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Intrasellar germinoma associated with hyperprolactinemia
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Intrasellar Germinoma Associated with Hyperprolactinemia S o r a n a M a r c o v i t z , M . D . , H a r v e y J. G u y d a , M . D . , M o r r i s o n H . F i n l a y s o n , M . D . , Roberto
Wee, M.D., and Jules Hardy, M.D.
Divisions of Endocrinology, Neuropathology, Radiology, and Neurosurgery, Montreal General Hospital and Montreal Children's Hospital, McGill University, and University of Montreal, Montreal, Quebec, Canada
Marcovitz S, Guyda HJ, Finls.ysonMH, Wee R, Hardy J. Intrasellar germinoma associated with hTperprolactinemia.Surg Neurol 1984;22:387-96. We report two young adult patients with hyperprolactinemia and neuroendocrine deficits due to predominantly intrasellar germinomas. In both cases the diagnosis of germinoma was confirmed histologically after transsphenoidal surgery. This very rare type of tumor may be intraseUar and it may mimic prolactinoma or craniopharyngioma. Dynamic testing of pituitary function and computed tomography scanning are of value in the early detection of this malignant but radiocurable lesion. KEY WORDS: Germinoma; Hyperprolactinemia; Hypopituitarism; Intrasellar tumor; Computed tomography; Dynamic pituitary function testing
Intracranial germinoma (also called ectopic pinealoma) is a rare lesion ( 0 . 5 % - 2 . 0 % of primary intracranial neoplasms [16]), which can arise in the region of the hypothalamus or o f the !pituitary stalk and present with neuroendocrinologic problems. Intrasellar germinomas are rarer still and not widely recognized: we were able to find only 33 documented cases in a search through the literature [1,2,4,11-13,17,19,23,29,32,33,35,39, 4 3 - 4 5 ] , and most of these were published before the era of prolactin radioimmunoassays and computed tomography scanning. In this paper we report the first two cases o f intrasellar germinoma associated with hyperprolactinemia. This entity can mimic prolactin-secreting adenoma or craniopha;yngioma, but an accurate diagnosis is essential because germinomas respond well only to radiotherapy.
Address reprint requests to. Dr. S. Marcovitz,Division of Endocrinology, Montreal General Hospital, 1650 Cedar Avenue, Montreal, Canada, H3G 1A4.
© 1984 by ElsevierSciencePublishingCo., Inc.
Case Reports Case 1
This 19-year-old male patient was first examined at the Montreal Children's Hospital when he was 8 years old; he had presented with enuresis and was found to have central diabetes insipidus. Skeletal survey and skull x-ray films at that time were normal. On arginine stimulation, the peak serum growth h o r m o n e (GH) had been 6.5 ng/mL, which was considered borderline adequate. Treatment was begun with pitressin tannate in oil with good response. The patient was then lost to our observation for about 5 years. In July 1975 (chronological age, 13%2) he returned with a new complaint of failure to grow; G H deficit was documented by an insulin-arginine challenge (peak G H value less than 1 ng/mL). The test was repeated after pretreatment with ethinyl estradiol 50 tzg p.o. twice a day for 3 days, and G H deficit was confirmed (peak G H level 3.0 ng/mL). H e was then started on human growth hormone therapy. In 1977, the cortisol response to hypoglycemia was borderline (baseline 3.25 la.g/dL and peak value 11.0 tzg/dL), and moderate hyperprolactinemia (baseline 38 ng/mL and peak value 39 ng/mL) was documented. A thyrotropin-releasing hormone (TRH) test elicited a normal thyrotropin (TSH) response (baseline 3.9 tzU/mL rising to 25.0 tzU/mL), although the serum thyroxine was borderline-low at 4.0/*g/dL (normal range, 4 - 1 1 tzg/dL) and this was interpreted as mild tertiary hypothyroidism; the serum prolactin was again elevated and showed a blunted response to thyrotropin-releasing hormone (baseline 55 ng/mL and peak value 75 ng/mL). Thyroxine (T4) replacement therapy was begun at this time. In 1978 the cortisol response to hypoglycemia was deficient (baseline 1.25 txg/dL and peak value 2.0/~g/dL and cortisone acetate (5 mg p.o. three times a day) supplements were started. At age 17 years the patient had not developed any signs of puberty. A gonadotropinreleasing hormone (LRH) test in December 1978 showed him to be gonadotropin deficient (baseline luteinizing hormone (LH) and follicle-stimulating hormone (FSH) 2.4 ~g/dL and 5.0 I-~g/dL respectively and peak values 0090-3019/84/$3.00
388
Surg Neurol 1984;22:387-96
2.2 ~o/dL and 7.2 ~g/dL respectively). H e was begun on depo-testosterone in April 1979. X-ray films o f the skull over the years had remained normal. A computed tomography scan done at the Montreal Children's Hospital in August 1979 (DELTA-50 FS scanner, Ohio Nuclear) was also normal. However, there was continuing concern about a possible hypothalamic lesion because serum prolactin levels had gradually risen to 100 ng/mL by February 1981. Thus in April 1981 he was referred to the Montreal General Hospital for another computed tomography scan, which was done with a new EMI CT 7070 scanner. This computed tomography scan (Figure 1) demonstrated a thick pituitary stalk with a fleck o f calcification within it; the pituitary gland was small. Contrast-medium injection (Figure 2) resulted in dense enhancement of the thick stalk and a small area within the gland. Tomograms o f the sella turcica were again normal. The patient was referred for an operation with a suspected diagnosis o f craniopharyngioma. Before operation he reported mild recurrent headaches, but no other new symptoms. Fundoscopy and formal (Goldmann) testing of the visual fields were normal. Because the lesion seen on the computed tomography scan was partially within the sella and the suprasellar portion was small, a transsphenoidal surgical approach was chosen. Greyish gristlelike tumor material was identified in the center of the gland and was removed piecemeal. The tumor was firmly adherent to a mass of geFigure 1. Case 1: Coronal computed tomography scan (EMI CT 7070) of sella from the tuberculum (a) to dorsum (d). Note the small calcification in the suprasellar mass (arrow) in (c) and the markedly thickened pituitary stalk in (d).
Marcovitz et al
Figure 2. Repeat computed tomography scan after contrast injection (Conray 60%, 1 mL/lb body weight) in patient I demonstrates enhancement of the suprasellar mass (b-d). Note enhanced area within the gland in (b). latinous tissue that resembled an enlarged pituitary stalk. Due to congenital absence of the diaphragma seUae, the tumor removal resulted in the opening of the third ventricle, necessitating duroplasty with lyophilized dura. The course after the operation was uneventful, and the serum prolactin decreased to 16 ng/mL; the patient was continued on hormonal replacement therapy and continued to require pitressin (DDAVP) for persistent diabetes insipidus. Pathological study of the tissue removed at the operation showed posterior lobe o f pituitary infilrated by a neoplastic germ cell tumor (Figure 3). Cerebrospinal fluid cytology 3 weeks after the operation was negative. The patient was given radiotherapy in a course of 5000 rads (4000 rads to the whole brain and an additional 1000 rads to the region of the third ventricle) over 5 weeks. H e has remained well and was last seen in D e c e m b e r 1983.
Case 2
The second patient was a 21-year-old woman who presented at age 18 years with primary amenorrhea. She had had a healthy childhood, and at age 13 had noted growth o f axillary and pubic hair and beginning o f breast development. At the time o f presentation she was 162.5 cm tall, but relatively short compared with family members (mother, 172.7 cm; father, 190.5 cm; brother, 188 cm; younger brother, 183 cm). She was examined at the Health Sciences Center o f the State University of N e w
Germinoma with Hyperprolactinemia
Surg Neurol 1984;22:387-96
389
A
Figure 3. (A) Electron micrograph of seminomalike cells invading the pituitary of case 1. A portion of a plasma cell is also seen (open arrow). The solid arrow indicates glycogen granules (× 14,000). (B) Microphotograph of germinoma showing large tumor cells (one in mitosis) interspersed with mononuclear inflammatory cells (H & E; x 800).
B
York at Stony Brook; serum follicle-stimulating hormone (11.5 mIU/mL), luteinizing hormone (13.5 mIU/mL), prolactin (17.4 ng/mL), and thyroid-stimulating hormone (4.3 /.~U/mL) were all normal. X-ray examination of the sella turcica and gross visual field examination by confrontation were also normal. She was given a 6-month trial of therapy with conjugated estrogens and medroxyprogesterone acetate, which resulted in vaginal bleeding; subsequently she had no spontaneous menses. She was then followed-up with serial serum gonadotropins and prolactin measurements. In January 1981 (2.5 years after presentation), her prolactin level became elevated (43 ng/mL). Subsequent formal examination of the visual fields was abnormal and a computed tomography scan showed a mass within the sella turcica with suprasellar expansion. The patient was
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Surg Neurol 1984;22:387-96
then referred for a transsphenoidal operation in June 1981 with a tentative diagnosis of prolactin-secreting adenoma or craniopharyngioma. The patient had never had galactorrhea. Several months before the operation she had begun to have frequent, rather severe bifrontal headaches and increased fatiguability. Before the transsphenoidal operation at the Montreal General Hospital, she underwent testing of pituitary function with insulin hypoglycemia, apomorphine, thyrotropin-releasing hormone, and gonadotropin-releasing hormone, which showed her to have deficits of growth hormone (peak values of 0.9 ng/mL and 1.0 ng/mL, on apomorphine and insulin hypoglycemia challenges, respectively), luteinizing hormone and follicle-stimulating hormone (baseline values 6 and 7 mIU/mL, respectively, and peak values 4 and 6 mIU/mL respectively), and elevated basal prolactin of 35-40 ng/mL; prolactin was suppressed by apomorphine (baseline value, 36 ng/mL and nadir, 13 ng/mL), but it did not quite double after thyrotropin-releasing hormone (39 ng/mL rising to 74 ng/mL) and did not rise significantly on insulin hypoglycemia challenge (baseline 35 ng/mL and peak value 39 ng/mL); basal plasma cortisol was low (2.4 /zg/dL) and unresponsive to hypoglycemia (peak value, 3.3 /zg/mL); thyrotropin response to thyrotropin-stimulating hormone was adequate (3.5/~U/mL, rising to 26 ~U/mL), though the concomitant serum T4 was somewhat low at 3.3 p,g/dL (normal range for assay was 5.0-13.7 /~g/dL), as was the adjusted T4 at 3.1 /~g/dL (normal, 4.4-14.4); serum T3 was 115 ng/dL (normal 65-200). Examination of the visual fields confirmed bitemporal hemianopsia. A film series of the skull and lateral tomograms of the sella turcica showed no evidence of raised intracranial pressure and no intracranial calcifications; the sella turcica was of normal size, but it showed undercutting of the tuberculum on the right side. A computed tomography scan after contrast medium injection showed an enhancing mass within the sella and in the suprasellar region, with a 5-mm, low-density, nonenhancing area within it (Figure 4). During the operation, a greyish purple tumor with a necrotic area in the lower portion was found and totally excised. The suprasellar expansion was rather firm and gristlelike and adherent to the arachnoid. After total excision of the tumor tissue, an enlarged pituitary stalk was identified. Normal-appearing pituitary tissue was seen and left intact. The patient received corticosteroid therapy for 5 days, and her course after the operation was uneventful. Dynamic pituitary function testing was repeated 9 and 10 days after the operation (4 days after corticosteroid therapy ended). The results were unchanged compared with the preoperative ones aside from the serum pro-
Marcovitz et al
Figure 4. Case 2: Coronal computed tomography scan after contrast medium injection shows an enhanced mass within the sella turcica and filling the suprasellar cistern to the level of the horizontal segment of the anterior cerebral arteries. Irregularly shaped area in the lower portion of the mass is not enhanced. (Technique as for Figures 1 and 2.)
lactin, which had decreased to 1-2 ng/mL, and the finding of a new thyrotropin deficit (basal value 1 /zU/mL and peak level 2 /zU/mL). The patient was then begun on replacement therapy of cortisone acetate, thyroxine, and estrogen and progesterone. Pathological study of the tissue removed at the operation showed germinoma infiltrating the normal anterior pituitary and surrounding fibrous tissue. Cerebrospinal fluid cytologic findings after the operation were normal, and the patient subsequently received radiation therapy with a total of 4600 rads (3000 rads to the whole brain and an additional 1600 rads to the region of the third ventricle) given over 6 weeks. This was well tolerated. She has remained well on the hormonal replacement therapy with no evidence of recurrence; she was last examined in August of 1983. Methods and Results Endocrinology
Dynamic testing of pituitary function at the Montreal General Hospital (case 2) consisted of studying responses to insulin hypoglycemia, apomorphine, thyrotropin-releasing hormone (TRH), and gonadotropin-releasing hormone (LRH) separately in the resting, fasting state both before and after the operation, as previously described [24]. The plasma samples were kept frozen
Germinoma with Hyperprolactinemia
at - 2 0 ° C until they were processed for radioimmunoassay of growth hormone (GH), prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyrotropin (TSH), or corti~ol at the Clinical Endocrinology Laboratory of the Montreal General Hospital [24]. Dynamic testing of pituitary function at the Montreal Children's Hospital was carried out according to similar protocols for thyrotropin-releasing hormone and gonadotropin-releasing hormone. Provocative testing for evaluation of growth hormone reserve and reserve of the pituitary-adrenocortical axis was done with a combined insulin (0.05 U/kg i.v.) and arginine (0.5 g/kg, up to 25 g i.v.) test [28]. Plasma samples were kept frozen at - 20°C until processed for radioimmunoassay of growth hormone (National Institutes of Health 1652 C standard), prolactin (Friesen 72-4-9 standard), luteinizing hormone (LER 907 standard), follicle-stimulating hormone (LER 907 standard), thyrotropin (TSH) (human TSH standard obtained from the International Laboratory for Biological Standards, Hampstead Laboratories, Holy Hill, London, England), or for competitive protein binding assay [26] of cortisol.
Pathology The tissue removed surgically was fixed in formalin except for small samples t]~at were fixed in gluteraldehyde and embedded in Epon for electron microscopic examination. Sections of formalin-fixed, paraffin-embedded tissue were stained with hematoxylin and eosin, periodic-acid-Schiff (PAS) (some after diastase treatment), by Herlant's method, and by Pearse's performic acid, alcian blue, and orange C method. On microscopic examination, the tissue resected from both patients had much the.same appearance. There was considerable fibrosis in and around the anterior pituitary, and a patchy mononuclear cell inflammatory infiltrate. Large, pale tumor cells were seen scattered or in small groups among the mononuclear cells. The posterior lobe was more e'ctensively invaded by this bicellular infiltrate than the anterior lobe. The cytoplasm of the large tumor cells was strongly PAS positive, and this property was removed by diastase digestion; many of these cells were in mitosis (Figure 3). On electron microscopic examination, the large cells contained many glycogen granules (Figure 3), and also small cytoplasmic lipid droplets, moderate numbers of small mitochondria, and occasional single strands or small parallel arrays of endoplasmic reticulum. Nuclear chromatin tended to be evenly dispersed, and the nucleoli were prominent and sometimes multiple. The mononuclear cells were found to be lymphocytes and plasma
Surg Neurol 1984;22:387-96
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cells in about equal numbers; there were also a few macrophages.
Discussion The patients described both had hyperprolactinemia and tumors located within the sella turcica in continuity with the suprasellar region. The light and electron microscopic features of the tumors were typical of the seminomalike type ofgerminoma (also referred to as ectopic pinealoma or ectopic pineal germinoma) [10,22,33,34]. In both patients the radiologic and surgical findings were those of a predominantly intrasellar tumor, but because of the finding of suprasellar extension one cannot rule out the possibility that the sellar involvement was in fact secondary to a germinoma that arose originally near the optic chiasm. Intracranial germinomas outside the pineal gland are rare; in our review of the literature we have found a total of only 164 histologically documented cases [ 1-4,6,7, 11-13,15,17,19,20,23,29,32,33,35,37,39-46]. Most of these patients were diagnosed late in their course, and very few had undergone detailed endocrinologic investigations. In retrospect, the first case of suprasellar germinoma was described by Starck in 1928, which was before the recognition of intracranial germinomas as a pathological entity [10,34]. Intrasellar germinomas are rarer still, and they have not been widely recognized. In the proposed classification of extrapineal germinomas [19], the lack of seUar involvement was considered as one of the important criteria in differentiating between these tumors and pituitary adenomas. In reviewing the reported series, however, we were able to find 33 histologically proven cases ofgerminoma with radiologic or pathological evidence of tumor within the sella turcica and their main features are listed in Table 1; data from individual patients were available for only 21 of the cases. The equal sex distribution (nine males, 12 females) is similar to that reported for suprasellar germinomas [6,19,32,44], whereas primary pineal germinomas occur mostly in males [4,44]. The patients were all between 8 and 22 years of age at the time of diagnosis, and five of them had long durations of symptoms (7, 4, 4, 7, and 9 years, respectively) like our patients; 19 of 21 patients had visual abnormalities. As shown in Table 1, at least 15 of the patients had some evidence of pituitary hypofunction, and two had precocious puberty; however, information about the endocrine aspects is scant in the published reports and many of the cases (eight were seen before 1950) had minimal if any laboratory investigations; prolactin measurements were not done in any of these patients. In
392
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Marcovitz et al
contrast to our two cases, in the instances where radiologic evidence of sellar enlargement was obtained, it was based on changes gross enough to be seen on plain x-ray films of the skull, pneumoencephalography, or ventriculography; none o f the previously reported patients with intrasellar germinomas had computed tomography scans. Nine published cases of histologically proven intracranial germinomas associated with hyperprolactinemia are listed in Table 2; none of these patients had tumor within the sella turcica. Several patients in this group had computed tomography scans, and all of these were found to have isodense lesions that showed enhancement after injection of contrast material, as had been described previously [8]. O f special interest in relation to our first case was the finding that suprasellar calcifications were previously detected radiographically in only two patients with suprasellar germinomas [43]. In 1969, however, Ghatak et al had reported the histologic finding o f specks of calcium within one of their intrasellar germinomas and predicted that such calcific deposits might lead to an erroneous radiologic diagnosis o f craniopharyngioma. The early cases of intracranial germinomas only treated surgically had dismal rates o f survival (e.g., Table 1). Since the recognition o f the efficacy of radiation therapy [14,32,45] this has become the accepted mode of treatment, with reported 5-year survival rates of 6 9 % - 7 7 % in several series [4,17,37,43,48]. Prophylactic irradiation o f the spinal cord [9] and chemotherapy [27,37] have been suggested by some authors, but these have not gained wide acceptance. The effects of radiotherapy on the pituitary deficits associated with suprasellar or
intrasellar germinomas have not been studied extensively. Sklar et al assessed the endocrine status o f six patients with histologically proven suprasellar germinomas after radiotherapy and found no recovery of preexisting pituitary deficits nor documentable instances of new pituitary dysfunction; however, the interval since completion of radiotherapy was relatively short for several of these patients; according to other reported experience [31,36,38] they might still be at risk for developing radiation-induced pituitary deficits. In the past, the diagnosis of intrasellar or suprasellar germinoma was often not made until autopsy. This was probably due in large part to the limitations of the radiologic techniques then available. As seen in our cases and in several other recent cases mentioned above, computed tomography scanning is extremely valuable in demonstrating these lesions, particularly if the scans are obtained in the coronal plane; but it may not be possible to differentiate between adenoma, craniopharyngioma, meningioma and germinoma on the basis of the appearance on computed tomography scan [30]. Another reason for the very poor survival in the early cases was the lack of recognition and treatment o f the endocrine abnormalities, which in many instances--including our two patients--were responsible for the initial symptoms up to several years before diagnosis. Recent advances in neuroendocrinology with widespread availability of radioimmunoassays for pituitary hormones and dynamic pituitary function testing should make it possible to detect and treat the endocrine manifestations ofgerminomas in the sellar region at an early stage. It is to be hoped that early radiotherapy given before the development of extensive pituitary deficits
Table 2. Cases of lntracranial Germinomas with Hyperprolactinemia Source Spiegel et al, 1976 Spiegel et al, 1976 Sklar et al, 1 9 8 1 (case 1) Sklar et al, 1981 (case 3) Sklar et al, 1 9 8 1 (case 4) Sklar et al, 1 9 8 1 (case 5) Sklar et al, 1981 (case 7) Balagura et al, 1979 Balagura et al, 1979
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G e r m i n o m a with Hyperp~rolactinemia
and visual loss will improve the total outcome in these radiocurable tumors. As we have seen in our cases, hyperprolactinemia may be associated with germinomas in the pituitary region, and potentially it can 1,2ad one to a wrong diagnosis of adenoma. The hyperprolactinemia in these cases is presumably due to interfi.=rence with normal delivery of prolactin-inhibiting factor to the adenohypophysis, as has been postulated in cases o f craniopharyngioma, meo ningioma, third ventricle tumors, aneurysms, and hypothalamic disease [3:~18,21]. However, the blunted prolactin responses to thyrotropin-releasing hormone (especially in case 1) found in these patients resembled those seen in prolactin-secreting adenomas [21] rather than the "stalk-section phenomenon," and we have also observed blunted responses in several cases of craniopharyngioma (Marcoviitz et al, unpublished observations); thus the prolactin response to thyrotropinreleasing hormone may not always be useful in distinguishing between various causes of hyperprolactinemia. Diagnostic tests with dopamine agonists and antagonists have been proposed to differentiate between hyperprolactinemia due to prolactin-secreting adenomas and that due to other causes, but the data are insufficient to use these tests as a means of distinguishing between adenomas and hypothalamic or stalk lesions [5,25]. Based on our two cases we suggest that patients presenting with diabetes insipidus, hypogonadotropic hypogonadism, or hyperprolactinemia should routinely have dynamic testing for a.ssessment of anterior pituitary functional reserve, and high-resolution computed tomography scans should be done even if x-ray films of the skull and sellar tomograms are normal. A finding of an enhancing mass with suprasellar expansion in a young patient with only moderately elevated serum prolactin may be a reason for considering the diagnosis of germinoma, and it shouild be an indication for recommending surgical intervention to obtain a tissue diagnosis for planning definitive therapy.
The authors wish to thank Dr. Z. Rosenwaks for referring the second patient.
References 1. Akamatu H. Ein fall yon primarem pinealom aus der hypothalamus-infundibulumgegend. Gann 1939;33:371-81. 2. Baggenstoss AH, Love JG. Pinealomas. Arch Neurol Psychiatry 1939;41:1187-206. 3. Balagura S, Frantz AG, Housepian EM, Carmel PW. The specificity of serum prolacfin as a diagnostic indicator of pituitary adenoma. J Neurosurg 1979;51:42-6.
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4. Bradfield JS, Perez CA. Pineal tumors and ectopic pinealomas: analysis of treatment and failures. Radiology 1972;103:399-406. 5. Cammani F, Genazzani AR, Massara F, La Rosa R, Cocchi D, Muller EE. Prolactin-releasing effect of domperidone in normoprolactinemic and hyperprolactinemic subjects. Neuroendocrinology 1980;30:2-6. 6. Camins MB, Mount LA. Primary suprasellar atypical teratoma. Brain 1974;97:447-56. 7. Dayan An, Marshall AHE, Miller AA, Pick FJ, Rankin NE. Atypical teratomas of the pineal and hypothalamus. J Pathol Bacteriol 1966;92:1-28. 8. Dupont MG, Gerard JM, Flament-Durand J, Baleriaux-Waha D, Mortelmans LL. Pathognomonic aspect of germinoma on CT scan. Neuroradiology 1977;14:209-11. 9- Fowler FD, Alexander E, Jr, David CH. Pinealomas with metastases in the central nervous system: rationale of treatment. J Neurosurg 1956;13:271-88. 10. Friedman NB. Germinoma of the pineal--its identity with germinoma Cseminoma") of the testis. Cancer Res 1947;7:363-9. 11. Fukushima K. Tumors of the diencephalon and precocious puberty. Arch FJap Chir 1958;27:553-78. 12. GhatakNR, HiranoA, ZimmermanHM. Intrasellargerminomas: a form of ectopic pinealoma. J Neurosurg 1969;31:670-5. 13. Horrax G, Wyatt JP. Ectopic pinealomas in the chiasmal region: report of 3 cases. J Neurosurg 1947;4:309-26. 14. Horrax G. Treatment of tumors of the pineal body: experience in a series of 22 cases. Arch Neurol Psychiatry 1950;64:227-42. 15. Izquierdo JM, Rougerie J, Lapras C, Sanz F. The so-called ectopic pinealomas: a cooperative study of 15 cases. Child's Brain 1979;5:505-12. 16. Jellinger K. Primary intracranial germ cell tumours. Acta Neuropathol (Berl) 1973;25:291-306. 17. Jenkin RDT, Simpson WJK, Keen CW. Pineal and suprasellar germinomas. J Neurosurg 1978;48:99-107. 18. Jenkins JS, Gilbert CJ, Ang V. Hypothalamic-pituitary function in patients with craniopharyngiomas. J Clin Endocrinol Metab 1976;43:394-9. 19. Kageyama N, Belsky R. Ectopic pinealoma in the chiasma region. Neurology 1961;11:318-27. 20. Kageyama N. Ectopic pinealoma in the region of the optic chiasm: report of five cases. J Neurosurg 1971;35:755-9. 21. Kleinberg DL, Noel GL, Frantz AG. Galactorrhea: a study of 235 cases, including 48 with pituitary tumors. N Engl J Med 1977;296:589-600. 22. Koide O, Watanabe Y, Sato K. A pathological survey of intracranial germinoma and pinealoma in Japan. Cancer 1980; 45:2119-30. 23. Lewis I, Baxter DW, Stratford JG. Atypical teratomas of the pineal. Can Med Assoc J 1963;89:103-10. 24. Marcovitz S, Goodyer CG, Guyda H, Gardiner RJ, Hardy J. Comparative study of human fetal, normal adult, and somatotropic adenoma pituitary function in tissue culture. J Clin Endocrinol Metab 1982;54:6-16. 25. Molitch ME, Reichlin S. The amenorrhea, galactorrhea and hyperprolactinemia syndromes. In: Stollerman GH, ed. Advances in internal medicine. Vol 26. Chicago: Year Book Medical Publishers, 1980:37-65. 26. Murphy BEP. Some studies of the protein binding of steroids and their application to the routine micro and ultramicro measurement of various steroids in body fluids by competitive protein-binding radioassay. J Clin Endocrinol Metab 1967;27:973-90. 27. Neuwelt EA, Glasberg M, Frenkel E, Clark WK. Malignant pineal region tumors: a clinico-pathological study. J Neurosurg 1979;51:597-607.
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28. Penny R, Blizzard RM, Davis WT. Sequential arginine and insulin tolerance tests on the same day. J Clin Endocrinol Metab 1969;29:1499-501. 29. Pomarede R, Czernichow P, FinidoriJ, Pfister A, Roger M, Kalifa C, Zucker JM, Pierre-Kahn A, Rappaport R. Endocrine aspects and tumoral markers in intracranial germinoma: an attempt to delineate the diagnostic procedure in 14 patients. J Pediatr 1982;101:374-8. 30. Post KD, Kasdon DL. Sellar and parasellar lesions mimicking adenoma. In: Post KD, Jackson IMD, Reichlin S, eds. The pituitary adenoma. New York: Plenum Medical 1980:159-216. 31. Richards GE, Wara WM, Grumbach MM, Kaplan SL, Sheline GE, Conte FA. Delayed onset of hypopituitarism: sequelae of therapeutic irradiation of central nervous system, eye, and middle ear tumors. J Pediatr 1976;89:553-9. 32. Rubin P, Kramer S. Ectopic pinealoma: A radiocurable neuroendocrinologic entity. Radiology 1965;85:512-23. 33. Russell DS. The pinealoma: its relationship to teratoma. J Pathol Bacteriol 1944;56:145-50. 34. Russell DS. "Ectopic pinealoma": its kinship to atypical teratoma of the pineal gland. Report of a case. J Pathol Bacteriol 1954;68:125-9. 35. Russell WO, Sachs E. Pinealoma: a clinicopathologic study of 7 cases with a review of the literature. Arch Pathol 1943;35:869-88. 36. Samaan NA, Bakdash MM, Caderao JB, Cangir A, Jesse RH, Ballantyne AJ. Hypopituitarism after external irradiation: evidence for both hypothalamic and pituitary origin. Ann Intern Med 1975;83:771-7. 37. Scully RE, Galdabini JJ, McNeely BU. Case records of the Massachusetts General Hospital (case 38-1975). N Engl J Med 1975;293:653-60. 38. Shalet SM, Beardwell CG, Pearson D, Jones MPH. The effect
Marcovitz et al
39. 40.
41.
42. 43.
44. 45. 46.
47.
48.
of varying doses of cerebral irradiation on growth hormone production in childhood. Clin Endocrinol 1976;5:287-90. Simson LR, Lampe I, Abell MR. Suprasellar germinomas. Cancer 1968;22:533-44. Sklar CA, Grumbach MM, Kaplan SL, Conte FA. Hormonal and metabolic abnormalities associated with central nervous system germinoma in children and adolescents and the effect of therapy: report of 10 patients. J Clin Endocrinol Metab 1981;52:9-16. Spiegel AM, Di Chiro G, Gorden P, Ommaya AK, Kolins J, Pomeroy TC. Diagnosis of radiosensitive hypothalamic tumors without craniotomy. Endocrine and neurologic studies of intracranial atypical teratomas. Ann Intern Med 1976;85:290-3. Starck H. Tumor der glandula pinealis und des hypophysis gebietes. Zentrabl Gesell Neurol Psychiat 1928;48:72-3. Sung DI, Harisiadis L, Chang CH. Midline pineal tumors and suprasellar germinomas: highly curable by irradiation. Radiology 1978;128:745-51. Takeuchi J, Handa H, Nagata I. Suprasellar germinoma. J Neurosurg 1978;49:41-8. Troland CE, Brown CA. Precocious puberty ofintracranialorigin. J Neurosurg 1948;5:541-55. Turpin G, Metzger J, Bataini J, de Gennes JL. Etude clinique, biologique, radiologique et therapeutique de 3 tumeurs hypothalamiques. Ann Endocrinol (Paris) 1979;40:371-84. Wara WM, Fellows CF, Sheline GE, Wilson CB, Townsend JJ. Radiation therapy for pineal tumors and suprasellar germinomas. Radiology 1977;124:221-3. Wara WM, Jenkin RDT, Evans A, Ertel I, Hiltle R, Ortega J, Wilson CB, Hammond D. Tumors of the pineal and supersellar region: children's cancer study group treatment results 1960-1975. Cancer 1979;43:698-701.
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Intrasellar Germinoma Associated with Hyperprolactinemia S o r a n a M a r c o v i t z , M . D . , H a r v e y J. G u y d a , M . D . , M o r r i s o n H . F i n l a y s o n , M . D . , Roberto
Wee, M.D., and Jules Hardy, M.D.
Divisions of Endocrinology, Neuropathology, Radiology, and Neurosurgery, Montreal General Hospital and Montreal Children's Hospital, McGill University, and University of Montreal, Montreal, Quebec, Canada
Marcovitz S, Guyda HJ, Finls.ysonMH, Wee R, Hardy J. Intrasellar germinoma associated with hTperprolactinemia.Surg Neurol 1984;22:387-96. We report two young adult patients with hyperprolactinemia and neuroendocrine deficits due to predominantly intrasellar germinomas. In both cases the diagnosis of germinoma was confirmed histologically after transsphenoidal surgery. This very rare type of tumor may be intraseUar and it may mimic prolactinoma or craniopharyngioma. Dynamic testing of pituitary function and computed tomography scanning are of value in the early detection of this malignant but radiocurable lesion. KEY WORDS: Germinoma; Hyperprolactinemia; Hypopituitarism; Intrasellar tumor; Computed tomography; Dynamic pituitary function testing
Intracranial germinoma (also called ectopic pinealoma) is a rare lesion ( 0 . 5 % - 2 . 0 % of primary intracranial neoplasms [16]), which can arise in the region of the hypothalamus or o f the !pituitary stalk and present with neuroendocrinologic problems. Intrasellar germinomas are rarer still and not widely recognized: we were able to find only 33 documented cases in a search through the literature [1,2,4,11-13,17,19,23,29,32,33,35,39, 4 3 - 4 5 ] , and most of these were published before the era of prolactin radioimmunoassays and computed tomography scanning. In this paper we report the first two cases o f intrasellar germinoma associated with hyperprolactinemia. This entity can mimic prolactin-secreting adenoma or craniopha;yngioma, but an accurate diagnosis is essential because germinomas respond well only to radiotherapy.
Address reprint requests to. Dr. S. Marcovitz,Division of Endocrinology, Montreal General Hospital, 1650 Cedar Avenue, Montreal, Canada, H3G 1A4.
© 1984 by ElsevierSciencePublishingCo., Inc.
Case Reports Case 1
This 19-year-old male patient was first examined at the Montreal Children's Hospital when he was 8 years old; he had presented with enuresis and was found to have central diabetes insipidus. Skeletal survey and skull x-ray films at that time were normal. On arginine stimulation, the peak serum growth h o r m o n e (GH) had been 6.5 ng/mL, which was considered borderline adequate. Treatment was begun with pitressin tannate in oil with good response. The patient was then lost to our observation for about 5 years. In July 1975 (chronological age, 13%2) he returned with a new complaint of failure to grow; G H deficit was documented by an insulin-arginine challenge (peak G H value less than 1 ng/mL). The test was repeated after pretreatment with ethinyl estradiol 50 tzg p.o. twice a day for 3 days, and G H deficit was confirmed (peak G H level 3.0 ng/mL). H e was then started on human growth hormone therapy. In 1977, the cortisol response to hypoglycemia was borderline (baseline 3.25 la.g/dL and peak value 11.0 tzg/dL), and moderate hyperprolactinemia (baseline 38 ng/mL and peak value 39 ng/mL) was documented. A thyrotropin-releasing hormone (TRH) test elicited a normal thyrotropin (TSH) response (baseline 3.9 tzU/mL rising to 25.0 tzU/mL), although the serum thyroxine was borderline-low at 4.0/*g/dL (normal range, 4 - 1 1 tzg/dL) and this was interpreted as mild tertiary hypothyroidism; the serum prolactin was again elevated and showed a blunted response to thyrotropin-releasing hormone (baseline 55 ng/mL and peak value 75 ng/mL). Thyroxine (T4) replacement therapy was begun at this time. In 1978 the cortisol response to hypoglycemia was deficient (baseline 1.25 txg/dL and peak value 2.0/~g/dL and cortisone acetate (5 mg p.o. three times a day) supplements were started. At age 17 years the patient had not developed any signs of puberty. A gonadotropinreleasing hormone (LRH) test in December 1978 showed him to be gonadotropin deficient (baseline luteinizing hormone (LH) and follicle-stimulating hormone (FSH) 2.4 ~g/dL and 5.0 I-~g/dL respectively and peak values 0090-3019/84/$3.00
388
Surg Neurol 1984;22:387-96
2.2 ~o/dL and 7.2 ~g/dL respectively). H e was begun on depo-testosterone in April 1979. X-ray films o f the skull over the years had remained normal. A computed tomography scan done at the Montreal Children's Hospital in August 1979 (DELTA-50 FS scanner, Ohio Nuclear) was also normal. However, there was continuing concern about a possible hypothalamic lesion because serum prolactin levels had gradually risen to 100 ng/mL by February 1981. Thus in April 1981 he was referred to the Montreal General Hospital for another computed tomography scan, which was done with a new EMI CT 7070 scanner. This computed tomography scan (Figure 1) demonstrated a thick pituitary stalk with a fleck o f calcification within it; the pituitary gland was small. Contrast-medium injection (Figure 2) resulted in dense enhancement of the thick stalk and a small area within the gland. Tomograms o f the sella turcica were again normal. The patient was referred for an operation with a suspected diagnosis o f craniopharyngioma. Before operation he reported mild recurrent headaches, but no other new symptoms. Fundoscopy and formal (Goldmann) testing of the visual fields were normal. Because the lesion seen on the computed tomography scan was partially within the sella and the suprasellar portion was small, a transsphenoidal surgical approach was chosen. Greyish gristlelike tumor material was identified in the center of the gland and was removed piecemeal. The tumor was firmly adherent to a mass of geFigure 1. Case 1: Coronal computed tomography scan (EMI CT 7070) of sella from the tuberculum (a) to dorsum (d). Note the small calcification in the suprasellar mass (arrow) in (c) and the markedly thickened pituitary stalk in (d).
Marcovitz et al
Figure 2. Repeat computed tomography scan after contrast injection (Conray 60%, 1 mL/lb body weight) in patient I demonstrates enhancement of the suprasellar mass (b-d). Note enhanced area within the gland in (b). latinous tissue that resembled an enlarged pituitary stalk. Due to congenital absence of the diaphragma seUae, the tumor removal resulted in the opening of the third ventricle, necessitating duroplasty with lyophilized dura. The course after the operation was uneventful, and the serum prolactin decreased to 16 ng/mL; the patient was continued on hormonal replacement therapy and continued to require pitressin (DDAVP) for persistent diabetes insipidus. Pathological study of the tissue removed at the operation showed posterior lobe o f pituitary infilrated by a neoplastic germ cell tumor (Figure 3). Cerebrospinal fluid cytology 3 weeks after the operation was negative. The patient was given radiotherapy in a course of 5000 rads (4000 rads to the whole brain and an additional 1000 rads to the region of the third ventricle) over 5 weeks. H e has remained well and was last seen in D e c e m b e r 1983.
Case 2
The second patient was a 21-year-old woman who presented at age 18 years with primary amenorrhea. She had had a healthy childhood, and at age 13 had noted growth o f axillary and pubic hair and beginning o f breast development. At the time o f presentation she was 162.5 cm tall, but relatively short compared with family members (mother, 172.7 cm; father, 190.5 cm; brother, 188 cm; younger brother, 183 cm). She was examined at the Health Sciences Center o f the State University of N e w
Germinoma with Hyperprolactinemia
Surg Neurol 1984;22:387-96
389
A
Figure 3. (A) Electron micrograph of seminomalike cells invading the pituitary of case 1. A portion of a plasma cell is also seen (open arrow). The solid arrow indicates glycogen granules (× 14,000). (B) Microphotograph of germinoma showing large tumor cells (one in mitosis) interspersed with mononuclear inflammatory cells (H & E; x 800).
B
York at Stony Brook; serum follicle-stimulating hormone (11.5 mIU/mL), luteinizing hormone (13.5 mIU/mL), prolactin (17.4 ng/mL), and thyroid-stimulating hormone (4.3 /.~U/mL) were all normal. X-ray examination of the sella turcica and gross visual field examination by confrontation were also normal. She was given a 6-month trial of therapy with conjugated estrogens and medroxyprogesterone acetate, which resulted in vaginal bleeding; subsequently she had no spontaneous menses. She was then followed-up with serial serum gonadotropins and prolactin measurements. In January 1981 (2.5 years after presentation), her prolactin level became elevated (43 ng/mL). Subsequent formal examination of the visual fields was abnormal and a computed tomography scan showed a mass within the sella turcica with suprasellar expansion. The patient was
390
Surg Neurol 1984;22:387-96
then referred for a transsphenoidal operation in June 1981 with a tentative diagnosis of prolactin-secreting adenoma or craniopharyngioma. The patient had never had galactorrhea. Several months before the operation she had begun to have frequent, rather severe bifrontal headaches and increased fatiguability. Before the transsphenoidal operation at the Montreal General Hospital, she underwent testing of pituitary function with insulin hypoglycemia, apomorphine, thyrotropin-releasing hormone, and gonadotropin-releasing hormone, which showed her to have deficits of growth hormone (peak values of 0.9 ng/mL and 1.0 ng/mL, on apomorphine and insulin hypoglycemia challenges, respectively), luteinizing hormone and follicle-stimulating hormone (baseline values 6 and 7 mIU/mL, respectively, and peak values 4 and 6 mIU/mL respectively), and elevated basal prolactin of 35-40 ng/mL; prolactin was suppressed by apomorphine (baseline value, 36 ng/mL and nadir, 13 ng/mL), but it did not quite double after thyrotropin-releasing hormone (39 ng/mL rising to 74 ng/mL) and did not rise significantly on insulin hypoglycemia challenge (baseline 35 ng/mL and peak value 39 ng/mL); basal plasma cortisol was low (2.4 /zg/dL) and unresponsive to hypoglycemia (peak value, 3.3 /zg/mL); thyrotropin response to thyrotropin-stimulating hormone was adequate (3.5/~U/mL, rising to 26 ~U/mL), though the concomitant serum T4 was somewhat low at 3.3 p,g/dL (normal range for assay was 5.0-13.7 /~g/dL), as was the adjusted T4 at 3.1 /~g/dL (normal, 4.4-14.4); serum T3 was 115 ng/dL (normal 65-200). Examination of the visual fields confirmed bitemporal hemianopsia. A film series of the skull and lateral tomograms of the sella turcica showed no evidence of raised intracranial pressure and no intracranial calcifications; the sella turcica was of normal size, but it showed undercutting of the tuberculum on the right side. A computed tomography scan after contrast medium injection showed an enhancing mass within the sella and in the suprasellar region, with a 5-mm, low-density, nonenhancing area within it (Figure 4). During the operation, a greyish purple tumor with a necrotic area in the lower portion was found and totally excised. The suprasellar expansion was rather firm and gristlelike and adherent to the arachnoid. After total excision of the tumor tissue, an enlarged pituitary stalk was identified. Normal-appearing pituitary tissue was seen and left intact. The patient received corticosteroid therapy for 5 days, and her course after the operation was uneventful. Dynamic pituitary function testing was repeated 9 and 10 days after the operation (4 days after corticosteroid therapy ended). The results were unchanged compared with the preoperative ones aside from the serum pro-
Marcovitz et al
Figure 4. Case 2: Coronal computed tomography scan after contrast medium injection shows an enhanced mass within the sella turcica and filling the suprasellar cistern to the level of the horizontal segment of the anterior cerebral arteries. Irregularly shaped area in the lower portion of the mass is not enhanced. (Technique as for Figures 1 and 2.)
lactin, which had decreased to 1-2 ng/mL, and the finding of a new thyrotropin deficit (basal value 1 /zU/mL and peak level 2 /zU/mL). The patient was then begun on replacement therapy of cortisone acetate, thyroxine, and estrogen and progesterone. Pathological study of the tissue removed at the operation showed germinoma infiltrating the normal anterior pituitary and surrounding fibrous tissue. Cerebrospinal fluid cytologic findings after the operation were normal, and the patient subsequently received radiation therapy with a total of 4600 rads (3000 rads to the whole brain and an additional 1600 rads to the region of the third ventricle) given over 6 weeks. This was well tolerated. She has remained well on the hormonal replacement therapy with no evidence of recurrence; she was last examined in August of 1983. Methods and Results Endocrinology
Dynamic testing of pituitary function at the Montreal General Hospital (case 2) consisted of studying responses to insulin hypoglycemia, apomorphine, thyrotropin-releasing hormone (TRH), and gonadotropin-releasing hormone (LRH) separately in the resting, fasting state both before and after the operation, as previously described [24]. The plasma samples were kept frozen
Germinoma with Hyperprolactinemia
at - 2 0 ° C until they were processed for radioimmunoassay of growth hormone (GH), prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyrotropin (TSH), or corti~ol at the Clinical Endocrinology Laboratory of the Montreal General Hospital [24]. Dynamic testing of pituitary function at the Montreal Children's Hospital was carried out according to similar protocols for thyrotropin-releasing hormone and gonadotropin-releasing hormone. Provocative testing for evaluation of growth hormone reserve and reserve of the pituitary-adrenocortical axis was done with a combined insulin (0.05 U/kg i.v.) and arginine (0.5 g/kg, up to 25 g i.v.) test [28]. Plasma samples were kept frozen at - 20°C until processed for radioimmunoassay of growth hormone (National Institutes of Health 1652 C standard), prolactin (Friesen 72-4-9 standard), luteinizing hormone (LER 907 standard), follicle-stimulating hormone (LER 907 standard), thyrotropin (TSH) (human TSH standard obtained from the International Laboratory for Biological Standards, Hampstead Laboratories, Holy Hill, London, England), or for competitive protein binding assay [26] of cortisol.
Pathology The tissue removed surgically was fixed in formalin except for small samples t]~at were fixed in gluteraldehyde and embedded in Epon for electron microscopic examination. Sections of formalin-fixed, paraffin-embedded tissue were stained with hematoxylin and eosin, periodic-acid-Schiff (PAS) (some after diastase treatment), by Herlant's method, and by Pearse's performic acid, alcian blue, and orange C method. On microscopic examination, the tissue resected from both patients had much the.same appearance. There was considerable fibrosis in and around the anterior pituitary, and a patchy mononuclear cell inflammatory infiltrate. Large, pale tumor cells were seen scattered or in small groups among the mononuclear cells. The posterior lobe was more e'ctensively invaded by this bicellular infiltrate than the anterior lobe. The cytoplasm of the large tumor cells was strongly PAS positive, and this property was removed by diastase digestion; many of these cells were in mitosis (Figure 3). On electron microscopic examination, the large cells contained many glycogen granules (Figure 3), and also small cytoplasmic lipid droplets, moderate numbers of small mitochondria, and occasional single strands or small parallel arrays of endoplasmic reticulum. Nuclear chromatin tended to be evenly dispersed, and the nucleoli were prominent and sometimes multiple. The mononuclear cells were found to be lymphocytes and plasma
Surg Neurol 1984;22:387-96
391
cells in about equal numbers; there were also a few macrophages.
Discussion The patients described both had hyperprolactinemia and tumors located within the sella turcica in continuity with the suprasellar region. The light and electron microscopic features of the tumors were typical of the seminomalike type ofgerminoma (also referred to as ectopic pinealoma or ectopic pineal germinoma) [10,22,33,34]. In both patients the radiologic and surgical findings were those of a predominantly intrasellar tumor, but because of the finding of suprasellar extension one cannot rule out the possibility that the sellar involvement was in fact secondary to a germinoma that arose originally near the optic chiasm. Intracranial germinomas outside the pineal gland are rare; in our review of the literature we have found a total of only 164 histologically documented cases [ 1-4,6,7, 11-13,15,17,19,20,23,29,32,33,35,37,39-46]. Most of these patients were diagnosed late in their course, and very few had undergone detailed endocrinologic investigations. In retrospect, the first case of suprasellar germinoma was described by Starck in 1928, which was before the recognition of intracranial germinomas as a pathological entity [10,34]. Intrasellar germinomas are rarer still, and they have not been widely recognized. In the proposed classification of extrapineal germinomas [19], the lack of seUar involvement was considered as one of the important criteria in differentiating between these tumors and pituitary adenomas. In reviewing the reported series, however, we were able to find 33 histologically proven cases ofgerminoma with radiologic or pathological evidence of tumor within the sella turcica and their main features are listed in Table 1; data from individual patients were available for only 21 of the cases. The equal sex distribution (nine males, 12 females) is similar to that reported for suprasellar germinomas [6,19,32,44], whereas primary pineal germinomas occur mostly in males [4,44]. The patients were all between 8 and 22 years of age at the time of diagnosis, and five of them had long durations of symptoms (7, 4, 4, 7, and 9 years, respectively) like our patients; 19 of 21 patients had visual abnormalities. As shown in Table 1, at least 15 of the patients had some evidence of pituitary hypofunction, and two had precocious puberty; however, information about the endocrine aspects is scant in the published reports and many of the cases (eight were seen before 1950) had minimal if any laboratory investigations; prolactin measurements were not done in any of these patients. In
392
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Marcovitz et al
contrast to our two cases, in the instances where radiologic evidence of sellar enlargement was obtained, it was based on changes gross enough to be seen on plain x-ray films of the skull, pneumoencephalography, or ventriculography; none o f the previously reported patients with intrasellar germinomas had computed tomography scans. Nine published cases of histologically proven intracranial germinomas associated with hyperprolactinemia are listed in Table 2; none of these patients had tumor within the sella turcica. Several patients in this group had computed tomography scans, and all of these were found to have isodense lesions that showed enhancement after injection of contrast material, as had been described previously [8]. O f special interest in relation to our first case was the finding that suprasellar calcifications were previously detected radiographically in only two patients with suprasellar germinomas [43]. In 1969, however, Ghatak et al had reported the histologic finding o f specks of calcium within one of their intrasellar germinomas and predicted that such calcific deposits might lead to an erroneous radiologic diagnosis o f craniopharyngioma. The early cases of intracranial germinomas only treated surgically had dismal rates o f survival (e.g., Table 1). Since the recognition o f the efficacy of radiation therapy [14,32,45] this has become the accepted mode of treatment, with reported 5-year survival rates of 6 9 % - 7 7 % in several series [4,17,37,43,48]. Prophylactic irradiation o f the spinal cord [9] and chemotherapy [27,37] have been suggested by some authors, but these have not gained wide acceptance. The effects of radiotherapy on the pituitary deficits associated with suprasellar or
intrasellar germinomas have not been studied extensively. Sklar et al assessed the endocrine status o f six patients with histologically proven suprasellar germinomas after radiotherapy and found no recovery of preexisting pituitary deficits nor documentable instances of new pituitary dysfunction; however, the interval since completion of radiotherapy was relatively short for several of these patients; according to other reported experience [31,36,38] they might still be at risk for developing radiation-induced pituitary deficits. In the past, the diagnosis of intrasellar or suprasellar germinoma was often not made until autopsy. This was probably due in large part to the limitations of the radiologic techniques then available. As seen in our cases and in several other recent cases mentioned above, computed tomography scanning is extremely valuable in demonstrating these lesions, particularly if the scans are obtained in the coronal plane; but it may not be possible to differentiate between adenoma, craniopharyngioma, meningioma and germinoma on the basis of the appearance on computed tomography scan [30]. Another reason for the very poor survival in the early cases was the lack of recognition and treatment o f the endocrine abnormalities, which in many instances--including our two patients--were responsible for the initial symptoms up to several years before diagnosis. Recent advances in neuroendocrinology with widespread availability of radioimmunoassays for pituitary hormones and dynamic pituitary function testing should make it possible to detect and treat the endocrine manifestations ofgerminomas in the sellar region at an early stage. It is to be hoped that early radiotherapy given before the development of extensive pituitary deficits
Table 2. Cases of lntracranial Germinomas with Hyperprolactinemia Source Spiegel et al, 1976 Spiegel et al, 1976 Sklar et al, 1 9 8 1 (case 1) Sklar et al, 1981 (case 3) Sklar et al, 1 9 8 1 (case 4) Sklar et al, 1 9 8 1 (case 5) Sklar et al, 1981 (case 7) Balagura et al, 1979 Balagura et al, 1979
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G e r m i n o m a with Hyperp~rolactinemia
and visual loss will improve the total outcome in these radiocurable tumors. As we have seen in our cases, hyperprolactinemia may be associated with germinomas in the pituitary region, and potentially it can 1,2ad one to a wrong diagnosis of adenoma. The hyperprolactinemia in these cases is presumably due to interfi.=rence with normal delivery of prolactin-inhibiting factor to the adenohypophysis, as has been postulated in cases o f craniopharyngioma, meo ningioma, third ventricle tumors, aneurysms, and hypothalamic disease [3:~18,21]. However, the blunted prolactin responses to thyrotropin-releasing hormone (especially in case 1) found in these patients resembled those seen in prolactin-secreting adenomas [21] rather than the "stalk-section phenomenon," and we have also observed blunted responses in several cases of craniopharyngioma (Marcoviitz et al, unpublished observations); thus the prolactin response to thyrotropinreleasing hormone may not always be useful in distinguishing between various causes of hyperprolactinemia. Diagnostic tests with dopamine agonists and antagonists have been proposed to differentiate between hyperprolactinemia due to prolactin-secreting adenomas and that due to other causes, but the data are insufficient to use these tests as a means of distinguishing between adenomas and hypothalamic or stalk lesions [5,25]. Based on our two cases we suggest that patients presenting with diabetes insipidus, hypogonadotropic hypogonadism, or hyperprolactinemia should routinely have dynamic testing for a.ssessment of anterior pituitary functional reserve, and high-resolution computed tomography scans should be done even if x-ray films of the skull and sellar tomograms are normal. A finding of an enhancing mass with suprasellar expansion in a young patient with only moderately elevated serum prolactin may be a reason for considering the diagnosis of germinoma, and it shouild be an indication for recommending surgical intervention to obtain a tissue diagnosis for planning definitive therapy.
The authors wish to thank Dr. Z. Rosenwaks for referring the second patient.
References 1. Akamatu H. Ein fall yon primarem pinealom aus der hypothalamus-infundibulumgegend. Gann 1939;33:371-81. 2. Baggenstoss AH, Love JG. Pinealomas. Arch Neurol Psychiatry 1939;41:1187-206. 3. Balagura S, Frantz AG, Housepian EM, Carmel PW. The specificity of serum prolacfin as a diagnostic indicator of pituitary adenoma. J Neurosurg 1979;51:42-6.
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4. Bradfield JS, Perez CA. Pineal tumors and ectopic pinealomas: analysis of treatment and failures. Radiology 1972;103:399-406. 5. Cammani F, Genazzani AR, Massara F, La Rosa R, Cocchi D, Muller EE. Prolactin-releasing effect of domperidone in normoprolactinemic and hyperprolactinemic subjects. Neuroendocrinology 1980;30:2-6. 6. Camins MB, Mount LA. Primary suprasellar atypical teratoma. Brain 1974;97:447-56. 7. Dayan An, Marshall AHE, Miller AA, Pick FJ, Rankin NE. Atypical teratomas of the pineal and hypothalamus. J Pathol Bacteriol 1966;92:1-28. 8. Dupont MG, Gerard JM, Flament-Durand J, Baleriaux-Waha D, Mortelmans LL. Pathognomonic aspect of germinoma on CT scan. Neuroradiology 1977;14:209-11. 9- Fowler FD, Alexander E, Jr, David CH. Pinealomas with metastases in the central nervous system: rationale of treatment. J Neurosurg 1956;13:271-88. 10. Friedman NB. Germinoma of the pineal--its identity with germinoma Cseminoma") of the testis. Cancer Res 1947;7:363-9. 11. Fukushima K. Tumors of the diencephalon and precocious puberty. Arch FJap Chir 1958;27:553-78. 12. GhatakNR, HiranoA, ZimmermanHM. Intrasellargerminomas: a form of ectopic pinealoma. J Neurosurg 1969;31:670-5. 13. Horrax G, Wyatt JP. Ectopic pinealomas in the chiasmal region: report of 3 cases. J Neurosurg 1947;4:309-26. 14. Horrax G. Treatment of tumors of the pineal body: experience in a series of 22 cases. Arch Neurol Psychiatry 1950;64:227-42. 15. Izquierdo JM, Rougerie J, Lapras C, Sanz F. The so-called ectopic pinealomas: a cooperative study of 15 cases. Child's Brain 1979;5:505-12. 16. Jellinger K. Primary intracranial germ cell tumours. Acta Neuropathol (Berl) 1973;25:291-306. 17. Jenkin RDT, Simpson WJK, Keen CW. Pineal and suprasellar germinomas. J Neurosurg 1978;48:99-107. 18. Jenkins JS, Gilbert CJ, Ang V. Hypothalamic-pituitary function in patients with craniopharyngiomas. J Clin Endocrinol Metab 1976;43:394-9. 19. Kageyama N, Belsky R. Ectopic pinealoma in the chiasma region. Neurology 1961;11:318-27. 20. Kageyama N. Ectopic pinealoma in the region of the optic chiasm: report of five cases. J Neurosurg 1971;35:755-9. 21. Kleinberg DL, Noel GL, Frantz AG. Galactorrhea: a study of 235 cases, including 48 with pituitary tumors. N Engl J Med 1977;296:589-600. 22. Koide O, Watanabe Y, Sato K. A pathological survey of intracranial germinoma and pinealoma in Japan. Cancer 1980; 45:2119-30. 23. Lewis I, Baxter DW, Stratford JG. Atypical teratomas of the pineal. Can Med Assoc J 1963;89:103-10. 24. Marcovitz S, Goodyer CG, Guyda H, Gardiner RJ, Hardy J. Comparative study of human fetal, normal adult, and somatotropic adenoma pituitary function in tissue culture. J Clin Endocrinol Metab 1982;54:6-16. 25. Molitch ME, Reichlin S. The amenorrhea, galactorrhea and hyperprolactinemia syndromes. In: Stollerman GH, ed. Advances in internal medicine. Vol 26. Chicago: Year Book Medical Publishers, 1980:37-65. 26. Murphy BEP. Some studies of the protein binding of steroids and their application to the routine micro and ultramicro measurement of various steroids in body fluids by competitive protein-binding radioassay. J Clin Endocrinol Metab 1967;27:973-90. 27. Neuwelt EA, Glasberg M, Frenkel E, Clark WK. Malignant pineal region tumors: a clinico-pathological study. J Neurosurg 1979;51:597-607.
396
Surg N e u r o l 1984;22:387-96
28. Penny R, Blizzard RM, Davis WT. Sequential arginine and insulin tolerance tests on the same day. J Clin Endocrinol Metab 1969;29:1499-501. 29. Pomarede R, Czernichow P, FinidoriJ, Pfister A, Roger M, Kalifa C, Zucker JM, Pierre-Kahn A, Rappaport R. Endocrine aspects and tumoral markers in intracranial germinoma: an attempt to delineate the diagnostic procedure in 14 patients. J Pediatr 1982;101:374-8. 30. Post KD, Kasdon DL. Sellar and parasellar lesions mimicking adenoma. In: Post KD, Jackson IMD, Reichlin S, eds. The pituitary adenoma. New York: Plenum Medical 1980:159-216. 31. Richards GE, Wara WM, Grumbach MM, Kaplan SL, Sheline GE, Conte FA. Delayed onset of hypopituitarism: sequelae of therapeutic irradiation of central nervous system, eye, and middle ear tumors. J Pediatr 1976;89:553-9. 32. Rubin P, Kramer S. Ectopic pinealoma: A radiocurable neuroendocrinologic entity. Radiology 1965;85:512-23. 33. Russell DS. The pinealoma: its relationship to teratoma. J Pathol Bacteriol 1944;56:145-50. 34. Russell DS. "Ectopic pinealoma": its kinship to atypical teratoma of the pineal gland. Report of a case. J Pathol Bacteriol 1954;68:125-9. 35. Russell WO, Sachs E. Pinealoma: a clinicopathologic study of 7 cases with a review of the literature. Arch Pathol 1943;35:869-88. 36. Samaan NA, Bakdash MM, Caderao JB, Cangir A, Jesse RH, Ballantyne AJ. Hypopituitarism after external irradiation: evidence for both hypothalamic and pituitary origin. Ann Intern Med 1975;83:771-7. 37. Scully RE, Galdabini JJ, McNeely BU. Case records of the Massachusetts General Hospital (case 38-1975). N Engl J Med 1975;293:653-60. 38. Shalet SM, Beardwell CG, Pearson D, Jones MPH. The effect
Marcovitz et al
39. 40.
41.
42. 43.
44. 45. 46.
47.
48.
of varying doses of cerebral irradiation on growth hormone production in childhood. Clin Endocrinol 1976;5:287-90. Simson LR, Lampe I, Abell MR. Suprasellar germinomas. Cancer 1968;22:533-44. Sklar CA, Grumbach MM, Kaplan SL, Conte FA. Hormonal and metabolic abnormalities associated with central nervous system germinoma in children and adolescents and the effect of therapy: report of 10 patients. J Clin Endocrinol Metab 1981;52:9-16. Spiegel AM, Di Chiro G, Gorden P, Ommaya AK, Kolins J, Pomeroy TC. Diagnosis of radiosensitive hypothalamic tumors without craniotomy. Endocrine and neurologic studies of intracranial atypical teratomas. Ann Intern Med 1976;85:290-3. Starck H. Tumor der glandula pinealis und des hypophysis gebietes. Zentrabl Gesell Neurol Psychiat 1928;48:72-3. Sung DI, Harisiadis L, Chang CH. Midline pineal tumors and suprasellar germinomas: highly curable by irradiation. Radiology 1978;128:745-51. Takeuchi J, Handa H, Nagata I. Suprasellar germinoma. J Neurosurg 1978;49:41-8. Troland CE, Brown CA. Precocious puberty ofintracranialorigin. J Neurosurg 1948;5:541-55. Turpin G, Metzger J, Bataini J, de Gennes JL. Etude clinique, biologique, radiologique et therapeutique de 3 tumeurs hypothalamiques. Ann Endocrinol (Paris) 1979;40:371-84. Wara WM, Fellows CF, Sheline GE, Wilson CB, Townsend JJ. Radiation therapy for pineal tumors and suprasellar germinomas. Radiology 1977;124:221-3. Wara WM, Jenkin RDT, Evans A, Ertel I, Hiltle R, Ortega J, Wilson CB, Hammond D. Tumors of the pineal and supersellar region: children's cancer study group treatment results 1960-1975. Cancer 1979;43:698-701.