A Rare Adolescent Case of Female Pseudohermaphroditism With Adrenocortical Carcinoma and Synchronous Teratoma
Xiao-Feng He, MD, ** Xing-Chen Peng, MD,* and Meng Qiu, MD*
Summary: A patient with female pseudohermaphroditism is chro- mosomally and gonadally a female individual but has male or ambiguous external genitalia. In this paper, we report a 12-year-old Chinese girl who was diagnosed with female pseudohermaphrodi- tism characterized by clitoridauxe, hirsutism, acne, hypertension, and karyotype 46 XX. Computed tomography scan revealed a huge left abdominal mass with distant metastases to bilateral lungs and a concomitant pelvic teratoma. Because the left abdominal mass was unresectable, the patient underwent a biopsy of the abdominal mass and a radical resection of the pelvic teratoma. Histopathology confirmed that the left abdominal mass was an adrenocortical carcinoma (ACC) and the pelvic teratoma was a mature cystic teratoma originating from the left ovary. After surgery, the patient received a transcatheter arterial chemoembolization of ACC, combined with 2 g mitotane daily for systemic treatment. It was a pity that she died 8 months later after diagnosis. So far, as we know, the simultaneous occurrence of pseudohermaphroditism, ACC, and ovarian teratomas has not been reported in the liter- atures before.
Key Words: female pseudohermaphroditism, adrenocortical carci- noma, teratoma
(J Pediatr Hematol Oncol 2013;35:e183-e186)
P atients with female pseudohermaphroditism (FPH) have female internal genitalia and karyotype (46 XX) but exhibit various degree of external genitalia virilization.1,2 External genitalia is masculinized congenitally when female fetus is exposed to excess androgenic environment. Con- genital adrenal hyperplasia is the commonest cause of FPH. Excessive maternal androgen levels because of maternal ovarian tumor or drug intake could also cause FPH. In addition, androgen-producing tumors of female fetus themselves, with either adrenal or ovarian origin, may also lead to masculinization.2 Here, we first report a case of FPH with a large adrenocortical carcinoma (ACC) and a synchronous ovarian mature teratoma, which can both be the causes of FPH.
CASE REPORT
A 12-year-old Chinese girl who complained with left abdominal discomfort was referred to our hospital on July 18, 2010. She was found to have an enlarged clitoris since the age of 8
years. The chromosome analysis demonstrated karyotype 46 XX, and an ultrasound of the pelvic region revealed an infantile uterus. Her family medical history did not suggest predisposition to can- cer, and her mother had no history of taking androgenic drugs or radiation exposure during pregnancy.
Clinical Features
The patient presented at our institution with elevated blood pressure (148/103 mm Hg), hirsutism, scattered acnes on her face, facial and pubic hair with male escutcheon, and with no breast development (Fig. 1). A palpable mass was touched on the left of abdomen, tenacious and fixed. External genitalia showed clitoral enlargement, with no labial fusion, and the opening of urethra and vagina were normal. Although quiet most of the time, she some- times behaved in a male-like manner, being irritable and ram- bunctious, and she spoke with a low rough voice.
Hormone Studies
Before surgery, the serum levels of testosterone (10.15 ng/mL; normal range, 2.49 to 8.36 ng/mL), dehydroepiandrosterone sulfate (DHEA-S) (>27.140 µmol/L; normal range, 0.92 to 7.60 umol/L), and aldosterone (349.84 ng/L; normal range, 45 to 175 ng/L) were significantly elevated, and the diurnal rhythm of cortisol was dis- turbed. In contrast, the levels of follicle-stimulating hormone (0.2 mIU/mL; normal range, 1.8 to 9.4 mIU/mL) and luteinizing hormone (<0.1 mIU/mL; normal range, 0.8 to 10.4 mIU/mL) were particularly low. After surgery, the levels of testosterone, DHEA-S, and aldosterone were still high, whereas after transcatheter arterial chemoembolization (TACE), only aldosterone level decreased slightly.
Computed Tomography
CT scanning (Fig. 2) showed a 19×16x12cm sized left abdominal mass with areas of definite calcification and necrosis, which enhanced intensely after contrast administration. Moreover, there were multiple nodules in bilateral lungs, which were consid- ered lung metastases. Furthermore, there was a 12× 10x 11 cm sized pelvic mass, well defined, with mixed adipose tissue, bone, calcification, and liquid densities.
Histopathology
Pelvic cavity: mature cystic teratoma. Retroperitoneum: ACC. Immunohistochemistry: «-Inhibin (+), Mart-1 (+), CR ( ±, focally), EMA (-), PCK (-), CK7 (-), CK8 (-), CgA (-), Syn (-), AFP (-), PLAP (-), CD30 (-), HCC (-), and Ki67 (+, 10% ~20%).
Treatment and Follow-Up
A palliative surgery was performed on August 10, 2010. On laparotomy, the teratoma was found originating from the left ovary, filled with hair and cartilage. The bilateral ovaries developed poorly. The left retroperitoneal mass was hard and had no clear boundaries with adjacent tissues. The ovarian teratoma was com- pletely resected, but just a biopsy was performed for the retro- peritoneal mass. It was found that the testosterone levels in the left suprarenal vein were markedly elevated compared with the low levels in the left ovarian vein. Subsequently, the patient received a TACE of ACC, with 20 mL lipiodol and 30 mg of adriamycin. Meanwhile, she took 2 g mitotane daily for systemic treatment and 40 mg spironolactone twice per day for blood pressure controlling.
From the *Cancer Center, Division of Abdominal Cancer, West China Hospital of Sichuan University; and Department of Medical Oncology, The First People’s Hospital of Longquanyi District, Chengdu, China.
The authors declare no conflict of interest.
Reprints: Meng Qiu, MD, Cancer Center, Division of Abdominal Cancer, West China Hospital of Sichuan University, 37 Guoxue Xiang Street, Chengdu, Sichuan Province, China 610041 (e-mail: qiumeng33@ hotmail.com).
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After half a month of receiving TACE, the blood pressure came down to normal range, and the serum levels of aldosterone had a slight decrease. CT scan showed that the adrenocortical tumor began to have a weakened enhancement and more liquefaction necrosis, although shrinked slightly (maximum diameter in 17.5 cm) (Fig. 2). It was a pity that she abandoned therapy later and died of massive hemoptysis because of the pulmonary meta- stasis on March 26, 2011. The survival period of the patient from the time of diagnosis was 8 months and that from the appearance of virilization signs was about 4 years.
DISCUSSION
Human beings’ sexual development depends on the successful completion of a series of steps under genetic and hormonal control. This process requires the accomplish- ment of 3 basic steps: chromosomal sex, gonadal sex, and phenotypic sex. When chromosomal sex and gonadal sex agree but the internal or external genitalia are ambiguous to some degree, affected individuals are either male or female pseudohermaphrodites.1 Because of the ambiguity of genitalia
and difficulties in making an accurate diagnosis, the inci- dence of pseudohermaphroditism is not well established. The incidence of male pseudohermaphroditism has been estimated to be 3 to 15 per 100,000 people versus 1 to 8 per 100,000 people of FPH.3 Female pseudohermaphrodites have chromosomal phenotype 46 XX and have ovaries, but they exhibit androgen-dependent masculinization of geni- talia.1 Excessive androgen levels in female individuals may affect primary sexual characteristics by masculinizing the fetal external genitalia to result in FPH or secondary sexual characteristics by inducing changes similar to those char- acteristic of male puberty resulting in virilization. Our patient was found of masculinization at the age of 8, and a large left ACC and a synchronous ovarian mature teratoma were discovered later at the age of 12, which could both be the causes of FPH, and this phenomena has not been reported before.
Teratomas are the most common germ cell tumors in children and adolescents, and the ovary is second only to the sacrococcygeal area as the most common site for their
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appearance in childhood. The mean age at diagnosis of ovarian teratomas is 13 and is similar for patients with immature or mature teratomas.4 Virilization from ovarian teratomas is exceptionally rare in pediatrics and ado- lescence.5 There are debates on whether mature teratomas have the function of androgen secretion, and currently only a few cases have been reported.5-8 All performances for virilization, androgens, and the androgen level returned to normal after surgery.6 Our patient was masculinized with hirsutism, acne, and clitoridauxe, whereas the testosterone levels of the left ovarian vein were not elevated, after a radical resection of the mature teratoma, and the androgen level was still high, which indicated that it may have nothing to do with FPH.
ACC is a rare malignancy, accounting annually for about 0.05% to 0.2% of all cancers and the incidence is 1 to 2 per million/y. The age distribution is reported as bimodal with a first peak in childhood and a second higher peak in the fourth and fifth decade.9 In children and adolescents, a worldwide incidence is estimated as 0.3 per 1 million children younger than 15 years of age.10 Adolescents and young adults tended to have Cushing syndrome or nonfunctional tumors at presentation, whereas >90% of young children had vir- ilizing features,11 marked overproduction of androgens, and a less aggressive clinical course.12
Most ACCs arise sporadically. To our knowledge, ACC has been reported to occur synchronously with rectal cancer, breast cancer, testicular seminoma, ganglioneuro- blastoma, osteosarcoma, renal cell carcinoma, and endo- metrioid adenocarcinoma,13 but there have been no report of ACC with synchronous ovarian teratoma in child patients. Here, we report the first case.
Various prognostic factors have been reported relative to poor survival outcomes in ACC, such as staging, large tumor size (diameter >12cm), high mitotic index (> 6/ 10 HPF), high Ki67 staining, mutated TP53, and the resec- tion status.14 Above all, staging is the most important and better-validated prognostic factor. In metastatic ACC, the 2 major predictors of survival were found to be the number of metastatic organs and mitotic index.15 Median overall sur- vival of stage IV disease is < 12 months.10 For our patient, the interval between the appearance of virilization signs and the diagnosis was about 4 years. When diagnosis was made, the girl was already in stage IV because of metastases to bilateral lungs. Furthermore, the tumor size was 19 cm in maximum diameter, which led to no chance of radical resection, and the Ki67 index was about 10~20%. In addi- tion, the patient did not stick to treatment. All the above factors indicated a dismal outcome.
Systemic treatment should be initiated as soon as an advanced-stage ACC is established. As it is well known that mitotane (o,p _- DDD) is the only adrenal-specific agent available for treatment of ACC and has been studied extensively, it is now clear that mitotane has, at best, a 19% to 22% response rate.16 The recommended first-line treat- ment regimens are mitotane monotherapy, etoposide, doxorubicin, cisplatin plus mitotane (EDP-M), or strepto- zotocin plus mitotane (Sz-M).17 If mitotane-based chemo- therapy fails, gemcitabine plus metronomic capecitabine can be an alternative choice.18 Nowadays, new “targeted therapies” have also been tested in patients with advanced ACC. However, the results of these studies were rather disappointing.19-21 So far, an orally available IGF-1 receptor inhibitor (OSI-906) has been seen with a prelim- inary antitumor activity in ACC,22 and a phase III trial on
this drug as a second-line or third-line therapy is ongoing in several countries.
In advanced-stage ACC, debulking surgery may be of benefit for patients with symptom control because of hor- mone overproduction.11 For inoperable disease, TACE or transcatheter arterial embolization may be an alternative option, which is a minimally invasive procedure success- fully performed in patients with unresectable primary and metastatic liver tumors. Although there is a less-extensive literature available regarding the use of transcatheter che- moembolization of adrenal tumors23; adrenal arterial embolization may play an effective role with mild side effects (eg, hypertension) in palliation of pain and reduction of hormone production.24,25 In our patient, the ACC revealed intense enhancement on CT scanning, which indicated rich blood supply; therefore, we performed adrenal arterial embolization of ACC with lipiodol and adriamycin at a slow rate (~1 mL/min). Meanwhile, a careful monitoring of the vital signs through an arterial line was carried out throughout the procedure, and a physician of endocrinology was present. The whole procedure was successful; however, only transient moderate increases in blood pressure occurred. After half a month, CT scan revealed the tumor with a weakened enhancement and more liquefaction necrosis, and the serum aldosterone levels decreased. Thus, adrenal arterial embolization combined with mitotane-based chemotherapy can be a choice in inoperable or recurrent ACC, although its safety and sur- vival benefits need to be confirmed in further studies.
In conclusion, we report the first case of FPH with ACC and synchronous ovarian teratoma. ACC was mainly responsible for virilization. In advanced-stage ACC, selec- tive adrenal arterial embolization combined with mitotane- based chemotherapy can be a palliative option without serious side effects for symptom control.
ACKNOWLEDGMENTS
The authors thank Drs Yao-Tiao Deng, Ze-Dong Du for revision of the English manuscript.
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