J Neurosnrg 74:832-836, 1991
Successful treatment of a pineal endodermal sinus tumor Case report CARINE S. KIRKOVE, M.D., ANDREW P. BROWN, F.R.C.R., AND
LINOSAY SYMON, F.R.C.S.
Department of Radiotherapy and Oncology, St Thomas" Hospital, and National Hospital for Nervous Diseases, London, England w" A patient with a pineal endodermal sinus tumor is presented who was successfullytreated by a combination of surgery, adjuvant chemotherapy, and craniospinal irradiation. Two years after diagnosis, he is free of any disease. A review of the literature shows that such an outcome is very unusual. A multidisciplinary treatment is recommended for this rare tumor, using chemotherapy as adjuvant treatment. KEY WORDS
9
chemotherapy
pineal endodermal sinus 9 radiotherapy
NDODERMALsinus tumors or yolk sac tumors are rare cancers of the germ-cell-derived extraembryonic tissues. Like other cancers of germinal origin, they arise in midline sites such as the gonads, sacrococcygeal area, retroperitoneum, mediastinum, suprasellar region, and pineal gland. Intracranial endodermal sinus tumors represent 7% of primary intracranial germinal cancers, which themselves represent only 0.4% to 3.5% of primary intracranial neoplasms in Western countries. ~s Histologically, 50% of pineal gland endodermal sinus tumors are mixed and contain various proportions of other germ-cell elements including germinoma, teratoma, embryonal-cell carcinoma, and choriocarcinoma. 6'3~Most pineal endodermal sinus tumors synthesize alpha-fetoprotein, and this marker, measured in serum and cerebrospinal fluid (CSF), may be useful for diagnosis and to assess responsiveness to treatment? 2,2~Endodermal sinus tumors of the pineal gland are highly aggressive neoplasms and the survival rate is poor. t8 We describe a case of long-term complete remission of a pineal gland endodermal sinus tumor treated by a combination of surgery, cytotoxic chemotherapy, and radiotherapy. We review the other reported cases and stress the importance of a combined therapeutic approach in the management of this rare tumor.
E
Case Report
This 14-year-old boy with unremarkable medical history first presented in April, 1988, with intermittent 832
9 tumor
9 alpha-fetoprotein
9
frontal headaches beginning 2 months before. He suffered diplopia, nausea, vomiting, and drowsiness. Examination. There was an absence of upward gaze and poor ocular convergence. Funduscopic examination disclosed papilledema without hemorrhage. No other neurological deficit was noted apart from mild ataxia. Computerized tomography revealed a pineal tumor and marked hydrocephalus (Fig. 1 left). Serum alpha-fetoprotein and human chorionic gonadotropin (HCG) levels were raised at 1050 kU/liter (normal < 10 kU/liter) and 151 IU/liter (normal _< 4 IU/liter), respectively.
Operation. Right occipital craniotomy with tmnstentorial microsurgical excision of the lesion was performed in May, 1988. The excision appeared grossly complete (Fig. 1 right). Histological examination showed a malignant endodermal sinus tumor (yolk sac tumor) with a high mitotic rate and pathognomonic Schiller-Dural bodies (Fig. 2). There was also an element of mature teratoma comprising keratinizing epithelium, smooth muscle, and endocrine-type cells. Postoperative Course. After surgery, the hydrocephalus resolved but upward vision was still limited and diplopia on fight lateral gaze persisted. The serum HCG content fell to less than 2 IU/liter but, after an initial impressive drop to 49 kU/liter, the alpha-fetoprotein level rose to 88 and 113 kU/liter 18 and 25 days, respectively, after surgery (Fig. 3). Alpha-fetoprotein but not HCG levels were also elevated in the CSF J. Neurosurg. / Volume 74/May, 1991
Pineal endodermal sinus t u m o r
FIG. 1. Left. Preoperative computerized tomography (CT) scans showing the enhancing tumor in the region of the pineal gland. Right." Postoperative CT scan confirming the macroscopically complete resection of tumor with consequent relief of hydrocephalus.
(97 kU/liter). Cytological examination of the CSF for tumor cells was negative and remained so on later lumbar punctures. Faced with the dismal prognosis, it was elected to treat the patient with chemotherapy according to the POMB-ACE regimen for anaplastic germ-cell tumors. This intensive regimen comprises an initial period of intravenous platinum (P), vincristine (O), methotrexate (M), and bleomycin (B) followed after a 10-day hiatus by actinomycin D (A), cyclophosphamide (C), and etoposide (E). This regimen was chosen because of a previous report 26 of its efficacy in several cases of nonseminomatous germ-cell tumors metastatic to the brain. The first cycle of POMB was begun on the 18th
postoperative day. It consisted of intravenous vincristine, 1 mg/sq m, and methotrexate, 300 mg/sq m on Day 1; bleomycin, 15 mg, on Days 2 and 3; and cisplatin, 120 mg/sq m, on Day 4. At the same time the patient was given 10 mg methotrexate intrathecally. After the POMB treatment, alpha-fetoprotein levels were still elevated in serum (67 kU/liter) and CSF (34 kU/liter). The patient was readmitted to the hospital 10 days later to receive a 3-day course of etoposide (VP- 16, 100 mg/sq m on Days 1 to 3), actinomycin D (0.5 mg on Days 2 and 3), and cyclophosphamide (500 mg/sq m on Day 3), as well as a second dose of intrathecal methotrexate (10 rag). The serum and CSF alpha-feto-
FIG. 2. Photomicrograph of the tumor specimen showing the typical appearance of an endodermal sinus tumor with large vacuolated cells and prominent nucleoli. In the center a pathognomonic Schiller-Duval body, a glomeruloid structure with surrounding crescentic space, can he seen. H & E, • 200.
FIG. 3. Plot of serum alpha-fetoprotein (AFP) level during and following treatment. The theoretical decay curve assumes a biological half-life of 5 days following a total extirpation of the tumor. For definitions of POMB and ACE chemotherapy see text; R/T = radiation therapy.
J. Neurosurg. / Volume 74/May, 1991
833
('. S. Kirkove. A. P. Brown, and L. Symon T..ABI.[ I R~'l~t'l~'d ~d~'~ IfftfitWa/ (~ltd(Jdo'l~ld/ ~//11t~ Ill~If(Jr5 Irc'al('d l~iI/toltl chetnotherapl,
Case NO.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Authors & Year Bestle, 1968 Albrechlsen, el a[.. 1972 Borit, 1969 Jellinger,(v al., 1970 Jellinger, 1973 (Case 6) Albrechtsen,el al, 1972 Jellinger,1973 Scully & MeNeely, 1974 Tavcar, el al., 1980 (Case 1) Chapman & Linggood, 1980 (Case 6) Burger& Vogel, 1976 Yoshiki,et al., 1976 yon Martin & Vogel. 1976 "[akei,(,! a[.. 1977 Lee, el at., 1978 Ho & Rassekh. 1979 Wilson,et al, 1979 Tavcar,c't al., 1980 Chapman & Linggood, 1980(Case 15) Murovic.e! al., 1981 Bamberg,el al., 1984 Bjornsson,et at., 1985
I tistolog~*
Surgeryf
Radiotherapy
Outcome, Survival Time Since Diagnosis
mixed {dermoid e)st)
B
no
died, postop
mixed (G, Emb Ca) mixed (T, G. Emb Ca)
S S& B
yes yes
died, 6 mos died, 2 mos
mixed (G) mixed (G) pure mixed (Ch, G, Emb Ca) mixed (Y. G) mixed (G, T) pure
+ + + no no no no
no no no no no no yes
died, postop died, postop died, postop died, unknown died, unknown died, unknown died, 2 mos
pure pure mixed (T, Ch. G, Emb Ca) pure? pure mixed (G) pure pure
S S& B S S S & PR S & PR S S & PR
no yes no yes yes yes yes yes
died, unknown died, 14 mos died, unknown died, unknown alive, > 6.5 mos died, l mo died, 7 mos died, 9 mos
alive, > 3.5 yrs pure PR yes died, 7 mos pure S& B yes died, 6 wks pure + no * Nonendodermal sinus tumor component of the tumors: G = germinoma; Emb Ca = embo, onal carcinoma; T = teratoma; Ch = choriocarcinoma. f B = biopsy" S = shunt; PR = partial removal: + = surgery bul no dctails available. 19 20 21
protein levels eventually fell to normal 2 weeks later (Fig. 3). A second course of P O M B was given but the dose of eisplatin was reduced to 100 mg because of intense nausea and vomiting during the first course and a transient rise in creatinine and urea. A second course of ACE, together with a third dose of 10 mg methotrexate intrathecally, was then given. Finally, it was decided to consolidate the treatment with craniospinal irradiation 3 weeks after the completion of chemotherapy. The whole brain received 2880 cGy in 16 fractions over a 3-week period with a subsequent boost to the third ventricle area, to a final t u m o r dose of 5400 cGy in 30 fractions over 46 days using a three-field technique. Spinal irradiation (2550 cGy in 17 fractions over 25 days) completed this treatment. Over the next year, i m p r o v e m e n t was noted in the patient's ocular movements; in particular, good upgaze was restored. Currently, 24 months after the diagnosis the patient is still clinically, biologically, and radiologically free of any disease. His pupils still react sluggishly to light and briskly to a c c o m m o d a t i o n . O f note, his pituitary function is normal and his scholastic performance remains unchanged. Discussion
Pineal endodermal sinus t u m o r is a very rare but highly aggressive n o n s e m i n o m a t o u s germ-cell neo834
plasm. O f the 29 patients reported in the literature (Tables I and 2), 24 were dead by 14 m o n t h s after the diagnosis. The results of surgery a n d / o r radiotherapy without chemotherapy are very, disappointing (Table 1). Only two of 21 patients survived at 6.5 m o n t h s and 3.5 years. Both underwent partial resection followed by craniospinal irradiation. The surgical procedure was limited to a biopsy a n d / o r insertion o f a shunt for the majority o f patients. In the earlier literature, surgery for pineal tumors carried an unacceptably high mortality rate ~'2~ but. with modern techniques, resection can be countenanced. ~ The c o m m o n e r g e r m i n o m a s of the pineal region are radiosensitive and patients are often cured by shunt placement and a therapeutic trial o f radiation, ~' but it is clear that such an approach cannot be relied upon to cure the rare patient with an endodermal sinus tumor. As shown in Table 1, no such t u m o r has been cured by radiotherapy alone. The emergence o f extremely effective chemotherapy for gonadal and extragonadal germ-cell tumors has changed m a n a g e m e n t concepts of intracranial germcell tumors. Protocols using synergistic cytotoxic agents, including vinblastine, vincristine, acfinomycin D, bleomycin, Adriamycin, cyclophosphamide, and cisplatin, have achieved complete remission rates o f 60% to 90% against localized and metastatic gonadal and extragoJ. N e u r o s u r g . / I ~ d u m e
74/May,
1991
Pineal e n d o d e r m a l sinus t u m o r TABLE 2 Reported cases q[pineal endoderma[ sintts tmnor,s treated with ctwmolherapj'
Case
Authors & Year
Histology*
Surgery?
Radiotherapy
pure
S & PR
yes
mixed (Ch) pure pure
S S S
yes yes yes
Chemotherapy$
No. 1 2 3 4
Prioleau& Wilson, 1976 Edwards, e/aL, 1988 Wilson,et at, 1979 Stachura& Mendelow, 1980 Arita, el a/, 1980
adjuvant: VAC
Outcome, Survival Time Since Diagnosis alive, > I3 yrs
adjuvant: PCB, VCR died, 9 mos recurrent tumor: BCNU died, 13 mos 1st recurrence: MTX died, 13 mos 2nd recurrence: VCR, bleo 5 Olsen,el a[., 1982 pure S & PR yes abdominal metastasis: VAC died, 22 mos 6 Anderson,1987 pure no yes frontal metastasis: VCB died, 12 mos 7 Allen,et al., 1987 pure (parietal) B or PR yes adjuvant: VAB alive,> 12 mos 8 Edwards,et aL, 1988 pure + yes recurrent tumor: bleo, VCR, died, 12 mos VP-t6, CP 9 Kirkove,et aL, 1991 mixed (T) PR yes adjuvant: CP, VCR, MTX, alive,> 24 mos bleo, VP-16, aclino-D, cyclo * Nonendodermal sinus tumor component of the tumors: Ch = choriocarcinoma;T = teratoma. "}"S = shunt; PR = partial removal; B = biopsy; + = surgery but no details available. :[:VAC = vincristine (VCR) + actinomycin D (Actino D) + cyclophosphamide(cydo); PCB = procarbazine; MTX = methotrexate: bleo = Neomycin; VCB = vinbfastine + cisplatin + bleomycin; VAB = vinblastine + Neomycin + cisplatin + cyclophosphamide;VP-16 = etoposide; CP = cisplatin.
nadal n o n s e m i n o m a t o u s germ-cell t u m o r s in combination with surgery and irradiation. 5,23,-'4Several complete responses to chemotherapy have also been reported in germ-cell brain metastases. 2L:326 Moreover, in a review of 81 cases of primary intracranial n o n s e m i n o m a t o u s germ-cell tumors, Graziano, et al., ~4 found nine long-term survivors, eight after chemotherapy and radiotherapy and only one after radiotherapy as the primary modality. We found only eight cases of pineal endodermai sinus t u m o r treated by chemotherapy (Table 2). Five patients who died received chemotherapy only when the t u m o r was k n o w n to have recurred or metastasized. Two of three patients who received adjuvant chemotherapy were alive 13 years and 12 m o n t h s after diagnosis. In the third adjuvant patient, there was an initial complete response after radiotherapy a n d chemotherapy, but the patient died 9 m o n t h s later with local recurrence a n d seeding to the spine and peritoneum. Metastatic spread through the CSF and ventriculopefitoneal shunts is a well-documented risk in pineal endodermal sinus tumors. 69~2427:~3233 Our patient, alive 2 years after diagnosis, was treated with a d j u v a n t chemotherapy following a macroscopically complete resection of the tumor. The serum alpha-fetoprotein levels (Fig. 3) fell initially and then rose, strongly suggesting that there was a microscopic residuum of tumor. The subsequent decrease to normal levels after the first round of POMBACE chemotherapy was an invaluable measure, and gave us the confidence to administer only one further course of POMB-ACE rather than an arbitrary (larger) n u m b e r of cycles. The decision to consolidate with craniospinal irradiation was not based on hard evidence, but influenced by anecdotal reports of patients with pineal t u m o r relapsing after an initial response to chemotherapy J. Neurosurg. / V o l u m e 7 4 ~ M a y , 1991
when radiotherapy was omitted. Radiotherapy with careful fractionation tailored to the doses used seemed to be an acceptable risk a n d in the event was well tolerated. There appeared to be no logic in omitting the spinal field in view of the high rate of CSF seeding described with pineal endodermal sinus tumors.
Conclusions We report the third case of long-term survival a m o n g patients with pineal endodermal sinus tumors managed with chemotherapy as a d j u v a n t treatment. We stress a multidisciplinary approach to pineal endodermal sinus tumors based on c o m b i n e d surgery, chemotherapy, and radiotherapy. Surgery allows a definite diagnosis and removes most of the t u m o r mass. C o m b i n a t i o n chemotherapy using a platinum-based regimen must be given as adjuvant treatment without delay. Radiotherapy (whole neuraxis irradiation) can be used to complete the treatment. The response to therapy should be monitored by serial determinations of t u m o r markers.
References 1. Albrechtsen R, Klee JG, Mr JE: Primary intracranial germ cell tumours including five cases of endodermal sinus tumour. Acta Pathol Microbiol Seand (A) 80 (Sup# 233):32-38, 1972 2. AlLen JC, Kim JH, Packer RJ: Neoadjuvant chemotherapy for newly diagnosed germ-cell tumors of the central nervous system. J Neurosurg 67:65-70, 1987 3. Anderson BA: Intracranial endodermal sinus tumour - role ['or chemotherapy. Can J Neurol Sci 14:166-171, 1987 4. Arita N, Bitoh S, Ushio Y, et al: Primary pineal endoderreal sinus tumor with elevated serum and CSF alphafetoprotein levels. Case report, a Neurosurg 53:244-248, 1980 835
C. S. Kirkove, A. P. Brown, and L. Symon 5. Athanikar N, Saikia TK, Ramkrishnan G, et al: Aggressive chemotherapy in endodermal sinus tumor. 3 Surg Oneol 40:17-20, 1989 6. Bamberg M, Metz K, Alberti W, et al: Endodermal sinus tumor of the pineal region: metastases through a ventriculoperitoneal shunt. Cancer 54:903-906, 1984 7. Bestle J: Extragonadal endodermal sinus tumours originating in the region of the pineal gland. Acta Pathol Microbiol Scand 74:214-222, 1968 8. Bj~rnsson J, Scheithauer BW, Okazaki H, et al: Intracranial germ-cell tumors: pathobiological and immunohistochemical aspects of 70 cases. J Neuropathol Exp Neurol 44:32-46, I985 9. Borit A: Embryonal carcinoma of the pineal region. J Pathol 97:165-168, 1969 10. Burger PC, Vogel FS: Surgical Pathology of the Nervous System and Its Coverings. New York: John Wiley & Sons, 1976 11. Chapman PH, Linggood RM: The management of pineal area tumors: a recent reappraisal. Cancer 46:1253-1257, t 980 12. Edwards MSB, Davis RL, Laurent JP: Tumor markers and cytologic features of cerebrospinal fluid. Cancer 56: 1773-1777~ 1985 13. Edwards MSB, Hudgins RJ, Wilson CB, et al: Pineal region tumors in children, d Neurosorg 68:689-697, 1988 14. Graziano SL, Paolozzi FP, Rudolph AR, et al: Mixed germ-cell tumor of the pineal region. Case report. J Neurosurg 66:300-304, 1987 15. Ho KL, Rassekh ZS: Endodermal sinus tumor of the pineal region. Case report and review of literature. Cancer 44:1081-1086, 1979 16. Jellinger K: Primary intracranial germ cell tumours. Acta Neuropathol 25:291-306, 1973 17. Jetlinger K, Minauf M, Kraus H, et al: Embryonales Karzinom der Epiphysenregion. Aeta Neuropathol 15: 176-182, 1970 18. Jennings MT, Gelman R, Hochberg F: Intracranial germcell tumors: natural history and pathogenesis. J Neurosurg 63:155-167, 1985 19. Lee SH, Sundaresan N, Jereb B, et al: Endodermal sinus tumor of the pineal region: case report. Neurosurgery 3: 407-4I 1, 1978 20. Loeffler JS, Mauch P: Tumors in the pineal region, in Williams CJ, Krikorian JG, Green MR, et al (eds): Textbook of Uncommon Cancer. New York: John Wiley & Sons, 1988, pp 693-705 21. Logothetis CJ, Samuels ML, Trindade A: The management of brain metastases in germ cell tumors. Cancer 49:
836
12-18, 1982 22. Murovic JA, Ongley JP, Parker JC Jr, et al: Manifestations and therapeutic considerations in pineal yolk-sac tumors. Case report. J Neurosurg 55:303-307, 1981 23. Newlands ES, Bagshawe KD, Begent RHJ, et al: Current optimum management of anaplastic germ cell tumors of the testis and other sites. Br J Urol 58:307-314, 1986 24. Olsen MM, Raffensperger JG, Gonzalez-Crussi F, el al: Endodermal sinus tumor: a clinical and pathological correlation. J Pediatr Surg 17:832-840, 1982 25. Prioleau G, Wilson CB: Endodermal sinus tumor of the pineal region. Case report. Cancer 38:2489-2493, 1976 26. Rustin GJS, Newlands ES, Bagshawe KD, el al: Successful management of metastatic and primary germ cell tumors in the brain. Cancer 57:2108-2113, 1986 27. Scully RE, McNeely BU (eds): Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 41-1974. N Engl J Med 291:837-843, 1974 28. Stachura I, Mendelow H: Endodermal sinus tumor originating in the region of the pineal gland. Ultrastructural and immunohistochemical study. Cancer 45:2131-2137, 1980 29. Takei Y, Mirra SS, Miles ML: Primary intracranial yolk sac tumor: report of three cases and an ultrastructural study. J Neuropathol Exp Neuro136:633, 1977 (Abstract) 30. Tavcar D, Robboy SJ, Chapman P: Endodermal sinus tumor of the pineal region. Cancer 45:2646-2651, 1980 31. von Martin H, Voge[ S: [Malignant stem cell tumor of the pineal region with unusual differentiation.] Zentralbl Allg Pathol 120:391-397, 1976 (Ger) 32. Wilson ER, Takei Y, Bikoff WT, et ah Abdominal metastases of primary intracranial yolk sac tumors through ventriculoperitoneal shunts: report of three cases. Neurosurgery 5:356-364, 1979 33, Yoshiki T, ltoh T, Shirai T, et al: Primary intracranial yolk sac tumor. Immunofluorescent demonstration of alpha-fetoprotein synthesis. Cancer 37:2343-2348, 1976
Manuscript received July 11, 1990. Accepted in final form October 22, 1990. Dr. Kirkove was supported by a grant from Joseph Maisin Foundation, University of Louvaim Brussels, Belgium. Dr. Brown received support from the Mike Shields Cancer Charity, England. Address reprint requests to: Carine S. Kirkove, M.D., Department of Radiotherapy, UCL 4750, Cliniques Universitaires Saint Luc, Avenue Hippocrate, 1200 Bruxelles, Belgium.
J. Neurosurg. / Volume 74~May, 1991
Successful treatment of a pineal endodermal sinus tumor Case report CARINE S. KIRKOVE, M.D., ANDREW P. BROWN, F.R.C.R., AND
LINOSAY SYMON, F.R.C.S.
Department of Radiotherapy and Oncology, St Thomas" Hospital, and National Hospital for Nervous Diseases, London, England w" A patient with a pineal endodermal sinus tumor is presented who was successfullytreated by a combination of surgery, adjuvant chemotherapy, and craniospinal irradiation. Two years after diagnosis, he is free of any disease. A review of the literature shows that such an outcome is very unusual. A multidisciplinary treatment is recommended for this rare tumor, using chemotherapy as adjuvant treatment. KEY WORDS
9
chemotherapy
pineal endodermal sinus 9 radiotherapy
NDODERMALsinus tumors or yolk sac tumors are rare cancers of the germ-cell-derived extraembryonic tissues. Like other cancers of germinal origin, they arise in midline sites such as the gonads, sacrococcygeal area, retroperitoneum, mediastinum, suprasellar region, and pineal gland. Intracranial endodermal sinus tumors represent 7% of primary intracranial germinal cancers, which themselves represent only 0.4% to 3.5% of primary intracranial neoplasms in Western countries. ~s Histologically, 50% of pineal gland endodermal sinus tumors are mixed and contain various proportions of other germ-cell elements including germinoma, teratoma, embryonal-cell carcinoma, and choriocarcinoma. 6'3~Most pineal endodermal sinus tumors synthesize alpha-fetoprotein, and this marker, measured in serum and cerebrospinal fluid (CSF), may be useful for diagnosis and to assess responsiveness to treatment? 2,2~Endodermal sinus tumors of the pineal gland are highly aggressive neoplasms and the survival rate is poor. t8 We describe a case of long-term complete remission of a pineal gland endodermal sinus tumor treated by a combination of surgery, cytotoxic chemotherapy, and radiotherapy. We review the other reported cases and stress the importance of a combined therapeutic approach in the management of this rare tumor.
E
Case Report
This 14-year-old boy with unremarkable medical history first presented in April, 1988, with intermittent 832
9 tumor
9 alpha-fetoprotein
9
frontal headaches beginning 2 months before. He suffered diplopia, nausea, vomiting, and drowsiness. Examination. There was an absence of upward gaze and poor ocular convergence. Funduscopic examination disclosed papilledema without hemorrhage. No other neurological deficit was noted apart from mild ataxia. Computerized tomography revealed a pineal tumor and marked hydrocephalus (Fig. 1 left). Serum alpha-fetoprotein and human chorionic gonadotropin (HCG) levels were raised at 1050 kU/liter (normal < 10 kU/liter) and 151 IU/liter (normal _< 4 IU/liter), respectively.
Operation. Right occipital craniotomy with tmnstentorial microsurgical excision of the lesion was performed in May, 1988. The excision appeared grossly complete (Fig. 1 right). Histological examination showed a malignant endodermal sinus tumor (yolk sac tumor) with a high mitotic rate and pathognomonic Schiller-Dural bodies (Fig. 2). There was also an element of mature teratoma comprising keratinizing epithelium, smooth muscle, and endocrine-type cells. Postoperative Course. After surgery, the hydrocephalus resolved but upward vision was still limited and diplopia on fight lateral gaze persisted. The serum HCG content fell to less than 2 IU/liter but, after an initial impressive drop to 49 kU/liter, the alpha-fetoprotein level rose to 88 and 113 kU/liter 18 and 25 days, respectively, after surgery (Fig. 3). Alpha-fetoprotein but not HCG levels were also elevated in the CSF J. Neurosurg. / Volume 74/May, 1991
Pineal endodermal sinus t u m o r
FIG. 1. Left. Preoperative computerized tomography (CT) scans showing the enhancing tumor in the region of the pineal gland. Right." Postoperative CT scan confirming the macroscopically complete resection of tumor with consequent relief of hydrocephalus.
(97 kU/liter). Cytological examination of the CSF for tumor cells was negative and remained so on later lumbar punctures. Faced with the dismal prognosis, it was elected to treat the patient with chemotherapy according to the POMB-ACE regimen for anaplastic germ-cell tumors. This intensive regimen comprises an initial period of intravenous platinum (P), vincristine (O), methotrexate (M), and bleomycin (B) followed after a 10-day hiatus by actinomycin D (A), cyclophosphamide (C), and etoposide (E). This regimen was chosen because of a previous report 26 of its efficacy in several cases of nonseminomatous germ-cell tumors metastatic to the brain. The first cycle of POMB was begun on the 18th
postoperative day. It consisted of intravenous vincristine, 1 mg/sq m, and methotrexate, 300 mg/sq m on Day 1; bleomycin, 15 mg, on Days 2 and 3; and cisplatin, 120 mg/sq m, on Day 4. At the same time the patient was given 10 mg methotrexate intrathecally. After the POMB treatment, alpha-fetoprotein levels were still elevated in serum (67 kU/liter) and CSF (34 kU/liter). The patient was readmitted to the hospital 10 days later to receive a 3-day course of etoposide (VP- 16, 100 mg/sq m on Days 1 to 3), actinomycin D (0.5 mg on Days 2 and 3), and cyclophosphamide (500 mg/sq m on Day 3), as well as a second dose of intrathecal methotrexate (10 rag). The serum and CSF alpha-feto-
FIG. 2. Photomicrograph of the tumor specimen showing the typical appearance of an endodermal sinus tumor with large vacuolated cells and prominent nucleoli. In the center a pathognomonic Schiller-Duval body, a glomeruloid structure with surrounding crescentic space, can he seen. H & E, • 200.
FIG. 3. Plot of serum alpha-fetoprotein (AFP) level during and following treatment. The theoretical decay curve assumes a biological half-life of 5 days following a total extirpation of the tumor. For definitions of POMB and ACE chemotherapy see text; R/T = radiation therapy.
J. Neurosurg. / Volume 74/May, 1991
833
('. S. Kirkove. A. P. Brown, and L. Symon T..ABI.[ I R~'l~t'l~'d ~d~'~ IfftfitWa/ (~ltd(Jdo'l~ld/ ~//11t~ Ill~If(Jr5 Irc'al('d l~iI/toltl chetnotherapl,
Case NO.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Authors & Year Bestle, 1968 Albrechlsen, el a[.. 1972 Borit, 1969 Jellinger,(v al., 1970 Jellinger, 1973 (Case 6) Albrechtsen,el al, 1972 Jellinger,1973 Scully & MeNeely, 1974 Tavcar, el al., 1980 (Case 1) Chapman & Linggood, 1980 (Case 6) Burger& Vogel, 1976 Yoshiki,et al., 1976 yon Martin & Vogel. 1976 "[akei,(,! a[.. 1977 Lee, el at., 1978 Ho & Rassekh. 1979 Wilson,et al, 1979 Tavcar,c't al., 1980 Chapman & Linggood, 1980(Case 15) Murovic.e! al., 1981 Bamberg,el al., 1984 Bjornsson,et at., 1985
I tistolog~*
Surgeryf
Radiotherapy
Outcome, Survival Time Since Diagnosis
mixed {dermoid e)st)
B
no
died, postop
mixed (G, Emb Ca) mixed (T, G. Emb Ca)
S S& B
yes yes
died, 6 mos died, 2 mos
mixed (G) mixed (G) pure mixed (Ch, G, Emb Ca) mixed (Y. G) mixed (G, T) pure
+ + + no no no no
no no no no no no yes
died, postop died, postop died, postop died, unknown died, unknown died, unknown died, 2 mos
pure pure mixed (T, Ch. G, Emb Ca) pure? pure mixed (G) pure pure
S S& B S S S & PR S & PR S S & PR
no yes no yes yes yes yes yes
died, unknown died, 14 mos died, unknown died, unknown alive, > 6.5 mos died, l mo died, 7 mos died, 9 mos
alive, > 3.5 yrs pure PR yes died, 7 mos pure S& B yes died, 6 wks pure + no * Nonendodermal sinus tumor component of the tumors: G = germinoma; Emb Ca = embo, onal carcinoma; T = teratoma; Ch = choriocarcinoma. f B = biopsy" S = shunt; PR = partial removal: + = surgery bul no dctails available. 19 20 21
protein levels eventually fell to normal 2 weeks later (Fig. 3). A second course of P O M B was given but the dose of eisplatin was reduced to 100 mg because of intense nausea and vomiting during the first course and a transient rise in creatinine and urea. A second course of ACE, together with a third dose of 10 mg methotrexate intrathecally, was then given. Finally, it was decided to consolidate the treatment with craniospinal irradiation 3 weeks after the completion of chemotherapy. The whole brain received 2880 cGy in 16 fractions over a 3-week period with a subsequent boost to the third ventricle area, to a final t u m o r dose of 5400 cGy in 30 fractions over 46 days using a three-field technique. Spinal irradiation (2550 cGy in 17 fractions over 25 days) completed this treatment. Over the next year, i m p r o v e m e n t was noted in the patient's ocular movements; in particular, good upgaze was restored. Currently, 24 months after the diagnosis the patient is still clinically, biologically, and radiologically free of any disease. His pupils still react sluggishly to light and briskly to a c c o m m o d a t i o n . O f note, his pituitary function is normal and his scholastic performance remains unchanged. Discussion
Pineal endodermal sinus t u m o r is a very rare but highly aggressive n o n s e m i n o m a t o u s germ-cell neo834
plasm. O f the 29 patients reported in the literature (Tables I and 2), 24 were dead by 14 m o n t h s after the diagnosis. The results of surgery a n d / o r radiotherapy without chemotherapy are very, disappointing (Table 1). Only two of 21 patients survived at 6.5 m o n t h s and 3.5 years. Both underwent partial resection followed by craniospinal irradiation. The surgical procedure was limited to a biopsy a n d / o r insertion o f a shunt for the majority o f patients. In the earlier literature, surgery for pineal tumors carried an unacceptably high mortality rate ~'2~ but. with modern techniques, resection can be countenanced. ~ The c o m m o n e r g e r m i n o m a s of the pineal region are radiosensitive and patients are often cured by shunt placement and a therapeutic trial o f radiation, ~' but it is clear that such an approach cannot be relied upon to cure the rare patient with an endodermal sinus tumor. As shown in Table 1, no such t u m o r has been cured by radiotherapy alone. The emergence o f extremely effective chemotherapy for gonadal and extragonadal germ-cell tumors has changed m a n a g e m e n t concepts of intracranial germcell tumors. Protocols using synergistic cytotoxic agents, including vinblastine, vincristine, acfinomycin D, bleomycin, Adriamycin, cyclophosphamide, and cisplatin, have achieved complete remission rates o f 60% to 90% against localized and metastatic gonadal and extragoJ. N e u r o s u r g . / I ~ d u m e
74/May,
1991
Pineal e n d o d e r m a l sinus t u m o r TABLE 2 Reported cases q[pineal endoderma[ sintts tmnor,s treated with ctwmolherapj'
Case
Authors & Year
Histology*
Surgery?
Radiotherapy
pure
S & PR
yes
mixed (Ch) pure pure
S S S
yes yes yes
Chemotherapy$
No. 1 2 3 4
Prioleau& Wilson, 1976 Edwards, e/aL, 1988 Wilson,et at, 1979 Stachura& Mendelow, 1980 Arita, el a/, 1980
adjuvant: VAC
Outcome, Survival Time Since Diagnosis alive, > I3 yrs
adjuvant: PCB, VCR died, 9 mos recurrent tumor: BCNU died, 13 mos 1st recurrence: MTX died, 13 mos 2nd recurrence: VCR, bleo 5 Olsen,el a[., 1982 pure S & PR yes abdominal metastasis: VAC died, 22 mos 6 Anderson,1987 pure no yes frontal metastasis: VCB died, 12 mos 7 Allen,et al., 1987 pure (parietal) B or PR yes adjuvant: VAB alive,> 12 mos 8 Edwards,et aL, 1988 pure + yes recurrent tumor: bleo, VCR, died, 12 mos VP-t6, CP 9 Kirkove,et aL, 1991 mixed (T) PR yes adjuvant: CP, VCR, MTX, alive,> 24 mos bleo, VP-16, aclino-D, cyclo * Nonendodermal sinus tumor component of the tumors: Ch = choriocarcinoma;T = teratoma. "}"S = shunt; PR = partial removal; B = biopsy; + = surgery but no details available. :[:VAC = vincristine (VCR) + actinomycin D (Actino D) + cyclophosphamide(cydo); PCB = procarbazine; MTX = methotrexate: bleo = Neomycin; VCB = vinbfastine + cisplatin + bleomycin; VAB = vinblastine + Neomycin + cisplatin + cyclophosphamide;VP-16 = etoposide; CP = cisplatin.
nadal n o n s e m i n o m a t o u s germ-cell t u m o r s in combination with surgery and irradiation. 5,23,-'4Several complete responses to chemotherapy have also been reported in germ-cell brain metastases. 2L:326 Moreover, in a review of 81 cases of primary intracranial n o n s e m i n o m a t o u s germ-cell tumors, Graziano, et al., ~4 found nine long-term survivors, eight after chemotherapy and radiotherapy and only one after radiotherapy as the primary modality. We found only eight cases of pineal endodermai sinus t u m o r treated by chemotherapy (Table 2). Five patients who died received chemotherapy only when the t u m o r was k n o w n to have recurred or metastasized. Two of three patients who received adjuvant chemotherapy were alive 13 years and 12 m o n t h s after diagnosis. In the third adjuvant patient, there was an initial complete response after radiotherapy a n d chemotherapy, but the patient died 9 m o n t h s later with local recurrence a n d seeding to the spine and peritoneum. Metastatic spread through the CSF and ventriculopefitoneal shunts is a well-documented risk in pineal endodermal sinus tumors. 69~2427:~3233 Our patient, alive 2 years after diagnosis, was treated with a d j u v a n t chemotherapy following a macroscopically complete resection of the tumor. The serum alpha-fetoprotein levels (Fig. 3) fell initially and then rose, strongly suggesting that there was a microscopic residuum of tumor. The subsequent decrease to normal levels after the first round of POMBACE chemotherapy was an invaluable measure, and gave us the confidence to administer only one further course of POMB-ACE rather than an arbitrary (larger) n u m b e r of cycles. The decision to consolidate with craniospinal irradiation was not based on hard evidence, but influenced by anecdotal reports of patients with pineal t u m o r relapsing after an initial response to chemotherapy J. Neurosurg. / V o l u m e 7 4 ~ M a y , 1991
when radiotherapy was omitted. Radiotherapy with careful fractionation tailored to the doses used seemed to be an acceptable risk a n d in the event was well tolerated. There appeared to be no logic in omitting the spinal field in view of the high rate of CSF seeding described with pineal endodermal sinus tumors.
Conclusions We report the third case of long-term survival a m o n g patients with pineal endodermal sinus tumors managed with chemotherapy as a d j u v a n t treatment. We stress a multidisciplinary approach to pineal endodermal sinus tumors based on c o m b i n e d surgery, chemotherapy, and radiotherapy. Surgery allows a definite diagnosis and removes most of the t u m o r mass. C o m b i n a t i o n chemotherapy using a platinum-based regimen must be given as adjuvant treatment without delay. Radiotherapy (whole neuraxis irradiation) can be used to complete the treatment. The response to therapy should be monitored by serial determinations of t u m o r markers.
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Manuscript received July 11, 1990. Accepted in final form October 22, 1990. Dr. Kirkove was supported by a grant from Joseph Maisin Foundation, University of Louvaim Brussels, Belgium. Dr. Brown received support from the Mike Shields Cancer Charity, England. Address reprint requests to: Carine S. Kirkove, M.D., Department of Radiotherapy, UCL 4750, Cliniques Universitaires Saint Luc, Avenue Hippocrate, 1200 Bruxelles, Belgium.
J. Neurosurg. / Volume 74~May, 1991
