Ovarian neoplasms and cysts represent only one per cent of all tumors of infants and children.1 Therefore, despite their role in the etiology of abdominal pain, abdominal masses, and iso- and heterosexual precocity, the diagnosis of ovarian tumor is rarely entertained in the pediatric population. It is the purpose of this article to emphasize the importance of ovarian tumors in infants, children, and adolescents and to review their pathology and treatment.
The first ovariotomy for an ovarian tumor in a child was performed on a 13-year-old girl by Giraldes2 in 1866. In 1905 Wiel3 reviewed 60 cases of ovarian tumors in children. In 1921 Downes4 found 26 additional cases, and in 1932 Loeb and Levy5 reviewed an additional 36 cases, bringing the total to 122. Witzberger and Agerty6 presented another 64 cases in 1937. A review of the world literature by Charache7 in 1959 brought the total to 263. From 1959 to 1967 an additional 107 cases were reported, bringing the total to 370. Additional cases continue to be reported as means of diagnosis, classification, and treatment continue to be refined.
Children with ovarian cysts and tumors have several typical clinical patterns. Rarely are patients completely asymptomatic.
The most frequent presenting complaint is abdominal pain. It may be acute in onset - requiring immediate hospitalization and therapy - or of a chronic, intermittent nature occurring over months to years.
The patient frequently is brought to the attention of the pediatrician because of an enlarging abdominal mass. This is especially common in neonatal ovarian cysts.
The importance of a bimanual examination with a finger in the rectum cannot be overemphasized in the evaluation of ovarian tumors. In the young female the uterus and ovaries are in the abdomen but as puberty approaches they lie in the pelvis, necessitating a bimanual examination for proper diagnosis.
Although relatively rare, functioning ovarian tumors are seen with the signs of iso- or heterosexual precocity. Most sexual precocity in female children, however, is rarely ascribed to a functioning ovarian tumor unless there is a palpable abdominal mass on careful bimanual examination.
The most common complication arising from ovarian tumors is torsion of the tumor upon its pedicle. Torsion produces a common picture of an acute abdomen - often misdiagnosed as appendicitis or an appendiceal abscess. The majority of childhood ovarian tumors appear to be right-sided.
Roentgenographic evaluation is often helpful in ruling out other causes of abdominal pain or masses. Abdominal x-rays may demonstrate a soft tissue mass or the calcification of a teratoma. Barium contrast studies may help to outline a mass, while arteriography often helps delineate cystic from solid lesions. An IVP rules out lithiasis, congenital defects of the urinary tract, and hydronephrosis. In addition, especially in the newborn period, the total body opacification effect of an IVP is an excellent aid in delineating abdominal masses The apparent lucency developed by an avascular mass during the circulation of injected contrast material through adjacent, well-vascularized structures is extremely helpful in delineating ovarian cysts. Air peritoneograms or peritoneoscopy are helpful with smaller tumors.
Classification of childhood ovarian tumors has proved to be a difficult task. Many of these tumors have characteristic histologic appearances but some are bizarre and confusing. Furthermore, because two or more cell types may be found in a single tumor, classification based upon histology has been unrewarding. Other criteria have included endocrine effect, morphology, or behavior with respect to malignancy. However, the most logical classification would seem to be based upon cellular origin of the tumor involved.8
MORPHOLOGIC CLASSIFICATION OF OVARIAN TUMORS
I. Non-neoplastic cyst of the ovary
A. Follicle cysts and corpus luteum cysts
B. Simple or unclassified cysts
II. Primary neoplasms
A. From Mullerian germinal epithelium
1. Serous cystadenoma
2. Pseudomucinous cystadenoma
B. From connective tissue
C. Mixed mesodermal origin
1. Benign cystic teratoma (dermoid)
2. Malignant teratoma
D. Tumors of germ cell origin
1. Granulosa cell tumor
Prompt surgical removal is the treatment of choice for all ovarian cysts and tumors. Whether the surgical approach is radical or conservative, with maximal preservation of normal tissue, varies from tumor to tumor and patient to patient. The conservative approach should be used whenever possible; however, it is of prime importance that the surgeon be familiar with the pathologic characteristics of all ovarian tumors in order to make an appropriate decision.
Fallopian tubes should be sacrificed only when absolutely necessary as the presence of one ovary and the contralateral tube is compatible with fertility. No functioning ovarian tissue should be removed, if avoidable, for the problems of castration in a child are formidable. The contralateral ovary should always be examined at the time of surgery to insure that the tumor is not bilateral. Obviously, malignant tumors require radical surgery; x-ray and chemotherapy may be useful tools on an individualized basis.
There is little authoritative guidance concerning radiotherapy. Not only may irradiation cause sterility but growth may be impaired. Ein et al.9 therefore recommend radiotherapy only when complete removal of malignant tumors is impossible or in malignant dysgerminomas and granulosa cell tumors, which have been shown to be rathosensitive.
It must be remembered that from birth, simple follicular cysts constantly develop normally to cystic proportions and then undergo atretic degeneration. This is especially true in constitutional precocious puberty, in which such cysts have incorrectly been thought to cause sexual precocity. Consequently, some children have had one or both ovaries removed unnecessarily.
Oophorectomy is recommended by Kilman et al.8 for solid ovarian tumors, cystic enlargements greater than 10 cm., multilobulated thick-walled masses, or vascular compromise to the ovary or tumor.
Children who have had both ovaries removed or destroyed by radiotherapy should have the benefit of exogenous estrogen therapy at the normal age of puberty to insure as normal as possible development of female secondary sexual characteristics.
Simple ovarian cysts in children are considered to be retention cysts, not true neoplasms.
These cysts may be seen in the immediate newborn period as a large abdominal mass, an acute surgical abdomen, or as respiratory distress secondary to impingement of the large mass on normal excursion of the diaphragm. Ovarian cysts continue to occur throughout childhood, generally seen as an abdominal mass, and may undergo torsion. They represent approximately 30 per cent of ail childhood ovarian tumors2 and are generally classified as follicular, theca luteum, or endometrial - depending upon their cell lining. They are benign but may cause serious difficulties such as chemical peritonitis if they rupture into the abdominal cavity. Simple excision with preservation of normal ovarian tissue is usually adequate treatment. However, if torsion and vascular compromise have occurred, salpingooophorectomy is indicated.
Follicular cysts are believed to arise from Graafian follicles. They may be unilocular or multilocular, hemorrhagic or nonhemorrhagic. The multilocular cysts are multiple simple cysts. Follicular cysts are thin-walled and contain clear or blood-tinged clear fluid.
Lutein cysts arise from corpora lutea. They are believed to arise from atretic follicles and are usually unilocular.
Simple ovarian cysts are benign cysts that may normally spontaneously appear and regress during childhood and adolescence. They should be observed over time rather than removed immediately, unless they are clearly symptomatic.
CYSTADENOMA AND CYSTADENOCARCINOMA
Cystadenoma and cystadenocarcinorna are common neoplasms of adulthood but are uncommon in patients under 20 years of age. Ovarian epithelial tumors of adults include not only serous and pseudomucinous cystadenomas, cystaden of ib romas, and cystadenocarcinomas, but also Brenner tumors, endometroid carcinomas, adenocarcinomas with squamous metaplasia, adenocarcinomas of mesonephric type, and mixed mesodermal tumors. In patients under 20 years of age, however, only serous and pseudomucinous tumors have been seen with any frequency. They represent approximately 19 per cent of ovarian tumors of childhood and adolescence, but they are extremely rare in children prior to puberty,10 which suggests their dependence on cyclic stimulation by pituitary gonadotropins.11
Cystadenomas originate from MuIlerian germinal epithelium. The two types - serous and pseudomucinous - can be differentiated on the basis of their epithelial lining and fluid content. Pseudomucinous cystadenomas are generally unilateral while approximately 20 per cent of serous cystadenomas have been reported to be bilateral.8 Papillomatous growths are more frequent in serous cystadenomas.8 If the mucinous cystadenoma ruptures, its epithelium may implant diffusely over the peritoneal surface, creating a condition known as pseudomyxoma peritonei. These implants may be difficult or impossible to remove surgically.
Although rare in adolescence, cystadenocarcinomas do occur. They are highly malignant and have a generally poor prognosis. Cystadenocarcinomas in children may require the same treatment as in adults but individualization of therapy may be worthwhile.11
Unless a cystadenoma or cystadenocarcinoma penetrates its tough capsule or metastasizes, unilateral oophorectomy is probably the best treatment. Radical surgery and irradiation should be reserved for advanced or recurrent disease.
Fibromas of the ovary are rare in childhood and adolescence. They are nonhormonal, solid, unilateral, benign tumors of nonspecialized ovarian stomal origin. They generally are seen as an abdominal mass. Resection of the fibroma with preservation of the remainder of the ovary is generally adequate treatment.
Teratomas are the most common tumors of the ovary in children; they comprise approximately 50 per cent of all ovarian neoplasms.1 Approximately 10 per cent are bilateral.
Willis12 theorizes that teratomas arise from foci of pluripotential embryonic tissue which escape the influence of the "primary organizer" during early development; the tumor may then develop into multiple types of tissue, thereby explaining the occurrence of such tumors as congenital lesions.
Teratomas generally are seen as abdominal masses, abdominal pain, or torsion.1 Roentgenographic evaluation is helpful in approximately 50 per cent of all teratomas. In such cases teeth, bone, or some nondescript calcification may be observed.
Grossly, teratomas may be either cystic or solid. All three germ layers are represented, although ectodermal tissue tends to predominate. Skin, cartilage, muscle, intestinal epithelium, and nervous tissue frequently occur. Benign cystic teratomas (dermoid cysts) are generally benign, as their name indicates. They are lined by well differentiated, stratified squamous epithelium and contain sebaceous material, mucous, or cerebrospinal-like fluid.
Approximately three per cent of childhood teratomas tend to be malignant.13 These are the solid teratomas (although they generally do contain some cystic elements). They are rapidly growing, highly malignant, and tend to metastasize via the blood stream to the lungs. The proportion of malignant teratomas decreases with age as the proportion of benign cystic teratomas increases.10
Treatment of benign cystic teratomas is surgical removal of the cystic lesion with examination of the contralateral ovary for bilateralism. Such surgery is curative for these lesions. Solid malignant teratomas are usually fatal,14 and treatment generally consists of bilateral salpingo-oophorectomy with total hysterectomy. Postoperative irradiation is probably of little or no value in these lesions. 13
Granulosa cell tumors and theca cell tumors contain cells similar to those of the zona granulosa and theca interna of the normal ovary. Willis12 believes they originate either in normal follicular tissue or from bipotential formative ovarian stroma. Granulosa cell tumors usually contain some theca cells, and although theca cell tumors are more often "pure," they often contain areas in which granulosa cells can be found.
Granulosa cell tumors are generally unilateral but they may be bilateral in one to ten per cent of cases. 1S They often produce isosexual precocity and are readily palpable by bimanual abdominal-rectal examination. Breast development may be the first manifestation of precocity, followed by anovulatory uterine bleeding and uterine enlargement. Body growth is often stimulated; pubic hair growth is a less common finding. Vaginal smears show evidence of unopposed estrogenic activity. Urinary excretion and blood levels of estrogens may either be greatly increased above adult levels or comparable to levels found in constitutional precocity. Although the gonadotropin levels are usually low in these tumors, they may, at times, be elevated. If the tumor is removed in children over the age of nine, little change occurs apart from cessation of bleeding and reduction in the size of the uterus.
Approximately 30 per cent of granulosa cell tumors are malignant;10 however, unlike most tumors, the microscopic appearance is often of little value in determining the degree of malignancy. In addition, late recurrence of granulosa cell tumors is not uncommon. Standard five-year survival rates are of limited value in determining -ultimate prognosis for patients with granulosa cell tumors. The treatment is complete resection with preservation of normal ovarian tissue. Radiation therapy may be useful in cases of malignant spread.
The dysgerminoma is a malignant tumor, most common in late adolescence, which is histologically undistinguishable from the seminoma. Dysgerminomas are thought to arise from sexually undifferentiated cells within the ovarian parenchyma. They are composed of discrete aggregates of intimately mixed germ cells and sex cord derivatives that resemble immature Sertoli and granulosa cells.
Dysgerminomas are generally hormonally inactive, although they may occasionally produce enough folliclestimulating hormone (FSH) to yield a positive pregnancy test. Dysgerminomas develop almost exclusively in abnormal gonads. The majority arise in a gonad of indeterminate nature but some may arise from a gonadal streak or in a cryptorchid or dysgenetic testes. Most cases in which the nature of the sexual disorder can be determined with reasonable certainty fall into the category of pure or mixed gonadal dysgenesis or male pseudohermaphroditism.
Dysgerminomas tend to metastasize locally. They are seen as a rapidly growing, asymptomatic mass; they have a long-term mortality of approximately 50 per cent.· Approximately 15 per cent are bilateral.15 Dysgerminomas are highly rathosensitive; however, initial therapy should always include unilateral adnexectomy with wedge resection of the contralateral ovary.
Pure thecomas, although rare, are approximately twice as common as granulosa cell tumors. Thecomas are generally benign, localized, unilateral tumors that often are difficult to separate by clinical or histologic criteria from fibromas of the ovary. Some thecomas, however, may be readily recognized by their functional effect of luteinization of the ovarian stroma or by the presence of fat in stromal cells. Thecomas also may be endocrinologically active, producing sexual precocity similar to that produced by granulosa cell tumors.
Finally, granulosa-theca cell tumor combinations commonly occur. These tumors are clinically and functionally similar to pure granulosa cell tumors. Pure theca cell tumors have not been reported in normal prepubertal children.13
Choriocarcinomas are highly malignant tumors that rarely occur in children. They are rapidly growing, may occur in various tissues (including the ovary), and cany an extremely poor prognosis, although in adults remarkable cures are reported with methotrexate therapy. Choriocarcinomas may produce isosexual precocity secondary to production of chorionic gonadotropins, which may now be distinguished from pituitary gonadotropins and are usually extremely elevated.
Arrhenoblastoma of the ovary is an extremely rare tumor of childhood and adolescence. Approximately 25 per cent of these tumors are malignant.10 Arrhenoblastomas arise from ovarian stromal tissue and produce androgenic hormones resulting in virilization. Testosterone is the major hormone secreted by arrhenoblastomas and is responsible for the virilization. The 17ketosteroids may also be elevated by arrhenoblastomas but, as testosterone itself is not actually measured when estimating urinary 17-ketosteroid excretion, normal or only slightly elevated levels of urinary 17-ketosteroids may be found.16 Partial, rather than complete, suppression of 17-ketosteroids following dexamethasone therapy suggests an ovarian rather than an adrenal source of the androgens.
Signs of rapid, marked virilization in a female, including hirsutism, amenorrhea, enlarging clitoris, and deepening voice, should always alert the clinician to the diagnosis of arrhenoblastoma. Buccal smear and karyotyping help to rule out abnormalities of sexual differentiation. Laparotomy with complete excision of the arrhenoblastoma is the treatment of choice.
Ovarian tumors constitute only a small percentage of neoplasms in early life. They are usually associated with abdominal pain or mass. A morphologic classification has been presented. Certain ovarian tumors are functional and may produce sexual precocity or virilization. The manifestations and treatment of the various types of ovarian tumors have been reviewed in this article.
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