- Email: [email protected]
Virilization persists in a woman with an androgen-secreting granulosa cell tumor
CASE REPORT Virilization persists in a woman with an androgen-secreting granulosa cell tumor Satin S. Patel, M.D.,a Kelley S. Carrick, M.D.,b and Bruce R. Carr, M.D.a a
Departments of Obstetrics & Gynecology, and b Pathology, University of Texas Southwestern Medical Center, Dallas, Texas
Objective: To report a case of a woman who presented with amenorrhea and masculinization secondary to an androgen-secreting granulosa cell (GC) tumor, with refractory masculinization. Design: Case report. Setting: University medical center. Patient(s): A 45-year-old woman with abrupt onset of virilization with high serum androgen levels. Intervention(s): Exploratory laparotomy with full staging. Main Outcome Measure(s): Surgical findings and histopathologic observations are included in this report. Result(s): Pathologic examination revealed an inhibin stain positive GC tumor of the adult type. Virilization has persisted for 8 years after surgery. Conclusion(s): Adult-type GC tumor is an extremely rare cause of virilization. Masculinization features may persist in the absence of high androgen levels. (Fertil Steril 2009;91:933.e13–e15. 2009 by American Society for Reproductive Medicine.) Key Words: Granulosa cell tumor, virilizing, masculinizing, androgen, testosterone, inhibin
Although rare, androgen-secreting tumors are an important cause of hyperandrogenemia. Only the theca cells in the ovary and the zona reticularis layer of the adrenal cortex are known to produce androgens in women (1). We report the first case of an androgen-secreting granulosa cell (GC) tumor in a premenopausal woman with persistent masculinization, despite long-term normalization of androgen levels. In addition, this is the second reported case of an inhibin stain positive androgenic GC tumor (2). CASE REPORT A 45-year-old parous African American woman presented to our reproductive endocrinology clinic with complaints of amenorrhea for 1 year followed by rapid onset masculinization. Physical examination revealed prominent hirsutism, temporal balding, a deepened voice, and a normal pelvic exam, except for mild clitoromegaly. Preliminary laboratory investigations revealed an elevated serum total T of 301 ng/dL (reference range 15–70 ng/dL), androstenedione (A) of 1.6 ng/mL (0.2–3.1 ng/mL), 17a-hyReceived August 12, 2008; revised October 16, 2008; accepted October 17, 2008. S.P. has nothing to disclose. K.S.C. has nothing to disclose. B.R.C. has nothing to disclose. Reprint requests: Bruce R. Carr, M.D., Department of Reproductive Endocrinology and Infertility, University of Texas at Southwestern at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390-9032 (FAX: 214-648-8066; E-mail: [email protected]).
0015-0282/09/$36.00 doi:10.1016/j.fertnstert.2008.10.038
droxyprogesterone (17-OHP) of 102.9 ng/dL (100–300 ng/ dL), an DHEAS of 140.8 mg/dL (80–350 mg/dL). Pelvic sonogram and magnetic resonance imaging (MRI) demonstrated a 7 6 4-cm cystic right ovarian mass. The patient received surgical intervention through an exploratory laparotomy, revealing a right adnexal complex cyst, appearing ovarian in origin (Fig. 1a). An intraoperative frozen section demonstrated a sex-cord stromal tumor, favor GC tumor. She underwent a total abdominal hysterectomy with bilateral salpingo-oophorectomy, along with a full staging procedure with appendectomy and pelvic and para-aortic lymph node sampling. Morphologic examination of the tumor revealed an 80-g, 8 5 4-cm yellow-tan ovarian mass with a smooth, intact external surface. The cut surface was yellow-tan and lobulated, predominantly solid with focal cyst formation. Permanent sections demonstrated a tumor composed of relatively uniform cells of small cell size, with scant cytoplasm and ovoid nuclei showing frequent nuclear grooves. The cells were arranged predominantly in a diffuse pattern and focally in cords. In addition, 5%–10% of the tumor was composed of scattered clusters of Leydig cells containing crystals of Reinke. An immunohistochemical stain for inhibin was positive in the tumor cells, supporting the morphologic impression of an adult-type GC tumor (Fig. 1b). The remaining pathology specimens, including the uterus, left adnexa, lymph nodes, omentum, and appendix, were uninvolved by tumor. The endometrium was inactive.
Fertility and Sterility Vol. 91, No. 3, March 2009 Copyright ª2009 American Society for Reproductive Medicine, Published by Elsevier Inc.
933.e13
FIGURE 1 (a) Intraoperative gross photograph, adult-type T-producing granulosa cell tumor. (b) Immunohistochemical stain for inhibin, showing moderate positivity in granulosa tumor cells (periphery of photo) and strong positivity in Leydig cells (centrally in photo) (Original magnification, 20).
Patel. Virilizing granulosa cell tumor. Fertil Steril 2009.
Postoperatively, the patient was carefully monitored by clinical and laboratory testing during the first year. During her first postoperative visit, the patient’s total T level declined to 18 ng/dL and her inhibin-B level was 2.4 U/mL (2.0–25.0 U/mL). Serial serum inhibin surveillance was extended annually. A 7-year follow-up visit confirmed remission with a total T level of 20 ng/dL. Despite long-term normalization of her serum androgen levels, her hirsutism, temporal balding, and deepened voice remain refractory to treatment. DISCUSSION We describe the first reported case of an androgen-secreting adult-type GC tumor with refractory masculinization. Androgen-producing GC tumors are rare, with only 34 cases reported in the literature (2). The majority of these cases have been described in the second and third decades of life. Some of these patients experienced virilization (2). In all reported cases with virilization, signs of hirsutism and virilization improved shortly after tumor resection (2–7). This is the first case of persistent masculinization resulting from an androgen-secreting GC tumor, despite a long-term postoperative normalization of androgen levels. In addition, this is the second reported case of an inhibin stain positive androgen-producing GC tumor (2). Granulosa cell tumors are more often associated with aberrant estrogen (E) secretion, resulting in symptoms such as breast tenderness, postmenopausal bleeding, and menstrual abnormalities. In addition, in a review of 118 patients with GC tumors, 55% were found to have endometrial hyperplasia, thereby placing them at high risk for concomitant endometrial carcinoma (8). 933.e14
Patel et al.
Virilizing granulosa cell tumor
A definitive diagnosis of adult-type GC tumor is made histologically. The presence of relatively uniform cells of small cell size with pale ovoid nuclei, at least some of which have nuclear grooves, is suggestive of a GC origin. Tumor cells may be arranged in a variety of patterns, although better differentiated tumors typically show, at least focally, a microfollicular pattern characterized by small cavities similar to the Call-Exner bodies of the developing graafian follicle, surrounded by GCs. This pattern was clearly evident in our patient. Although scarce Leydig cells containing crystals of Reinke were identified, they were unlikely to be the source of aberrant androgen production. Leydig cells, which are synonymous with ovarian hilar cells, comprise 5% of a normal human ovary. In addition, Leydig cell tumors are characterized histologically by large lipid-laden cells with distinct borders (9). These features were not visualized in our pattern. Furthermore, a morphologic diagnosis of GC tumor is further supported by immunohistochemical staining of tumor cells for inhibin. Surgical management is guided by the extent of disease at the time of surgery, along with the patient’s desire to preserve her fertility. Although the majority of GC tumors are unilateral, a unilateral oophorectomy should be followed by a full staging procedure with meticulous inspection of the contralateral ovary and tube, along with pelvic and para-aortic lymph node sampling. In women who have completed childbearing, a total abdominal hysterectomy and bilateral salpingo-oophorectomy is the standard of care (10). Women with stage I disease, who desire reproductive potential, may choose to preserve their uterus and contralateral unaffected ovary (11). Alternatively, women with advanced stage disease may benefit from adjuvant radiation and cisplatin-based chemotherapy (12). Vol. 91, No. 3, March 2009
As in all cases of ovarian neoplasms of a malignant or potentially malignant nature, close postoperative surveillance is essential to diagnose early recurrence and direct prompt management. Typically, patients may be followed by serial inhibin levels and radiographic imaging if clinically indicated (12, 13). In cases of androgen-secreting GC tumors, it is reasonable to follow interval serum androgens levels. In the first postoperative year, our patient underwent quarterly serum inhibin screening for tumor recurrence. Subsequently, she has been undergoing annual inhibin screening. Continued surveillance on an annual basis is imperative, as GC tumors have been documented to recur as long as 20 years postoperatively. Because all other reported cases of androgen-secreting GC tumors described experienced a significant regression of masculinization, a sudden reappearance of signs of hirsutism and virilization may prompt a screen for recurrence. However, as in the case with following E2 levels in E2-secreting GC tumors, relying on serum androgen measurements may be an inconsistent means of screening for disease recurrence. Furthermore, as in the case of our patient where symptoms of masculinization have not improved despite normalization of serum androgen levels, assessing phenotypic features would be unlikely to aid in the detection of a tumor recurrence. Androgen-producing GC tumors are rare. To our knowledge, this is the first published case of refractory masculinization after an apparent surgical cure for an androgen-secreting GC tumor. Given the tendency for late recurrence, heightened long-term surveillance for these patients is advisable. Acknowledgment: The authors acknowledge the contributions of Dr. David Miller, consultant gynecologic oncologist in the management of this case.
Fertility and Sterility
REFERENCES 1. Beshay VE, Havelock JC, Sirianni R, Ye P, Suzuki T, Rainey WE, et al. The mechanism for protein kinase C inhibition of androgen production and 17alpha-hydroxylase expression in a theca cell tumor model. J Clin Endocrinol Metab 2007;92:4802–9. 2. Kabaca C, Karateke A, Gurbuz A, Cesur S. Androgenic adult granulosa cell tumor in a teenager: a case report and review of the literature. Int J Gynecol Cancer 2006;16(Suppl 1):368–74. 3. Zaydon C, Bogaars HA, Tucci JR. Virilizing granulosa cell tumor responsive to human chorionic gonadotropin and oral contraceptive with 8-year followup. Int J Gynaecol Obstet 1989;29:87–90. 4. Castro CY, Malpica A, Hearne RH, Silva EG. Androgenic adult granulosa cell tumor in a 13-year-old prepubertal patient: a case report and review of the literature. Int J Gynecol Pathol 2000;19:266–71. 5. Nomelini RS, Micheletti AM, Adad SJ, Murta EF. Androgenic juvenile granulosa cell tumor of the ovary with cystic presentation: a case report. Eur J Gynaecol Oncol 2007;28:236–8. 6. Demopoulos RI, Bell DA. The fine structure of a virilizing human granulosa-theca cell tumor. Observations on the nature of the hormone producing cell. Cancer 1983;51:1858–65. 7. Martinez L, Salmeron M, Carvia RE, Campello TR, Molina R, Herruzo AJ, et al. Androgen producing luteinized granulosa cell tumor. Acta Obstet Gynecol Scand 1997;76:285–6. 8. Evans AT 3rd, Gaffey TA, Malkasian GD Jr, Annegers JF. Clinicopathologic review of 118 granulosa and 82 theca cell tumors. Obstet Gynecol 1980;55:231–8. 9. Kumar V, Abbas AK, Fausto N, Robbins SL, Cotran RS. Robbins and Cotran pathologic basis of disease. 7th ed. Philadelphia: Elsevier Saunders, 2005. 10. Miller BE, Barron BA, Wan JY, Delmore JE, Silva EG, Gershenson DM. Prognostic factors in adult granulosa cell tumor of the ovary. Cancer 1997;79:1951–5. 11. Giuntoli RL, Celebre JA, Wu CH, Wheeler JE, Mikuta JJ. Androgenic function of a granulosa cell tumor. Obstet Gynecol 1976;47:77–9. 12. Schumer ST, Cannistra SA. Granulosa cell tumor of the ovary. J Clin Oncol 2003;21:1180–9. 13. Stuart GC, Dawson LM. Update on granulosa cell tumours of the ovary. Curr Opin Obstet Gynecol 2003;15:33–7.
933.e15
Departments of Obstetrics & Gynecology, and b Pathology, University of Texas Southwestern Medical Center, Dallas, Texas
Objective: To report a case of a woman who presented with amenorrhea and masculinization secondary to an androgen-secreting granulosa cell (GC) tumor, with refractory masculinization. Design: Case report. Setting: University medical center. Patient(s): A 45-year-old woman with abrupt onset of virilization with high serum androgen levels. Intervention(s): Exploratory laparotomy with full staging. Main Outcome Measure(s): Surgical findings and histopathologic observations are included in this report. Result(s): Pathologic examination revealed an inhibin stain positive GC tumor of the adult type. Virilization has persisted for 8 years after surgery. Conclusion(s): Adult-type GC tumor is an extremely rare cause of virilization. Masculinization features may persist in the absence of high androgen levels. (Fertil Steril 2009;91:933.e13–e15. 2009 by American Society for Reproductive Medicine.) Key Words: Granulosa cell tumor, virilizing, masculinizing, androgen, testosterone, inhibin
Although rare, androgen-secreting tumors are an important cause of hyperandrogenemia. Only the theca cells in the ovary and the zona reticularis layer of the adrenal cortex are known to produce androgens in women (1). We report the first case of an androgen-secreting granulosa cell (GC) tumor in a premenopausal woman with persistent masculinization, despite long-term normalization of androgen levels. In addition, this is the second reported case of an inhibin stain positive androgenic GC tumor (2). CASE REPORT A 45-year-old parous African American woman presented to our reproductive endocrinology clinic with complaints of amenorrhea for 1 year followed by rapid onset masculinization. Physical examination revealed prominent hirsutism, temporal balding, a deepened voice, and a normal pelvic exam, except for mild clitoromegaly. Preliminary laboratory investigations revealed an elevated serum total T of 301 ng/dL (reference range 15–70 ng/dL), androstenedione (A) of 1.6 ng/mL (0.2–3.1 ng/mL), 17a-hyReceived August 12, 2008; revised October 16, 2008; accepted October 17, 2008. S.P. has nothing to disclose. K.S.C. has nothing to disclose. B.R.C. has nothing to disclose. Reprint requests: Bruce R. Carr, M.D., Department of Reproductive Endocrinology and Infertility, University of Texas at Southwestern at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390-9032 (FAX: 214-648-8066; E-mail: [email protected]).
0015-0282/09/$36.00 doi:10.1016/j.fertnstert.2008.10.038
droxyprogesterone (17-OHP) of 102.9 ng/dL (100–300 ng/ dL), an DHEAS of 140.8 mg/dL (80–350 mg/dL). Pelvic sonogram and magnetic resonance imaging (MRI) demonstrated a 7 6 4-cm cystic right ovarian mass. The patient received surgical intervention through an exploratory laparotomy, revealing a right adnexal complex cyst, appearing ovarian in origin (Fig. 1a). An intraoperative frozen section demonstrated a sex-cord stromal tumor, favor GC tumor. She underwent a total abdominal hysterectomy with bilateral salpingo-oophorectomy, along with a full staging procedure with appendectomy and pelvic and para-aortic lymph node sampling. Morphologic examination of the tumor revealed an 80-g, 8 5 4-cm yellow-tan ovarian mass with a smooth, intact external surface. The cut surface was yellow-tan and lobulated, predominantly solid with focal cyst formation. Permanent sections demonstrated a tumor composed of relatively uniform cells of small cell size, with scant cytoplasm and ovoid nuclei showing frequent nuclear grooves. The cells were arranged predominantly in a diffuse pattern and focally in cords. In addition, 5%–10% of the tumor was composed of scattered clusters of Leydig cells containing crystals of Reinke. An immunohistochemical stain for inhibin was positive in the tumor cells, supporting the morphologic impression of an adult-type GC tumor (Fig. 1b). The remaining pathology specimens, including the uterus, left adnexa, lymph nodes, omentum, and appendix, were uninvolved by tumor. The endometrium was inactive.
Fertility and Sterility Vol. 91, No. 3, March 2009 Copyright ª2009 American Society for Reproductive Medicine, Published by Elsevier Inc.
933.e13
FIGURE 1 (a) Intraoperative gross photograph, adult-type T-producing granulosa cell tumor. (b) Immunohistochemical stain for inhibin, showing moderate positivity in granulosa tumor cells (periphery of photo) and strong positivity in Leydig cells (centrally in photo) (Original magnification, 20).
Patel. Virilizing granulosa cell tumor. Fertil Steril 2009.
Postoperatively, the patient was carefully monitored by clinical and laboratory testing during the first year. During her first postoperative visit, the patient’s total T level declined to 18 ng/dL and her inhibin-B level was 2.4 U/mL (2.0–25.0 U/mL). Serial serum inhibin surveillance was extended annually. A 7-year follow-up visit confirmed remission with a total T level of 20 ng/dL. Despite long-term normalization of her serum androgen levels, her hirsutism, temporal balding, and deepened voice remain refractory to treatment. DISCUSSION We describe the first reported case of an androgen-secreting adult-type GC tumor with refractory masculinization. Androgen-producing GC tumors are rare, with only 34 cases reported in the literature (2). The majority of these cases have been described in the second and third decades of life. Some of these patients experienced virilization (2). In all reported cases with virilization, signs of hirsutism and virilization improved shortly after tumor resection (2–7). This is the first case of persistent masculinization resulting from an androgen-secreting GC tumor, despite a long-term postoperative normalization of androgen levels. In addition, this is the second reported case of an inhibin stain positive androgen-producing GC tumor (2). Granulosa cell tumors are more often associated with aberrant estrogen (E) secretion, resulting in symptoms such as breast tenderness, postmenopausal bleeding, and menstrual abnormalities. In addition, in a review of 118 patients with GC tumors, 55% were found to have endometrial hyperplasia, thereby placing them at high risk for concomitant endometrial carcinoma (8). 933.e14
Patel et al.
Virilizing granulosa cell tumor
A definitive diagnosis of adult-type GC tumor is made histologically. The presence of relatively uniform cells of small cell size with pale ovoid nuclei, at least some of which have nuclear grooves, is suggestive of a GC origin. Tumor cells may be arranged in a variety of patterns, although better differentiated tumors typically show, at least focally, a microfollicular pattern characterized by small cavities similar to the Call-Exner bodies of the developing graafian follicle, surrounded by GCs. This pattern was clearly evident in our patient. Although scarce Leydig cells containing crystals of Reinke were identified, they were unlikely to be the source of aberrant androgen production. Leydig cells, which are synonymous with ovarian hilar cells, comprise 5% of a normal human ovary. In addition, Leydig cell tumors are characterized histologically by large lipid-laden cells with distinct borders (9). These features were not visualized in our pattern. Furthermore, a morphologic diagnosis of GC tumor is further supported by immunohistochemical staining of tumor cells for inhibin. Surgical management is guided by the extent of disease at the time of surgery, along with the patient’s desire to preserve her fertility. Although the majority of GC tumors are unilateral, a unilateral oophorectomy should be followed by a full staging procedure with meticulous inspection of the contralateral ovary and tube, along with pelvic and para-aortic lymph node sampling. In women who have completed childbearing, a total abdominal hysterectomy and bilateral salpingo-oophorectomy is the standard of care (10). Women with stage I disease, who desire reproductive potential, may choose to preserve their uterus and contralateral unaffected ovary (11). Alternatively, women with advanced stage disease may benefit from adjuvant radiation and cisplatin-based chemotherapy (12). Vol. 91, No. 3, March 2009
As in all cases of ovarian neoplasms of a malignant or potentially malignant nature, close postoperative surveillance is essential to diagnose early recurrence and direct prompt management. Typically, patients may be followed by serial inhibin levels and radiographic imaging if clinically indicated (12, 13). In cases of androgen-secreting GC tumors, it is reasonable to follow interval serum androgens levels. In the first postoperative year, our patient underwent quarterly serum inhibin screening for tumor recurrence. Subsequently, she has been undergoing annual inhibin screening. Continued surveillance on an annual basis is imperative, as GC tumors have been documented to recur as long as 20 years postoperatively. Because all other reported cases of androgen-secreting GC tumors described experienced a significant regression of masculinization, a sudden reappearance of signs of hirsutism and virilization may prompt a screen for recurrence. However, as in the case with following E2 levels in E2-secreting GC tumors, relying on serum androgen measurements may be an inconsistent means of screening for disease recurrence. Furthermore, as in the case of our patient where symptoms of masculinization have not improved despite normalization of serum androgen levels, assessing phenotypic features would be unlikely to aid in the detection of a tumor recurrence. Androgen-producing GC tumors are rare. To our knowledge, this is the first published case of refractory masculinization after an apparent surgical cure for an androgen-secreting GC tumor. Given the tendency for late recurrence, heightened long-term surveillance for these patients is advisable. Acknowledgment: The authors acknowledge the contributions of Dr. David Miller, consultant gynecologic oncologist in the management of this case.
Fertility and Sterility
REFERENCES 1. Beshay VE, Havelock JC, Sirianni R, Ye P, Suzuki T, Rainey WE, et al. The mechanism for protein kinase C inhibition of androgen production and 17alpha-hydroxylase expression in a theca cell tumor model. J Clin Endocrinol Metab 2007;92:4802–9. 2. Kabaca C, Karateke A, Gurbuz A, Cesur S. Androgenic adult granulosa cell tumor in a teenager: a case report and review of the literature. Int J Gynecol Cancer 2006;16(Suppl 1):368–74. 3. Zaydon C, Bogaars HA, Tucci JR. Virilizing granulosa cell tumor responsive to human chorionic gonadotropin and oral contraceptive with 8-year followup. Int J Gynaecol Obstet 1989;29:87–90. 4. Castro CY, Malpica A, Hearne RH, Silva EG. Androgenic adult granulosa cell tumor in a 13-year-old prepubertal patient: a case report and review of the literature. Int J Gynecol Pathol 2000;19:266–71. 5. Nomelini RS, Micheletti AM, Adad SJ, Murta EF. Androgenic juvenile granulosa cell tumor of the ovary with cystic presentation: a case report. Eur J Gynaecol Oncol 2007;28:236–8. 6. Demopoulos RI, Bell DA. The fine structure of a virilizing human granulosa-theca cell tumor. Observations on the nature of the hormone producing cell. Cancer 1983;51:1858–65. 7. Martinez L, Salmeron M, Carvia RE, Campello TR, Molina R, Herruzo AJ, et al. Androgen producing luteinized granulosa cell tumor. Acta Obstet Gynecol Scand 1997;76:285–6. 8. Evans AT 3rd, Gaffey TA, Malkasian GD Jr, Annegers JF. Clinicopathologic review of 118 granulosa and 82 theca cell tumors. Obstet Gynecol 1980;55:231–8. 9. Kumar V, Abbas AK, Fausto N, Robbins SL, Cotran RS. Robbins and Cotran pathologic basis of disease. 7th ed. Philadelphia: Elsevier Saunders, 2005. 10. Miller BE, Barron BA, Wan JY, Delmore JE, Silva EG, Gershenson DM. Prognostic factors in adult granulosa cell tumor of the ovary. Cancer 1997;79:1951–5. 11. Giuntoli RL, Celebre JA, Wu CH, Wheeler JE, Mikuta JJ. Androgenic function of a granulosa cell tumor. Obstet Gynecol 1976;47:77–9. 12. Schumer ST, Cannistra SA. Granulosa cell tumor of the ovary. J Clin Oncol 2003;21:1180–9. 13. Stuart GC, Dawson LM. Update on granulosa cell tumours of the ovary. Curr Opin Obstet Gynecol 2003;15:33–7.
933.e15