Virilization of a postmenopausal woman by a mucinous cystoadenoma

Virilization of a postmenopausal woman by a mucinous cystoadenoma Objective: To describe the case of the most hyperandrogenaemic ovarian mucinous cystadenoma reported to date. Methods: We present the clinical, laboratory and radiologic findings in a patient with an unusual diagnosis according to age and the clinical behaviour of the tumour, as well as a review of relevant literature. Results: A 77-year-old women came to our consult because of fronto-parietal alopecia and an augmentation of the abdominal perimeter since 1 year ago. Clitoromegaly was observed during the physical examination. Hormonal analysis showed elevated testosterone and dehydroepiandrostenerone-sulphate levels (659 ng/dL and 1950 ng/ml, respectively), and imaging examination described an andexal cystic mass dependent on the right ovary. Pathological diagnosis was “mucinous cystoadenoma”. After surgery, clinical and analytical alterations were normalized. Conclusion: Although ovarian mucinous cystadenomas are classically classified as “nonfunctional” tumours, they exceptionally can act as functional, and produce testosterone levels as high as directly secreting hormones or germ cell tumours. examination, the following findings were recorded: blood pres- CASE REPORT sure: 125/80 mmHg, pulse: 88 bpm, height: 1.74 m, weight: A 77-year-old woman was evaluated in our outpatient endo- 53 kg, body mass index: 24.5 kg/m and waist circumference: crinology clinic because of alopecia. She reported a 1-year his- 99 cm. She showed a male-baldness pattern (Ludwig score: II-2/ tory of frontal and parietal alopecia and progressive abdominal III). She had no hirsutism (modified Ferriman–Gallwey score: 3). swelling. She had not noticed the development of hirsutism, She presented a significant abdominal wall distension, with a deepening of her voice, increased muscle mass or menorrhagia. big palpable mass on the right hemiabdomen. A pelvic examin- No other diseases of interest were known and no treatment ation revealed female external genitalia with clitoromegaly. No had been followed. About her obstetric history, she referred other findings were found. menarche at 17 years, with regular cycles. She had two healthy Virilization of recent onset and rapid progression sug- children and no miscarriages. Menopause was diagnosed at age gested an androgen-secreting tumour. We simultaneously 52. She had never been checked by a gynaecologist. On physical ordered an androgen profile, tumour markers and a transvaginal Received: June 15, 2017. Revised: September 18, 2017. Accepted: November 2, 2017 © The Author 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/omcr/article-abstract/2018/1/omx084/4812539 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Virilization of a postmenopausal woman 25 Neoplasm histopathology showed a 24 cm × 9cm × 11 cm large cystic tumour of 3.5 kg of weight originated from the right ovary. It had a whitish-grey coloration and a cystic membran- ous appearance within a yellowish serous content. Its micro- scopic examination showed nests of luteinized cells in the cyst wall (Fig. 2) with a final diagnosis of ’mucinous cystadenoma with stromal luteinization’. Three months after surgery, the patient had a normal serum total testosterone of 36 ng/dl. DISCUSSION The present clinical case exemplifies how many times postme- nopausal hyperandrogenism becomes in a diagnostic challenge. Postmenopausal virilization may be associated to adrenal or ovarian androgen-secreting tumours or to benign conditions. A detailed clinical history is critical to make out between the mild phenotype that characterizes benign causes from the rapid pro- gression and severe hyperandrogenism, including virilization, of androgen-secreting tumours. When symptoms clearly develop after menopause, hyperandrogenism is severe, progression is rapid and virilization or defeminization is present, adrenal and ovarian imaging must be immediately ruled out. Postmenopausal virilization may result from adrenal tumours, including androgen-secreting carcinomas and adenomas; from ovarian Figure 1: Abdomino-pelvic magnetic nuclear resonance. Voluminous mass, tumours, including Sertoli–Leydig cell tumours (androblastoma, with a cystic appearance, dependent on pelvic structures arrhenoblastoma), granulosa-theca cell tumours and hilus cell tumours; or from benign ovarian conditions such as ovarian stro- mal hyperplasia and hyperthecosis [1]. Rare causes, such as trans- fer of testosterone from a male partner using testosterone gels, have been also described. Ovarian mucinous cystadenomas are classically considered as ‘non-functional’ tumours. This neoplasm represents around 8–25% of all ovarian tumours. It is more prevalent from the third to fifth decades of life, being exceptional before puberty and after menopause. Very few cases of postmenopausal women with an androgen-producing mucinous cystadenoma had been reported, most of them in pregnant women [2–5]. Anecdotically, this tumour is diagnosed in adolescents [6], and to the best of our knowledge, only two cases have been reported in postmenopausal women [7, 8]. Only three of them had severe hyperandrogenemia [3, 7, 8]. In our patient, circulat- ing total testosterone levels were on male range, a feature asso- ciated to other androgen-secreting neoplasms and germ cell tumours [9]. The reason why those epithelial tumours can secrete andro- Figure 2: Histopathologic examination, ovarian cells with a positive inhibin gens as a functional one is not well known. Some authors have staining, which makes us believe in the presence of luteinized stromal cells proposed that tumour cells may synthesize several stimulus that are polygonal shaped and have enlarged pale eosinophilic cytoplasm for proliferation and differentiation into hormone-producing cells including gonadotropins or β-hCG [10]. In conceptual ultrasonography. Laboratory findings showed a total testosterone agreement, most of these tumours are diagnosed during preg- (by radioimmunoassay) of 659 ng/dl (10–70 ng/dl), dehy- nancy. In our case, FSH was normal for postmenopausal range, droepiandrosterone-sulphate of 1950 ng/ml (170–900 ng/ml), LH was mildly suppressed according to androgen levels and FSH of 75 IU/l, LH of 28 IU/l and estradiol of 25 pg/ml. Biochemical β-HCG was normal. Lastly, another hypothesis is the presence tumour markers studied including human chorionic gonado- of a mechanical effect, so that, the amount of hormone produc- tropin (β-HCG), alpha-fetoprotein, carcinoembryonic antigen, tion would be due to a direct contact between neoplastic epi- CA-125, CA19-9, lactate dehydrogenase were all negative and thelial and stromal cells surfaces [2–5]. other biochemical parameters were normal as well. We would like to emphasize that these kinds of tumours Transvaginal sonography revealed a 22 cm × 16 cm right appear to present with higher testosterone levels in postmeno- adnexal cystic mass. An ulterior abdomino-pelvic magnetic res- pausal women than in younger patients, a fact to be considered onance imaging confirmed a huge 20 cm × 14 cm × 22 cm cystic in future studies. lesion dependent of pelvic structures (Fig. 1). Both, radiologic In conclusion, we report an unusual case of a postmenopau- and laboratory, data agreed with an ovarian neoplasm. A hys- sal woman with an androgen-producing ovarian mucinous terectomy with double oophorectomy was indicated and per- cystadenoma, which is a very rare diagnosis according to its formed with no surgical complications. behaviour as a functional neoplasm, especially in that range of Downloaded from https://academic.oup.com/omcr/article-abstract/2018/1/omx084/4812539 by Ed 'DeepDyve' Gillespie user on 16 March 2018 26 S. Alonso Díaz et al. age. This case shows that stromal cells-derived tumours are 3. Cotton DB, Hanson FW, Oi RH. A mucinous cystadenoma able to induce severe hyperandrogenism and virilization, and associated with testorterone production. J Reprod Med 1989; they have to be included in the differential diagnosis of a post- 26:276–8. menopausal women with hyperandrogenism. 4. Antoniou N, Varras M, Akrivis CH, Demou A, Bellou A, Stefanaki S. Mucinous cystadenoma of the ovary with func- tioning stroma and virilization in pregnancy: a case report and FUNDING review of the literature. Clin Exp Obstet Gynecol 2003;30:248–52. This work has been supported by a grant Fondo de Investigación 5. Bolat F, Parlakgumus A, Canpolat T, Tuncer I. Benign Sanitaria (PI1400649) from Instituto de Salud Carlos III, Spanish mucinous cystadenoma with stromal luteinization respon- Ministry of Economy and Competitiveness. M.L.-R. has a local sible for maternal virilization and fetal intrauterine growth grant for clinical research from the Instituto Ramón y Cajal de restriction. J Obstet Gynaecol Res 2011;37:893–6. Investigación Sanitaria (IRYCIS). CIBERDEM is also an initiative 6. Thomas RL, Carr BR, Ziadie MS, Wilson EE. Bilateral muci- of Instituto de Salud Carlos III, partially supported by Fondo nosus cystadenomas and massive edema of the ovaries Europeo de Desarrollo Regional FEDER. There were no other in a virilised adolescent girl. Obstet Gynecol 2012;120: sources of funding. 473–6. 7. Detre Z, Földes E. Mucinous cystadenocarcinoma of ovary CONFLICT OF INTEREST STATEMENT with Leydig cell hyperplasia. Pathol Res Pract 1984;178: 400–2. None declared. 8. Alvarez RD, Varner RE. Hyperandrogenic state associated with a mucinous cystadenoma. Obstet Gynecol 1987;69:507–10. REFERENCES 9. Glintborg D, Altinok ML, Petersen KR, Ravn P. Total testos- terone levels are often more than three times elevated in 1. Alpañés M, González-Casbas JM, Sánchez J, Pián H, Escobar- patients with androgen-secreting tumours. BMJ Case Rep Morreale HF. Management of postmenopausal virilization. 2015;2015:bcr2014204797. J Clin Endocrinol Metab 2012;97:2584–9. 10. Quinn MA, Baker HWG, Rome R, Fortune D, Brown JB. 2. Kucur SK, Acar C, Temizkan O, Ozagari A, Gozukara I, Akyol A. Response of a mucinous ovarian tumor of borderline malig- A huge ovarian mucinous cystadenoma causing virilization, nancy to human chorionic gonadotropin. Obstet Gynecol preterm labor, and persistent supine hypotensive syndrome 1983;61:121–6. during pregnancy. Autops Case Rep 2016;6:39–43. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/1/omx084/4812539 by Ed 'DeepDyve' Gillespie user on 16 March 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Oxford Medical Case Reports Oxford University Press

Virilization of a postmenopausal woman by a mucinous cystoadenoma

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Abstract

Objective: To describe the case of the most hyperandrogenaemic ovarian mucinous cystadenoma reported to date. Methods: We present the clinical, laboratory and radiologic findings in a patient with an unusual diagnosis according to age and the clinical behaviour of the tumour, as well as a review of relevant literature. Results: A 77-year-old women came to our consult because of fronto-parietal alopecia and an augmentation of the abdominal perimeter since 1 year ago. Clitoromegaly was observed during the physical examination. Hormonal analysis showed elevated testosterone and dehydroepiandrostenerone-sulphate levels (659 ng/dL and 1950 ng/ml, respectively), and imaging examination described an andexal cystic mass dependent on the right ovary. Pathological diagnosis was “mucinous cystoadenoma”. After surgery, clinical and analytical alterations were normalized. Conclusion: Although ovarian mucinous cystadenomas are classically classified as “nonfunctional” tumours, they exceptionally can act as functional, and produce testosterone levels as high as directly secreting hormones or germ cell tumours. examination, the following findings were recorded: blood pres- CASE REPORT sure: 125/80 mmHg, pulse: 88 bpm, height: 1.74 m, weight: A 77-year-old woman was evaluated in our outpatient endo- 53 kg, body mass index: 24.5 kg/m and waist circumference: crinology clinic because of alopecia. She reported a 1-year his- 99 cm. She showed a male-baldness pattern (Ludwig score: II-2/ tory of frontal and parietal alopecia and progressive abdominal III). She had no hirsutism (modified Ferriman–Gallwey score: 3). swelling. She had not noticed the development of hirsutism, She presented a significant abdominal wall distension, with a deepening of her voice, increased muscle mass or menorrhagia. big palpable mass on the right hemiabdomen. A pelvic examin- No other diseases of interest were known and no treatment ation revealed female external genitalia with clitoromegaly. No had been followed. About her obstetric history, she referred other findings were found. menarche at 17 years, with regular cycles. She had two healthy Virilization of recent onset and rapid progression sug- children and no miscarriages. Menopause was diagnosed at age gested an androgen-secreting tumour. We simultaneously 52. She had never been checked by a gynaecologist. On physical ordered an androgen profile, tumour markers and a transvaginal Received: June 15, 2017. Revised: September 18, 2017. Accepted: November 2, 2017 © The Author 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/omcr/article-abstract/2018/1/omx084/4812539 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Virilization of a postmenopausal woman 25 Neoplasm histopathology showed a 24 cm × 9cm × 11 cm large cystic tumour of 3.5 kg of weight originated from the right ovary. It had a whitish-grey coloration and a cystic membran- ous appearance within a yellowish serous content. Its micro- scopic examination showed nests of luteinized cells in the cyst wall (Fig. 2) with a final diagnosis of ’mucinous cystadenoma with stromal luteinization’. Three months after surgery, the patient had a normal serum total testosterone of 36 ng/dl. DISCUSSION The present clinical case exemplifies how many times postme- nopausal hyperandrogenism becomes in a diagnostic challenge. Postmenopausal virilization may be associated to adrenal or ovarian androgen-secreting tumours or to benign conditions. A detailed clinical history is critical to make out between the mild phenotype that characterizes benign causes from the rapid pro- gression and severe hyperandrogenism, including virilization, of androgen-secreting tumours. When symptoms clearly develop after menopause, hyperandrogenism is severe, progression is rapid and virilization or defeminization is present, adrenal and ovarian imaging must be immediately ruled out. Postmenopausal virilization may result from adrenal tumours, including androgen-secreting carcinomas and adenomas; from ovarian Figure 1: Abdomino-pelvic magnetic nuclear resonance. Voluminous mass, tumours, including Sertoli–Leydig cell tumours (androblastoma, with a cystic appearance, dependent on pelvic structures arrhenoblastoma), granulosa-theca cell tumours and hilus cell tumours; or from benign ovarian conditions such as ovarian stro- mal hyperplasia and hyperthecosis [1]. Rare causes, such as trans- fer of testosterone from a male partner using testosterone gels, have been also described. Ovarian mucinous cystadenomas are classically considered as ‘non-functional’ tumours. This neoplasm represents around 8–25% of all ovarian tumours. It is more prevalent from the third to fifth decades of life, being exceptional before puberty and after menopause. Very few cases of postmenopausal women with an androgen-producing mucinous cystadenoma had been reported, most of them in pregnant women [2–5]. Anecdotically, this tumour is diagnosed in adolescents [6], and to the best of our knowledge, only two cases have been reported in postmenopausal women [7, 8]. Only three of them had severe hyperandrogenemia [3, 7, 8]. In our patient, circulat- ing total testosterone levels were on male range, a feature asso- ciated to other androgen-secreting neoplasms and germ cell tumours [9]. The reason why those epithelial tumours can secrete andro- Figure 2: Histopathologic examination, ovarian cells with a positive inhibin gens as a functional one is not well known. Some authors have staining, which makes us believe in the presence of luteinized stromal cells proposed that tumour cells may synthesize several stimulus that are polygonal shaped and have enlarged pale eosinophilic cytoplasm for proliferation and differentiation into hormone-producing cells including gonadotropins or β-hCG [10]. In conceptual ultrasonography. Laboratory findings showed a total testosterone agreement, most of these tumours are diagnosed during preg- (by radioimmunoassay) of 659 ng/dl (10–70 ng/dl), dehy- nancy. In our case, FSH was normal for postmenopausal range, droepiandrosterone-sulphate of 1950 ng/ml (170–900 ng/ml), LH was mildly suppressed according to androgen levels and FSH of 75 IU/l, LH of 28 IU/l and estradiol of 25 pg/ml. Biochemical β-HCG was normal. Lastly, another hypothesis is the presence tumour markers studied including human chorionic gonado- of a mechanical effect, so that, the amount of hormone produc- tropin (β-HCG), alpha-fetoprotein, carcinoembryonic antigen, tion would be due to a direct contact between neoplastic epi- CA-125, CA19-9, lactate dehydrogenase were all negative and thelial and stromal cells surfaces [2–5]. other biochemical parameters were normal as well. We would like to emphasize that these kinds of tumours Transvaginal sonography revealed a 22 cm × 16 cm right appear to present with higher testosterone levels in postmeno- adnexal cystic mass. An ulterior abdomino-pelvic magnetic res- pausal women than in younger patients, a fact to be considered onance imaging confirmed a huge 20 cm × 14 cm × 22 cm cystic in future studies. lesion dependent of pelvic structures (Fig. 1). Both, radiologic In conclusion, we report an unusual case of a postmenopau- and laboratory, data agreed with an ovarian neoplasm. A hys- sal woman with an androgen-producing ovarian mucinous terectomy with double oophorectomy was indicated and per- cystadenoma, which is a very rare diagnosis according to its formed with no surgical complications. behaviour as a functional neoplasm, especially in that range of Downloaded from https://academic.oup.com/omcr/article-abstract/2018/1/omx084/4812539 by Ed 'DeepDyve' Gillespie user on 16 March 2018 26 S. Alonso Díaz et al. age. This case shows that stromal cells-derived tumours are 3. Cotton DB, Hanson FW, Oi RH. A mucinous cystadenoma able to induce severe hyperandrogenism and virilization, and associated with testorterone production. J Reprod Med 1989; they have to be included in the differential diagnosis of a post- 26:276–8. menopausal women with hyperandrogenism. 4. Antoniou N, Varras M, Akrivis CH, Demou A, Bellou A, Stefanaki S. Mucinous cystadenoma of the ovary with func- tioning stroma and virilization in pregnancy: a case report and FUNDING review of the literature. Clin Exp Obstet Gynecol 2003;30:248–52. This work has been supported by a grant Fondo de Investigación 5. Bolat F, Parlakgumus A, Canpolat T, Tuncer I. Benign Sanitaria (PI1400649) from Instituto de Salud Carlos III, Spanish mucinous cystadenoma with stromal luteinization respon- Ministry of Economy and Competitiveness. M.L.-R. has a local sible for maternal virilization and fetal intrauterine growth grant for clinical research from the Instituto Ramón y Cajal de restriction. J Obstet Gynaecol Res 2011;37:893–6. Investigación Sanitaria (IRYCIS). CIBERDEM is also an initiative 6. Thomas RL, Carr BR, Ziadie MS, Wilson EE. Bilateral muci- of Instituto de Salud Carlos III, partially supported by Fondo nosus cystadenomas and massive edema of the ovaries Europeo de Desarrollo Regional FEDER. There were no other in a virilised adolescent girl. Obstet Gynecol 2012;120: sources of funding. 473–6. 7. Detre Z, Földes E. Mucinous cystadenocarcinoma of ovary CONFLICT OF INTEREST STATEMENT with Leydig cell hyperplasia. Pathol Res Pract 1984;178: 400–2. None declared. 8. Alvarez RD, Varner RE. Hyperandrogenic state associated with a mucinous cystadenoma. Obstet Gynecol 1987;69:507–10. REFERENCES 9. Glintborg D, Altinok ML, Petersen KR, Ravn P. Total testos- terone levels are often more than three times elevated in 1. Alpañés M, González-Casbas JM, Sánchez J, Pián H, Escobar- patients with androgen-secreting tumours. BMJ Case Rep Morreale HF. Management of postmenopausal virilization. 2015;2015:bcr2014204797. J Clin Endocrinol Metab 2012;97:2584–9. 10. Quinn MA, Baker HWG, Rome R, Fortune D, Brown JB. 2. Kucur SK, Acar C, Temizkan O, Ozagari A, Gozukara I, Akyol A. Response of a mucinous ovarian tumor of borderline malig- A huge ovarian mucinous cystadenoma causing virilization, nancy to human chorionic gonadotropin. Obstet Gynecol preterm labor, and persistent supine hypotensive syndrome 1983;61:121–6. during pregnancy. Autops Case Rep 2016;6:39–43. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/1/omx084/4812539 by Ed 'DeepDyve' Gillespie user on 16 March 2018

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