J Neurosurg 47:101-105, 1977
Human chorionic gonadotropin produced by ectopic pinealoma in a girl with precocious puberty Case report
OSAMI KUnO, M.D., NAOMI YAMASAKI, M.D., YASUO KAMIJO, M.D., KEIICHI AMANO, M.D., KOICHI KITAMURA, M.D., AND REIKO DEMURA, M.D. Departments of Neurosurgery and Internal Medicine, Tokyo Women's Medical College, Tokyo, Japan A case is reported in which a human chorionic gonadotropin (HCG)-producing ectopic pinealoma was found in a 5-year-old girl with precocious puberty. Physical examination revealed abnormal breast enlargement. Endocrinological study disclosed a high plasma HCG concentration of 1192 ng/ml with a normal follicular stimulating hormone (FSH) level. The HCG content of the tumor was as high as 400 ng/mg of acetone dried tissue, but no FSH was detectable. This is the first reported case of precocious puberty associated with pineal tumor in a female.
KEY WORDS 9 ectopic pinealoma human chorionic gonadotropin
HE causative mechanism of precocious puberty in patients with pineal-parasellar tumor is unknown. The pineal body, and dysfunction of the hypothalamus have been implicated, and recently, the ectopic secretion of human chorionic gonadotropin ( H C G ) from the tumor itself. P r e c o c i o u s p u b e r t y associated with pinealoma in the pineal-parasellar region has until now been seen exclusively in males. We are reporting the first such case in a young girl. We believe that precocious puberty in this patient was caused by an HCG-producing ectopic pinealoma of the anterior third ventricle, verified at surgery. The clinicopathological and endocrinological aspects of this rare case are briefly discussed.
T
J. Neurosurg. / Volume 47 / July, 1977
9 precocious puberty
9
Case Report This 5-year-old girl was admitted to our neurosurgical department on August 5, 1975, with complaints of headache, nausea, and vomiting. She had had a generalized convulsion 8 months before admission, and had begun to complain of progressive headache. She was found to have choked discs and was referred to our clinic. Family history and past history were noncontributory. Examination. She was a somewhat drowsy girl with normal physical development except for bilateral breast enlargement as shown in Fig. 1. Bone age was 5 years. The m a m m a r y gland was palpable and slightly tender but there was no nipple discharge. N o axillary or ]0]
O. Kubo, et al.
FIG. 1. Early development of the breasts.
pubic hair was seen. She had not experienced menarche and no clitoral enlargement was evident. A vaginal smear was not performed. Neurological examination showed bilateral choked discs but no focal neurological deficits. The visual acuity and fields were normal. Laboratory data revealed normal urinalysis, complete blood count, and serum electrolytes. A ventricular puncture performed soon after admission revealed an opening pressure of 400 mm H20, and grossly normal appearance of the cerebrospinal fluid (CSF). The CSF analysis showed protein 142 mg/dl,
FIG. 2. Dimer-X ventriculogram revealed a filling defect of the anterior third ventricle and no abnormalities of the pineal and suprapineal recesses. ]02
glucose 70 mg/dl, HCG 2000 ng/ml, and HCB-/3 146 ng/ml. Skull x-ray films showed diastasis of the sutures and erosion of the sella turcica. Right brachial angiogram showed straightening of the anterior cerebral artery, and stretching of the anterior choroidal, lenticulostriate, and thalamoperforating arteries. Dimer-X ventriculogram revealed a filling defect in the anterior floor of the third ventricle outlining the tumor but no abnormalities in the pineal and suprapineal recesses (Fig. 2). A ventriculoperitoneal shunt was performed on the fourth hospital day to relieve progressively increasing intracranial pressure. Operation. A right frontal craniotomy was performed 14 days after admission. A reddish-brown tumor was seen to fill most of the anterior third ventricle. Partial resection of the tumor was carried out by the transventricular approach. Postoperatively the patient was given a course of irradiation, with a total dose of 4350 rads. Breast enlargement had disappeared by the completion of radiotherapy. Histological Study. The surgical tissue was fixed in 10% formalin. The sections were stained with hematoxylin-eosin (H & E), PAS, and Azan. In the routine H & E preparation, the tumor tissue was seen to be composed of two types of cells, epithelioid cells and small cells like lymphocytes (Fig. 3). In the PAS preparation, fine granules were demonstrated in the epithelioid cells. Ectopic pinealoma of the two-cell pattern was diagnosed. Electron Microscopic Study. The specimens were immediately fixed in 2% glutaraldehyde, then fixed in 1% osmium tetroxide solution with phosphate buffer for 2 hours, dehydrated with a graded concentration of ethanol, and finally embedded in Epon 812. The ultrathin sections were stained with uranyl acetate followed by lead citrate. The specimen was examined with a Hitachi l i D electron microscope.* The electron micrograph of the tumor cells revealed both clear and dark cells. The most prominent finding was the presence of multiple electron-dense granules in the dark tumor *Hitachi I 1D electron microscope manufactured by Niseisangiyo Ltd., 2-Sakuragawa-cho, Shibanishikubo Minato-ku, Tokyo 105, Japan.
J. Neurosurg. / Volume 47 / July, 1977
Pinealoma and precocious puberty cells. They were round, uniform in shape, and measured approximately 500 m# (Fig. 4). Endocrinological Studies. We measured plasma luteinizing hormone (LH) and follicular stimulating hormone (FSH) by radioimmunoassay (RIA) using RIA kitst with a reference standard of 2nd IRP-HMG (International Reference Preparation-Human Menopausal Gonadotropin) (mlU/ml). The plasma HCG was measured by RIA with the RIA kit for HCG,~ expressed as ng/ml (1 mg is equivalent to 6600 IU of the 2nd ISHCG (International Standard-Human Chorionic Gonadotropin)). The LH and HCG cross reacted nonspecifically with each other and the LH kit measured HCG at about a half of LH and the HCG kit measured LH at about one-third of HCG. We measured the HCG-# subunit by RIA using an antibody against HCG-# subunit, which permits the selective measurement of H C G in the presence of physiologic amounts of LH. The plasma prolactin was measured by RIA with a Friesen No. 2 kit.w We measured plasma estradiol and testosterone by RIA using antisera raised in our laboratory. The tumor contents of gonadotropins were determined by RIA after the extraction of acetonedried tumor tissue with a modification of Hartree's method? The luteinizing hormonereleasing hormone ( L H - R H ) and thyrotropin releasing hormone (TRH) test was performed by the intravenous administration of 100 ug of L H - R H mixed with 10 izg/kg of TRH. During the test the patient was not allowed any food intake. Blood samples were drawn before and 30, 60, 90, and 120 minutes after the injection. Basal plasma levels of various hormones before and after surgical excision and radiotherapy of the tumor are shown in Table 1. The HCG and HCG-# values were markedly high and LH was also measured to be high #Radioimmunoassay kits for FSH manufactured by Daiichi Radioisotope Labs, Ltd., 10-5 Nihonbashi 3-chome, Chuo-ku, Tokyo 103, Japan. :~Radioimmunoassay kit for HCG manufactured by CEA-IRE-SORIN: CEA - - D6partement des Radio616ments, Gif-sur-Yvette, France; I R E Institut National des Radio616ments, 2400 Mol; SORIN Centro Ricerche Nucleari, Saluggia (Vercelli), Italy. w No. 2 kit was a gift of the National Institutes of Health, Bethesda, Maryland. -
-
J. Neurosurg. / Volume 47 / July, 1977
FIG. 3. A light microscopic finding of the resected tumor shows a typical two-cell pattern pinealoma. H & E, X 50.
before treatment but all of them decreased rapidly immediately after treatment. The basal level of FSH was at the upper limit of normal for age both before and 4 months after treatment. Estradiol was not detectable either before or after treatment. Plasma concentration of cortisol and thyroid hormones were normal. Figure 5 shows the response of HCG, LH, FSH, prolactin, and T S H to the LH-RH and T R H test. The HCG, LH, and FSH response to L H - R H was negative both
FIG. 4. Electron micrograph showing dark and clear cells. In the dark cell, secretory granules (G) with a diameter of about 500 mu were seen. X 5000. I03
O. Kubo,
e t al.
TABLE 1
Basal levels of various hormones before and after treatment* Hormone HCG (ng/ml) LH (mIU/ml) FSH (mlU/ml) prolactin (ng/ml) TSH (uU/ml) HGH (ng/ml) estradiol (pg/ml) testosterone (ng/dl) HCG-/3 (ng/ml)
Normal Range
Before Treatment
2 Months after Treatment
4 Months after Treatment
ND 2.8-5.4 2.4-6.6 2-20 1-6 1-6
Human chorionic gonadotropin produced by ectopic pinealoma in a girl with precocious puberty Case report
OSAMI KUnO, M.D., NAOMI YAMASAKI, M.D., YASUO KAMIJO, M.D., KEIICHI AMANO, M.D., KOICHI KITAMURA, M.D., AND REIKO DEMURA, M.D. Departments of Neurosurgery and Internal Medicine, Tokyo Women's Medical College, Tokyo, Japan A case is reported in which a human chorionic gonadotropin (HCG)-producing ectopic pinealoma was found in a 5-year-old girl with precocious puberty. Physical examination revealed abnormal breast enlargement. Endocrinological study disclosed a high plasma HCG concentration of 1192 ng/ml with a normal follicular stimulating hormone (FSH) level. The HCG content of the tumor was as high as 400 ng/mg of acetone dried tissue, but no FSH was detectable. This is the first reported case of precocious puberty associated with pineal tumor in a female.
KEY WORDS 9 ectopic pinealoma human chorionic gonadotropin
HE causative mechanism of precocious puberty in patients with pineal-parasellar tumor is unknown. The pineal body, and dysfunction of the hypothalamus have been implicated, and recently, the ectopic secretion of human chorionic gonadotropin ( H C G ) from the tumor itself. P r e c o c i o u s p u b e r t y associated with pinealoma in the pineal-parasellar region has until now been seen exclusively in males. We are reporting the first such case in a young girl. We believe that precocious puberty in this patient was caused by an HCG-producing ectopic pinealoma of the anterior third ventricle, verified at surgery. The clinicopathological and endocrinological aspects of this rare case are briefly discussed.
T
J. Neurosurg. / Volume 47 / July, 1977
9 precocious puberty
9
Case Report This 5-year-old girl was admitted to our neurosurgical department on August 5, 1975, with complaints of headache, nausea, and vomiting. She had had a generalized convulsion 8 months before admission, and had begun to complain of progressive headache. She was found to have choked discs and was referred to our clinic. Family history and past history were noncontributory. Examination. She was a somewhat drowsy girl with normal physical development except for bilateral breast enlargement as shown in Fig. 1. Bone age was 5 years. The m a m m a r y gland was palpable and slightly tender but there was no nipple discharge. N o axillary or ]0]
O. Kubo, et al.
FIG. 1. Early development of the breasts.
pubic hair was seen. She had not experienced menarche and no clitoral enlargement was evident. A vaginal smear was not performed. Neurological examination showed bilateral choked discs but no focal neurological deficits. The visual acuity and fields were normal. Laboratory data revealed normal urinalysis, complete blood count, and serum electrolytes. A ventricular puncture performed soon after admission revealed an opening pressure of 400 mm H20, and grossly normal appearance of the cerebrospinal fluid (CSF). The CSF analysis showed protein 142 mg/dl,
FIG. 2. Dimer-X ventriculogram revealed a filling defect of the anterior third ventricle and no abnormalities of the pineal and suprapineal recesses. ]02
glucose 70 mg/dl, HCG 2000 ng/ml, and HCB-/3 146 ng/ml. Skull x-ray films showed diastasis of the sutures and erosion of the sella turcica. Right brachial angiogram showed straightening of the anterior cerebral artery, and stretching of the anterior choroidal, lenticulostriate, and thalamoperforating arteries. Dimer-X ventriculogram revealed a filling defect in the anterior floor of the third ventricle outlining the tumor but no abnormalities in the pineal and suprapineal recesses (Fig. 2). A ventriculoperitoneal shunt was performed on the fourth hospital day to relieve progressively increasing intracranial pressure. Operation. A right frontal craniotomy was performed 14 days after admission. A reddish-brown tumor was seen to fill most of the anterior third ventricle. Partial resection of the tumor was carried out by the transventricular approach. Postoperatively the patient was given a course of irradiation, with a total dose of 4350 rads. Breast enlargement had disappeared by the completion of radiotherapy. Histological Study. The surgical tissue was fixed in 10% formalin. The sections were stained with hematoxylin-eosin (H & E), PAS, and Azan. In the routine H & E preparation, the tumor tissue was seen to be composed of two types of cells, epithelioid cells and small cells like lymphocytes (Fig. 3). In the PAS preparation, fine granules were demonstrated in the epithelioid cells. Ectopic pinealoma of the two-cell pattern was diagnosed. Electron Microscopic Study. The specimens were immediately fixed in 2% glutaraldehyde, then fixed in 1% osmium tetroxide solution with phosphate buffer for 2 hours, dehydrated with a graded concentration of ethanol, and finally embedded in Epon 812. The ultrathin sections were stained with uranyl acetate followed by lead citrate. The specimen was examined with a Hitachi l i D electron microscope.* The electron micrograph of the tumor cells revealed both clear and dark cells. The most prominent finding was the presence of multiple electron-dense granules in the dark tumor *Hitachi I 1D electron microscope manufactured by Niseisangiyo Ltd., 2-Sakuragawa-cho, Shibanishikubo Minato-ku, Tokyo 105, Japan.
J. Neurosurg. / Volume 47 / July, 1977
Pinealoma and precocious puberty cells. They were round, uniform in shape, and measured approximately 500 m# (Fig. 4). Endocrinological Studies. We measured plasma luteinizing hormone (LH) and follicular stimulating hormone (FSH) by radioimmunoassay (RIA) using RIA kitst with a reference standard of 2nd IRP-HMG (International Reference Preparation-Human Menopausal Gonadotropin) (mlU/ml). The plasma HCG was measured by RIA with the RIA kit for HCG,~ expressed as ng/ml (1 mg is equivalent to 6600 IU of the 2nd ISHCG (International Standard-Human Chorionic Gonadotropin)). The LH and HCG cross reacted nonspecifically with each other and the LH kit measured HCG at about a half of LH and the HCG kit measured LH at about one-third of HCG. We measured the HCG-# subunit by RIA using an antibody against HCG-# subunit, which permits the selective measurement of H C G in the presence of physiologic amounts of LH. The plasma prolactin was measured by RIA with a Friesen No. 2 kit.w We measured plasma estradiol and testosterone by RIA using antisera raised in our laboratory. The tumor contents of gonadotropins were determined by RIA after the extraction of acetonedried tumor tissue with a modification of Hartree's method? The luteinizing hormonereleasing hormone ( L H - R H ) and thyrotropin releasing hormone (TRH) test was performed by the intravenous administration of 100 ug of L H - R H mixed with 10 izg/kg of TRH. During the test the patient was not allowed any food intake. Blood samples were drawn before and 30, 60, 90, and 120 minutes after the injection. Basal plasma levels of various hormones before and after surgical excision and radiotherapy of the tumor are shown in Table 1. The HCG and HCG-# values were markedly high and LH was also measured to be high #Radioimmunoassay kits for FSH manufactured by Daiichi Radioisotope Labs, Ltd., 10-5 Nihonbashi 3-chome, Chuo-ku, Tokyo 103, Japan. :~Radioimmunoassay kit for HCG manufactured by CEA-IRE-SORIN: CEA - - D6partement des Radio616ments, Gif-sur-Yvette, France; I R E Institut National des Radio616ments, 2400 Mol; SORIN Centro Ricerche Nucleari, Saluggia (Vercelli), Italy. w No. 2 kit was a gift of the National Institutes of Health, Bethesda, Maryland. -
-
J. Neurosurg. / Volume 47 / July, 1977
FIG. 3. A light microscopic finding of the resected tumor shows a typical two-cell pattern pinealoma. H & E, X 50.
before treatment but all of them decreased rapidly immediately after treatment. The basal level of FSH was at the upper limit of normal for age both before and 4 months after treatment. Estradiol was not detectable either before or after treatment. Plasma concentration of cortisol and thyroid hormones were normal. Figure 5 shows the response of HCG, LH, FSH, prolactin, and T S H to the LH-RH and T R H test. The HCG, LH, and FSH response to L H - R H was negative both
FIG. 4. Electron micrograph showing dark and clear cells. In the dark cell, secretory granules (G) with a diameter of about 500 mu were seen. X 5000. I03
O. Kubo,
e t al.
TABLE 1
Basal levels of various hormones before and after treatment* Hormone HCG (ng/ml) LH (mIU/ml) FSH (mlU/ml) prolactin (ng/ml) TSH (uU/ml) HGH (ng/ml) estradiol (pg/ml) testosterone (ng/dl) HCG-/3 (ng/ml)
Normal Range
Before Treatment
2 Months after Treatment
4 Months after Treatment
ND 2.8-5.4 2.4-6.6 2-20 1-6 1-6
