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Juvenile granulosa cell tumor in association with a high serum inhibin level
GYNECOLOGIC ONCOLOGY
40, 90-94 (1991)
CASE REPORT Juvenile Granulosa Cell Tumor in Association with a High Serum lnhibin Level MAKOTO NISHIDA, M.D., SHOJI JIMI, M.D., MASAFUMI HAJI, M.D.,* ITSURO HAYASHI, M.D. ,t TAKESHI KAI, M.D. ,$ AND HIDEKO TASAKA, M.D.+ Departments of Gynecology, ?Pathology, and fpediatrics, National Kyushu Cancer Center, Notame 3-l-1, Minami-ku, Fukuoka 815, and *Third Department of Internal Medicine, Kyushu University Faculty of Medicine, Maidashi 3-l-1, Higashi-ku, Fukuoka 812, Japan
ReceivedJuly 13, 1990
talization she was aware of vaginal spotting. Ultrasonography (US) and computed tomography (CT) revealed an abdominal mass. She was therefore transferred to the National Kyushu Cancer Center for treatment on January
Inhibin is a glycoprotein hormone produced mainly by ovarian granulosa cells. Recently measurement of serum inhibin levels was made possible by radioimmunoassay. We describe a patient with a juvenile granulosa cell tumor, a distinctive and rare form of granulosa cell tumor. This patient’s serum inhibin level was extremely high preoperatively and returned to normal after the tumor was resected. This case suggests that serum inhibin level may be a useful marker of granulosa cell tumors. 0 lW1 Academic
17.
She was 99.5 cm tall and weighed 16.4 kg. Physical examination revealed breast enlargement and abdominal distension. There was neither axillary nor pubic hair. The Press, Inc. external genitalia were normal without clitoromegaly. Inspection by speculum under anesthesia showed no vaginal bleeding. On digital examination, a fist-sized movable INTRODUCTION mass was palpable in the periumbilical region, and the Granulosa cell tumors (GCTs), which arise from sex uterus was normal in size. US and CT (Fig. 1) disclosed cord-stroma, account for 1 to 2% of all ovarian tumors a large tumor in the midabdomen. On cytologic exami[l]. Most GCTs are found in women over 40 years of age nation of the vaginal smear, malignant cells were not [2]; however, approximately 5% of GCTs occur before found, but an estrogenic effect was noted. The serum normal puberty [l]. Scully [l] described the distinctive cancer antigen 125 (CA-125) level was elevated (124 histological features of GCTs found in children and com- U/ml; normal ~35 U/ml), but serum levels of a-fetopared these to GCTs found in older women. The GCTs protein (AFP), carcinoembryonic antigen (CEA), squaencountered more commonly in children were named ju- mous cell carcinoma antigen (SCC), and the p subunit of human chorionic gonadotropin (P-hCG) were normal. venile granulosa cell tumors (JGCTs). Inhibin is a glycoprotein hormone produced mainly by The preoperative serum levels of various hormones are ovarian granulosa cells. Recently, measurement of serum shown in Table 1. Estradiol and progesterone levels were inhibin levels was made possible by radioimmunoassay elevated as compared to those values in age-matched con(RIA) [3], and elevation of serum inhibin level in women trols; serum levels of estrone, estriol, testosterone, and with GCTs was reported [4]. In this case report, we de- prolactin were normal; and serum levels of luteinizing scribe a 3-year-old girl with JGCT whose preoperative hormone (LH) and follicle-stimulating hormone (FSH) serum inhibin level was extremely elevated. were low. Since the normal range of serum inhibin levels in children has not been determined, we measured serum inhibin levels in five healthy age-matched girls (2-5 years CASE REPORT of age). The results were 8.3 and 7.6 III/ml in two girls, A 3-year-old Japanese girl was admitted to a local clinic and undetectable (under 3.6 IU/ml) in the other three because of abdominal pain and vomiting. During hospi- girls. The serum inhibin level in this patient was 94 III/ml. 90 009t-8258191 $1.50 Copyright 0 1991 by Academic Press, Inc. All rights of reproduction in any form reserved.
91
CASE REPORT
FIG.
1. Preoperative
CT examination
of the abdomen. Note the large, irregularly
This value was much higher than those in the age-matched controls. Laparotomy was performed on January 19. A tumor (9 X 10 X 6 cm), arising from the left ovary, and bloody ascites (about 50 ml) were found. A high concentration of inhibin (97 IU/ml) was detected in the ascites and TABLE 1 Serum Levels of Various Hormones before and after Surgery Hormone Estrone Estradiol Estriol Progesterone Testosterone LH FSH Prolactin Inhibin
Before surgery
m/ml m/ml &ml e/ml x/ml mIU/ml mIU/ml w/ml W/ml
After surgery
< 10
< 10
59.4 < 10 1.13 10 < 0.5 < 0.5 8.4 94
< 10 < 10 0.11 6 < 0.5 5.1 20.8 < 3.6
enhanced tumor.
cytologic examination of the ascites was negative for malignant cells. Torsion of the pedicle was found, but the capsule of the tumor was intact. A left salpingo-oophorectomy was carried out. The tumor was composed of cystic parts with areas of massive hemorrhage and necrosis and pale-yellowish solid parts (Fig. 2). Histological examination revealed proliferation of granulosa cells in macrofollicular, diffuse (sarcomatoid), or trabecular patterns with luteinization (Figs. 3, 4). The nuclei were round or fusiform and moderately hyperchromatic. They had a high mitotic rate. Call-Exner bodies were not found. Immunohistochemical examination of the paraffin-embedded sections of the tumor tissue was performed using antisera to estradiol and progesterone according to the method of Sternberger et al. [5]. Numerous estradiol-positive cells were observed (Fig. 5), while progesterone-positive cells were not found. Based on these features, the diagnosis of JGCT was made. After surgery, the serum levels of estradiol, progesterone, FSH, and inhibin returned to normal. The postoperative course was uneventful, and
92
NISHIDA
FIG.
2.
Gross appearance of the resected left ovary. The tumor is composed of solid and cystic parts with hemorrhage
she was discharged from the hospital in good condition. She has remained free of disease up to the present time. DISCUSSION Juvenile granulosa cell tumor is a distinctive and rare form of GCT that is encountered mostly in children and women under 30 years of age [ 11. The characteristic features of JGCTs were described by several authors on the basis of histological findings [ 1,6,7]. We describe a case of JGCT in a 3-year-old girl with isosexual pseudoprecocity. The preoperative estradiol level was elevated and the vaginal smear showed an estrogenic effect. Microscopically, the tumor cells proliferated mainly in a macrofollicular pattern with luteinization, and Call-Exner bodies were not seen. Numerous mitotic figures were found in the nuclei. These findings are consistent with those in JGCTs. FIG. 3. FIG. 4.
ET AL.
Low-power High-power
and necrosis.
Inhibin, purified originally from bovine follicular fluid by Robertson et al. [8], is secreted by ovarian granulosa cells and acts on the hypothalamopituitary axis to regulate FSH secretion. Inhibin is present in human serum and its level varies during the menstrual cycle [9]. Lappohn et al. [4] reported four patients with GCTs in whom serum inhibin levels were elevated, and suggested that inhibin is a useful marker of these tumors. In the present case, the preoperative inhibin level (94 IU/ml) was extremely elevated as compared to those in the control group and dropped to an undetectable level postoperatively. This finding, together with the presence of inhibin in the ascites, suggests that the serum inhibin was derived from the tumor. On the other hand, the serum FSH level was low before surgery and returned to the normal level after removal of the tumor. This may be attributed to the suppressive effect of inhibin on FSH secretion before surgery. Our report suggeststhat serum inhibin level is useful
view of the tumor. Note the formation of follicles. H&E. X20. view of the tumor showing proliferation of luteinized granulosa cells. H&E,
X50.
94
NISHIDA
ET AL
FIG. 5. Immunohistochemical stain of the tumor tissue for estradiol. Note the positive cells. X100.
as a tumor marker for GCTs. This may be the first report describing production of inhibin by a JGCT in a 3-yearold premenarchal girl.
5.
ACKNOWLEDGMENT We are grateful to Dr. H. Iguchi (National Kyushu Cancer Center, Fukuoka, Japan) for reviewing this manuscript.
REFERENCES 1. Scully, R. E. Sex cord-stromal tumors, in Pathology of the female genital tract (A. Blaustein, Ed.), Springer-Verlag, New York, pp. 505-526 (1977). 2. Evans, A. T., III, Gaffey, T. A., Malkasian, G. D., Jr., and Annegers, J. F. Clinicopathologic review of 118 granulosa and 82 theta cell tumors, Obstet. Gynecol. 55, 231-238 (1980). 3. Hamada, T., Watanabe, G., Kokuho, T., Taya, K., Sasamoto, S., Hasegawa, Y., Miyamoto, K., and Igarashi, M. Radioimmunoassay of inhibin in various mammals, J. Endocrinol. 122, 697-704 (1989). 4. Lappohn, R. E., Burger, H. G., Bouma, J., Bangah, M., Krans,
6.
7.
8.
9.
M., and de Bruijn, H. W. A. Inhibin as a marker for granulosa-cell tumors, N. Engl. J. Med. 321, 790-793 (1989). Sternberger, L. A., Hardy, P. H., Jr., Cuculis, J. J., and Meyer, H. G. The unlabeled antibody enzyme method of immunohistochemistry. Preparation and properties of soluble antigen-antibody complex (horseradish peroxidase-antihorseradish peroxidase) and its use in identification of spirochetes, J. Histochem. Cytochem. l&315333 (1970). Young, R. H., Dickersin, G. R., and Scully, R. E. Juvenile granulosa cell tumor of the ovary. A clinicopathological analysis of 125 cases, Amer. J. Surg. Pathol. 8, 575-596 (1984). Lack, E. E., Perez-Atayde, A. R., Murthy, A. S. K., Goldstein, D. P., Crigler, J. F., Jr., and Vawter, G. F. Granulosa theta cell tumors in premenarchal girls. A clinical and pathologic study of ten cases, Cancer 48, 1846-1854 (1981). Robertson, D. M., Foulds, L. M., Leversha, L., Morgan, F. J., Hearn, M. T. W., Burger, H. G., Wettenhall, R. E. H., and de Kretser, D. M. Isolation of inhibin from bovine follicular fluid, Biochem. Biophys. Res. Commun. 126, 220-226 (1985). McLachlan, R. I., Robertson, D. M., Healy, D. L., Burger, H. G., and de Kretser, D. M. Circulating immunoreactive inhibin levels during the normal human menstrual cycle, J. Clin. Endocrinol. Metab. 65, 954-961 (1987).
40, 90-94 (1991)
CASE REPORT Juvenile Granulosa Cell Tumor in Association with a High Serum lnhibin Level MAKOTO NISHIDA, M.D., SHOJI JIMI, M.D., MASAFUMI HAJI, M.D.,* ITSURO HAYASHI, M.D. ,t TAKESHI KAI, M.D. ,$ AND HIDEKO TASAKA, M.D.+ Departments of Gynecology, ?Pathology, and fpediatrics, National Kyushu Cancer Center, Notame 3-l-1, Minami-ku, Fukuoka 815, and *Third Department of Internal Medicine, Kyushu University Faculty of Medicine, Maidashi 3-l-1, Higashi-ku, Fukuoka 812, Japan
ReceivedJuly 13, 1990
talization she was aware of vaginal spotting. Ultrasonography (US) and computed tomography (CT) revealed an abdominal mass. She was therefore transferred to the National Kyushu Cancer Center for treatment on January
Inhibin is a glycoprotein hormone produced mainly by ovarian granulosa cells. Recently measurement of serum inhibin levels was made possible by radioimmunoassay. We describe a patient with a juvenile granulosa cell tumor, a distinctive and rare form of granulosa cell tumor. This patient’s serum inhibin level was extremely high preoperatively and returned to normal after the tumor was resected. This case suggests that serum inhibin level may be a useful marker of granulosa cell tumors. 0 lW1 Academic
17.
She was 99.5 cm tall and weighed 16.4 kg. Physical examination revealed breast enlargement and abdominal distension. There was neither axillary nor pubic hair. The Press, Inc. external genitalia were normal without clitoromegaly. Inspection by speculum under anesthesia showed no vaginal bleeding. On digital examination, a fist-sized movable INTRODUCTION mass was palpable in the periumbilical region, and the Granulosa cell tumors (GCTs), which arise from sex uterus was normal in size. US and CT (Fig. 1) disclosed cord-stroma, account for 1 to 2% of all ovarian tumors a large tumor in the midabdomen. On cytologic exami[l]. Most GCTs are found in women over 40 years of age nation of the vaginal smear, malignant cells were not [2]; however, approximately 5% of GCTs occur before found, but an estrogenic effect was noted. The serum normal puberty [l]. Scully [l] described the distinctive cancer antigen 125 (CA-125) level was elevated (124 histological features of GCTs found in children and com- U/ml; normal ~35 U/ml), but serum levels of a-fetopared these to GCTs found in older women. The GCTs protein (AFP), carcinoembryonic antigen (CEA), squaencountered more commonly in children were named ju- mous cell carcinoma antigen (SCC), and the p subunit of human chorionic gonadotropin (P-hCG) were normal. venile granulosa cell tumors (JGCTs). Inhibin is a glycoprotein hormone produced mainly by The preoperative serum levels of various hormones are ovarian granulosa cells. Recently, measurement of serum shown in Table 1. Estradiol and progesterone levels were inhibin levels was made possible by radioimmunoassay elevated as compared to those values in age-matched con(RIA) [3], and elevation of serum inhibin level in women trols; serum levels of estrone, estriol, testosterone, and with GCTs was reported [4]. In this case report, we de- prolactin were normal; and serum levels of luteinizing scribe a 3-year-old girl with JGCT whose preoperative hormone (LH) and follicle-stimulating hormone (FSH) serum inhibin level was extremely elevated. were low. Since the normal range of serum inhibin levels in children has not been determined, we measured serum inhibin levels in five healthy age-matched girls (2-5 years CASE REPORT of age). The results were 8.3 and 7.6 III/ml in two girls, A 3-year-old Japanese girl was admitted to a local clinic and undetectable (under 3.6 IU/ml) in the other three because of abdominal pain and vomiting. During hospi- girls. The serum inhibin level in this patient was 94 III/ml. 90 009t-8258191 $1.50 Copyright 0 1991 by Academic Press, Inc. All rights of reproduction in any form reserved.
91
CASE REPORT
FIG.
1. Preoperative
CT examination
of the abdomen. Note the large, irregularly
This value was much higher than those in the age-matched controls. Laparotomy was performed on January 19. A tumor (9 X 10 X 6 cm), arising from the left ovary, and bloody ascites (about 50 ml) were found. A high concentration of inhibin (97 IU/ml) was detected in the ascites and TABLE 1 Serum Levels of Various Hormones before and after Surgery Hormone Estrone Estradiol Estriol Progesterone Testosterone LH FSH Prolactin Inhibin
Before surgery
m/ml m/ml &ml e/ml x/ml mIU/ml mIU/ml w/ml W/ml
After surgery
< 10
< 10
59.4 < 10 1.13 10 < 0.5 < 0.5 8.4 94
< 10 < 10 0.11 6 < 0.5 5.1 20.8 < 3.6
enhanced tumor.
cytologic examination of the ascites was negative for malignant cells. Torsion of the pedicle was found, but the capsule of the tumor was intact. A left salpingo-oophorectomy was carried out. The tumor was composed of cystic parts with areas of massive hemorrhage and necrosis and pale-yellowish solid parts (Fig. 2). Histological examination revealed proliferation of granulosa cells in macrofollicular, diffuse (sarcomatoid), or trabecular patterns with luteinization (Figs. 3, 4). The nuclei were round or fusiform and moderately hyperchromatic. They had a high mitotic rate. Call-Exner bodies were not found. Immunohistochemical examination of the paraffin-embedded sections of the tumor tissue was performed using antisera to estradiol and progesterone according to the method of Sternberger et al. [5]. Numerous estradiol-positive cells were observed (Fig. 5), while progesterone-positive cells were not found. Based on these features, the diagnosis of JGCT was made. After surgery, the serum levels of estradiol, progesterone, FSH, and inhibin returned to normal. The postoperative course was uneventful, and
92
NISHIDA
FIG.
2.
Gross appearance of the resected left ovary. The tumor is composed of solid and cystic parts with hemorrhage
she was discharged from the hospital in good condition. She has remained free of disease up to the present time. DISCUSSION Juvenile granulosa cell tumor is a distinctive and rare form of GCT that is encountered mostly in children and women under 30 years of age [ 11. The characteristic features of JGCTs were described by several authors on the basis of histological findings [ 1,6,7]. We describe a case of JGCT in a 3-year-old girl with isosexual pseudoprecocity. The preoperative estradiol level was elevated and the vaginal smear showed an estrogenic effect. Microscopically, the tumor cells proliferated mainly in a macrofollicular pattern with luteinization, and Call-Exner bodies were not seen. Numerous mitotic figures were found in the nuclei. These findings are consistent with those in JGCTs. FIG. 3. FIG. 4.
ET AL.
Low-power High-power
and necrosis.
Inhibin, purified originally from bovine follicular fluid by Robertson et al. [8], is secreted by ovarian granulosa cells and acts on the hypothalamopituitary axis to regulate FSH secretion. Inhibin is present in human serum and its level varies during the menstrual cycle [9]. Lappohn et al. [4] reported four patients with GCTs in whom serum inhibin levels were elevated, and suggested that inhibin is a useful marker of these tumors. In the present case, the preoperative inhibin level (94 IU/ml) was extremely elevated as compared to those in the control group and dropped to an undetectable level postoperatively. This finding, together with the presence of inhibin in the ascites, suggests that the serum inhibin was derived from the tumor. On the other hand, the serum FSH level was low before surgery and returned to the normal level after removal of the tumor. This may be attributed to the suppressive effect of inhibin on FSH secretion before surgery. Our report suggeststhat serum inhibin level is useful
view of the tumor. Note the formation of follicles. H&E. X20. view of the tumor showing proliferation of luteinized granulosa cells. H&E,
X50.
94
NISHIDA
ET AL
FIG. 5. Immunohistochemical stain of the tumor tissue for estradiol. Note the positive cells. X100.
as a tumor marker for GCTs. This may be the first report describing production of inhibin by a JGCT in a 3-yearold premenarchal girl.
5.
ACKNOWLEDGMENT We are grateful to Dr. H. Iguchi (National Kyushu Cancer Center, Fukuoka, Japan) for reviewing this manuscript.
REFERENCES 1. Scully, R. E. Sex cord-stromal tumors, in Pathology of the female genital tract (A. Blaustein, Ed.), Springer-Verlag, New York, pp. 505-526 (1977). 2. Evans, A. T., III, Gaffey, T. A., Malkasian, G. D., Jr., and Annegers, J. F. Clinicopathologic review of 118 granulosa and 82 theta cell tumors, Obstet. Gynecol. 55, 231-238 (1980). 3. Hamada, T., Watanabe, G., Kokuho, T., Taya, K., Sasamoto, S., Hasegawa, Y., Miyamoto, K., and Igarashi, M. Radioimmunoassay of inhibin in various mammals, J. Endocrinol. 122, 697-704 (1989). 4. Lappohn, R. E., Burger, H. G., Bouma, J., Bangah, M., Krans,
6.
7.
8.
9.
M., and de Bruijn, H. W. A. Inhibin as a marker for granulosa-cell tumors, N. Engl. J. Med. 321, 790-793 (1989). Sternberger, L. A., Hardy, P. H., Jr., Cuculis, J. J., and Meyer, H. G. The unlabeled antibody enzyme method of immunohistochemistry. Preparation and properties of soluble antigen-antibody complex (horseradish peroxidase-antihorseradish peroxidase) and its use in identification of spirochetes, J. Histochem. Cytochem. l&315333 (1970). Young, R. H., Dickersin, G. R., and Scully, R. E. Juvenile granulosa cell tumor of the ovary. A clinicopathological analysis of 125 cases, Amer. J. Surg. Pathol. 8, 575-596 (1984). Lack, E. E., Perez-Atayde, A. R., Murthy, A. S. K., Goldstein, D. P., Crigler, J. F., Jr., and Vawter, G. F. Granulosa theta cell tumors in premenarchal girls. A clinical and pathologic study of ten cases, Cancer 48, 1846-1854 (1981). Robertson, D. M., Foulds, L. M., Leversha, L., Morgan, F. J., Hearn, M. T. W., Burger, H. G., Wettenhall, R. E. H., and de Kretser, D. M. Isolation of inhibin from bovine follicular fluid, Biochem. Biophys. Res. Commun. 126, 220-226 (1985). McLachlan, R. I., Robertson, D. M., Healy, D. L., Burger, H. G., and de Kretser, D. M. Circulating immunoreactive inhibin levels during the normal human menstrual cycle, J. Clin. Endocrinol. Metab. 65, 954-961 (1987).