohistochemical Study Case No.
HCG
PLAP
AFP
CEA
1
+
-
-
-
3 4 5 6
+ +
+ + + +
+
+
7
-
+
-
-
H i s t o l o g i c diagnosis Choriocarcinoma and germinoma Germinoma Germinoma Germinoma Embryonal carcinoma with germinoma and teratoma Germinoma
Abbreviations: H C G , human chorionic gonadotropin; PLAP, placental alkaline phosphatase; AFP, a-fetoprotein; CEA, carcinoembryonic antigen.
Germinal Neoplasm
Figure 3. Immunoperoxidasestudy of germinomas. Case3 (left): a positive reaction for human chorionic gonadotropin is seen in syncytiotrophoblastic giant cells (counterstained with hematoxylin, × 250). Case 4 (right): positive localization of placental alkaline phosphatase is demonstrated in the cytoplasm of the largepolygonal cells (counterstained with hematoxylin. × 62.5).
otropin in germinomas is rather low, however, especially in the biopsy specimens (only case 3; Figure 3, left). Uchida et al [30] described immunohistochemical staining of placental alkaline phosphatase in testicular tumors. The very high incidence of seminoma (approximately 90%) revealed a positive staining of placental alkaline phosphatase, mainly on the cell membrane of tumor cells and often in the cytoplasm of large polygonal cells. We obtained similar results in intracranial germ cell tumors to those described by Uchida et al and Paiva et al [25,30]. Placental alkaline phosphatase is an oncodevelopmental protein that is expressed by placental syncytiotroptloblastic cells by the twelfth week of pregnancy, but is also produced ectopically by a variety of malignant tumors, including germinomas in particular [5,6,11,19,30,33]. The elevated levels of serum placental alkaline phosphatase in testicular seminoma patients have been evaluated by several investigators [7,8,11,14,15,33]. Serologic and cerebrospinal diagnoses of intracranial germinomas producing placental alkaline phosphatase are now under investigation in our laboratories. The results o f treatments, mainly by radiation, in the cases with germ cell tumors in the thalamus and basal ganglia have been excellent in six cases (cases 2 - 4 and 6-8), although the prognosis without proper treatment is p o o r (case 1). Combined chemotherapy must be carefully used, as long as the tumor can be treated by radiation (case 5).
Surg Neurol 1986;26:24-28
27
Conclusions The management and outcome of germinal neoplasms in the thalamus and basal ganglia are summarized. The incidence of intracranial germinal neoplasms is 4 % to 19%. Knowledge of the clinical features, male predominance, and age distribution of the patients, combined with tumor markers and neuroradiologic findings, allows for increased accuracy in indicating the pathological diagnosis. Stereotactic biopsies in conjunction with immunohistochemical studies of tumor markers further establish the tissue diagnosis. H u m a n chorionic gonadotropin has been used as a tumor marker for choriocarcinomas, a-fetoprotein for embryonal carcinomas or endodermal sinus tumors, and carcinoembryonic antigen for teratomas [3,17,18,23,27]. It now appears that the placental isoenzyme of alkaline phosphatase may be a useful tumor marker for germinomas.
The authors thank Professor Chihiro Ohye, Department of Neurosurgery, for reviewing the manuscript; Professor Yoichi Ishida, First Department of Pathology, for histological diagnosis; and Toshikazu Ushida, M.D., Department of Pathology,Nihon University Schoolof Medicine, for supplying antibodies to placental alkaline phosphatase.
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