Pseudoprecocity Due to Lesions of the Ovary

Published on 22/03/2015 by admin

Filed under Pediatrics

Last modified 22/04/2025

Print this page

This article have been viewed 1446 times

Chapter 581 Pseudoprecocity Due to Lesions of the Ovary

Alvina R. Kansra, Patricia A. Donohoue

Ovarian tumors are rare in pediatrics, occurring at a rate of less than 3/100,000. Most ovarian masses are benign, but 10-30% may be malignant. Ovarian malignancies, the most common genital neoplasms in adolescence, account for only 1% of childhood cancers. More than 60% are germ cell tumors, most of which are dysgerminomas that can secrete tumor markers and hormones (Chapter 497). Five to 10% of them occur in phenotypic females with abnormal gonads associated with the presence of a Y chromosome. Next most common are epithelial cell tumors (20%), and nearly 10% are sex cord/stromal tumors (granulosa, Sertoli cell, and mesenchymal tumors). Multiple tumor markers can be seen in ovarian tumors, including α-fetoprotein, human chorionic gonadotropin (hCG), carcinoembryonic antigen, oncoproteins, p105, p53, KRAS mutations, cyclin D1, epidermal growth factor–related proteins and receptors, cathepsin B, and others. Variable levels of inhibin-activin subunit gene expression have been detected in ovarian tumors.

Functioning lesions of the ovary consist of benign cysts or malignant tumors. The majority synthesize estrogens; a few synthesize androgens. The most common estrogen producing ovarian tumor causing precocious puberty is the granulosa cell tumor. Other tumors that can cause precocious puberty are thecomas, luteomas, mixed types, theca-leutein and follicular cysts, and ovarian tumors (i.e., teratoma, choriocarcinoma, and dysgerminoma).

Estrogenic Lesions of the Ovary

These lesions cause isosexual precocious sexual development but account for only a small percentage of all cases of precocity. Benign ovarian follicular cysts are the most common tumors associated with isosexual precocious puberty in girls; they may rarely be gonadotropin dependent.

Juvenile Granulosa Cell Tumor

In childhood, the most common neoplasm of the ovary with estrogenic manifestations is the granulosa cell tumor, although it makes up only 1-10% of all ovarian tumors. These tumors have distinctive histologic features that differ from those encountered in older women (adult granulosa cell tumor). The cells have high mitotic activity, follicles are often irregular, Call-Exner bodies are rare, and luteinization is frequent. The tumor may be solid or cystic, or both. It usually is benign. In a few instances, this tumor has been associated with multiple enchondromas (Ollier disease) and, in fewer still, with multiple subcutaneous hemangiomas (Maffucci syndrome).

Clinical Manifestations and Diagnosis

The tumor has been observed in newborns and may manifest with sexual precocity at 2 yr of age or younger; about half these tumors have occurred before 10 yr of age. The mean age at diagnosis is 7.5 yr. The tumors are almost always unilateral. The breasts become enlarged, rounded, and firm and the nipples prominent. The external genitals resemble those of a normal girl at puberty, and the uterus is enlarged. A white vaginal discharge is followed by irregular or cyclic menstruation. Ovulation, however, does not occur. The presenting manifestation may be abdominal pain or swelling. Pubic hair is usually absent unless there is mild virilization.

A mass is readily palpable in the lower portion of the abdomen in most children by the time sexual precocity is evident. The tumor may be small, however, and escape detection even on careful rectal and abdominal examination; the tumors may be detected by ultrasonography, but multidetector CT scans are most sensitive. Most such tumors (90%) are diagnosed at very early stages of malignancy (FIGO [International Federation of Gynecology and Obstetrics] stage I).

Plasma estradiol levels are markedly elevated. Plasma levels of gonadotropins are suppressed and do not respond to gonadotropin-releasing hormone (GnRH) analog stimulation. Levels of antimüllerian hormone (AMH), inhibin B, and α-fetoprotein may be elevated. Activating mutations of GSα are seen in 30%, and GATA-4 expression is retained in the more aggressive tumors while AMH levels are inversely proportional to tumor size. Osseous development is moderately advanced. Several case reports showing the association of 45X/46XY karyotype and ambiguous genitalia with ovarian granulosa tumor have been published in literature.

Treatment and Prognosis

The tumor should be removed as soon as the diagnosis is established. Prognosis is excellent because fewer than 5% of these tumors in children are malignant. Advanced-stage tumors, however, behave aggressively and require difficult decisions regarding surgical approaches as well as the use of irradiation and chemotherapy. In adults with granulosa cell tumors, p53 expression is associated with unfavorable prognosis. Vaginal bleeding immediately after removal of the tumor is common. Signs of precocious puberty abate and may disappear within a few months after the operation. The secretion of estrogens returns to normal.

Sex cord tumor with annular tubules is a distinctive tumor, thought to arise from granulosa cells, that occurs primarily in patients with Peutz-Jeghers syndrome. These tumors are multifocal, bilateral, and usually benign. The presence of calcifications aids ultrasonographic detection. Increased aromatase production by these tumors results in gonadotropin-independent precocious puberty. Inhibin A and B levels are elevated and decrease after tumor removal. In 1 study, 9 of 13 sex cord/stromal tumors exhibited follicle-stimulating hormone (FSH) receptor mutations, suggesting a role for such mutation in the development of these tumors.

Chorioepithelioma has been reported only rarely. This highly malignant tumor is thought to arise from a pre-existing teratoma. The usually unilateral tumor produces large amounts of hCG, which stimulates the contralateral ovary to secrete estrogen. Elevated levels of hCG are diagnostic.

Follicular Cyst

Small ovarian cysts (<0.7 cm in diameter) are common in prepubertal children. At puberty and in girls with true isosexual precocious puberty, larger cysts (1-6 cm) are often seen; these are secondary to stimulation by gonadotropins. However, similar larger cysts occur occasionally in young girls with precocious puberty in the absence of LH and FSH. Because surgical removal or spontaneous involution of these cysts results in regression of pubertal changes, there is little doubt that they are its cause. The mechanism of production of these autonomously functioning cysts is unknown. Such cysts may form only once, or they may disappear and recur, resulting in waxing and waning of the signs of precocious puberty. They may be unilateral or bilateral. The sexual precocity that occurs in young girls with McCune-Albright syndrome is usually associated with autonomous follicular cysts caused by a somatic-activating mutation of the GSα-protein occurring early in development (Chapter 556.6). Gonadotropins are suppressed, and estradiol levels are often markedly elevated, but they may fluctuate widely and even temporarily may return to normal. GnRH analog stimulation fails to evoke an increase in gonadotropins. Ultrasonography is the method of choice for the detection and monitoring of such cysts. Aromatase inhibitors are shown to be the mainstay of the therapy in females with McCune-Albright Syndrome and persistent estradiol elevation. A short period of observation to ascertain the lack of spontaneous resolution is advisable before cyst aspiration or cystectomy is considered. Cystic neoplasms must be considered in the differential diagnosis.

Androgenic Lesions of the Ovary

Virilizing ovarian tumors are rare at all ages but particularly so in prepubertal girls. Arrhenoblastoma has been reported as early as 14 days of age, but few cases have been reported in girls younger than 16 yr of age.

The Gonadoblastoma occurs exclusively in dysgenetic gonads, particularly in phenotypic females who have a Y chromosome or a Y fragment in their genotype (46,XY; 45,X/46,XY; 45,X/46,X-fra). As noted above, there is a proposed gonadoblastoma locus on the Y chromosome (GBY). The tumors may be bilateral. Virilization occurs with some but not all tumors. The clinical features are the same as those seen in patients with virilizing adrenal tumors and include accelerated growth, acne, clitoral enlargement, and growth of sexual hair. A palpable, abdominal mass is found in about 50% of patients. Plasma levels of testosterone and androstenedione are elevated, and those of gonadotropins are suppressed. Ultrasonography, CT, and MRI usually localize the lesion. The dysgenetic gonad of phenotypic females with a Y chromosome or fragment of Y chromosome containing GBY should be removed prophylactically. When a unilateral tumor is removed, the contralateral dysgenetic gonad should also be removed. Association of gonadoblastoma and WAGR syndrome is also reported in the literature. In an immunohistochemical study of 2 gonadoblastomas, expressions of WT1, p53, and MIS as well as inhibin were all demonstrated.

Virilizing manifestations occur occasionally in girls with juvenile granulosa cell tumors. Adrenal rests and hilum cell tumors rarely lead to virilization. Activating mutations of G-protein genes have been described in ovarian (and testicular) tumors. GSα mutations, usually seen in gonadal tumors associated with McCune-Albright syndrome, were also noted in 4 of 6 Leydig cell tumors (3 ovarian, 1 testicular). Two granulosa cell tumors and 1 thecoma of 10 ovarian tumors studied were found to have GIP-2 mutations.

Sertoli-Leydig cell tumors, rare sex cord/stromal neoplasms, constitute less than 1% of ovarian tumors. The average age at diagnosis is 25 yr; less than 5% of these tumors occur before puberty. AFP levels may be mildly elevated. In one 12 mo old with Sertoli-Leydig cell tumor presenting with isosexual precocity the only detectable tumor marker was the serum inhibin level, with elevations in both A and B subunits. Five-year survival rates are 70-90%.

Of 102 consecutive patients who underwent surgery because of ovarian masses over a 15 yr period, the presenting symptoms were acute abdominal pain in 56% and abdominal or pelvic mass in 22%. Of 9 children whose cause for surgery was presumed malignancy, 3 had dysgerminomas, 2 had teratomas, 2 had juvenile granulosa cell tumors, 1 had a Sertoli-Leydig cell tumor, and 1 had a yolk sac tumor.

Anttonen M, Unkila-Kallio L, Leminen A, et al. High GATA-4 expression associates with aggressive behavior, whereas low anti-Müllerian hormone expression associates with growth potential of ovarian granulosa cell tumors. J Clin Endocrinol Metab. 2005;90:6529-6535.

Calaminus G, Wessalowski R, Harms D, et al. Juvenile granulosa cell tumors of the ovary in children and adolescents: results from 33 patients registered in a prospective cooperative study. Gynecol Oncol. 1997;65:447-452.

Cass DL, Hawkins E, Brandt ML, et al. Surgery for ovarian masses in infants, children, and adolescents: 102 consecutive patients treated in a 15-year period. J Pediatr Surg. 2001;36:693-699.

Choong CS, Fuller PJ, Chu S, et al. Sertoli-Leydig cell tumor of the ovary, a rare cause of precocious puberty in a 12 month-old infant. J Clin Endocrinol Metab. 2002;87:49-56.

Fink D, Kubik-Huch RA, Wildermuth S. Juvenile granulosa cell tumor. Abdom Imaging. 2001;26:550-552.

Fotiou SK. Ovarian malignancies in adolescence. Ann N Y Acad Sci. 1997;816:338-346.

Kalfa N, Ecochard A, Patte C, et al. Activating mutations of the stimulatory G protein in juvenile ovarian granulosa cell tumors: a new prognostic factor? J Clin Endocrinol Metab. 2006;91:1842-1847.

Lazar EL, Stolar CJ. Evaluation and management of pediatric solid ovarian tumors. Semin Pediatr Surg. 1998;7:29-34.

Powell JL, Connor GP, Henderson GS. Management of recurrent juvenile granulosa cell tumor of the ovary. Gynecol Oncol. 2001;81:113-116.

Silverman LA, Gitelman SE. Immunoreactive inhibin, müllerian inhibitory substance, and activin as biochemical markers for juvenile granulosa cell tumors. J Pediatr. 1996;129:918-921.

Stepanian M, Cohn D. Gynecologic malignancies in adolescents. Adolesc Med. 2004;15:549-568.

Related

Nelson Textbook of Pediatrics Expert Consult