Gynecologic Malignancies in Adolescents

In the United States, 10,000 cancers are diagnosed annually in patients who are younger than 20. After injuries, cancer is the second most common cause of death in this age group [1]. The diagnosis of a gynecologic malignancy in a pediatric patient is especially disheartening, because the potential physical and psychological sequelae may be difficult to overcome. Abnormal development and infertility may be adverse effects of current treatment regimens, which often include surgery, chemotherapy, and radiation. Psychologically, these patients may suffer from a lifetime of poor body self image and depression.

Ovarian or adnexal masses in pediatric patients

Pediatric ovarian and adnexal masses are uncommon; they account for approximately 1% of all malignant pediatric neoplasms but comprise 60% to 70% of all gynecologic malignancies in this population. The estimated incidence of pediatric ovarian neoplasms is 2.6 per 100,000 girls per year. Although most ovarian masses are benign neoplasms or functional cysts, 10% to 30% are malignant. As such, the clinician must have some understanding of the epidemiology of malignant ovarian tumors to help in determining when referral to a specialist is necessary. With the advent of sensitive transvaginal ultrasonography and serum tumor markers, most ovarian tumors can be stratified initially as to their potential for malignancy. Ultrasound features of an adnexal mass that suggest malignancy include large size (regardless of morphology), a complex (not entirely cystic) appearance, the presence of loculations and excrescences within or on the surface of the tumor, and measurable fluid (ascites) in the posterior cul de sac [2]. In some departments, the routine use of Doppler studies to demonstrate ovarian blood flow has led to the understanding that dilated and randomly dispersed vessels, centrally located blood flow, blood flow along septa, and flow within papillary excrescences is suggestive of malignancy.

Ovarian cancers in pediatric and adolescent patients

Introduction

Ovarian cancer in the pediatric age group is rare. The North American Association of Central Cancer Registries for the period from 1992 to 1997 reported greater than 1.6 million females with a cancer diagnosis. Of these 67,746 were ovarian cancers, with 1563 (or 2.3%) occurring in patients younger than 25. Close to 50% (780 cases) were reported among women aged 20 to 24, while there were only 481 cases in the 15- to 19-year-old group and 302 cases in the birth to 14-year-old group [3].

Staging of ovarian cancers

The goal of a patient undergoing surgery for an ovarian mass is to confirm the diagnosis, determine the extent of disease, and excise gross tumor. In the adolescent and pediatric patient, these goals always must be weighed against the potential negative impact these procedures may have on reproductive and hormonal function. As such, a clear understanding of the ovarian malignancies encountered in these populations is imperative, and a pediatric or adolescent patient undergoing surgery for an ovarian mass should be explored by a physician with knowledge of the differences in management of a young patient with an ovarian cancer. With the appropriate surgery, preservation of fertility and ovarian function without a negative impact on survival is generally feasible in girls and young women diagnosed with ovarian cancer. Specific management options for pediatric and adolescent patients diagnosed with ovarian cancer are described.

Fertility preservation in ovarian and gynecologic cancers

If outcomes from all cancers in pediatric patients are analyzed, an overall 15% fertility deficit among adult survivors is seen [4]. When treating a pediatric patient with a gynecologic cancer, consideration of conservation of reproductive potential is of paramount importance when devising a treatment plan. In patients in whom the reproductive organs are salvageable at the time of surgery, the amount of ovarian damage from adjuvant chemotherapy or radiation depends on the chemotherapeutic agents used and the cumulative radiation dose. Radiation damage to the ovaries is related directly to the dose delivered to the ovary, and thus is related inversely to the distance from the radiation source and the ovaries. Ovarian failure almost always occurs at doses greater than 800 centigray (cGy), whereas doses less than 60 cGy have no consistent deleterious effect.

The chemotherapeutic regimens used to treat pediatric gynecologic cancer are, in most cases, multi-agent regimens, thereby making it somewhat difficult to determine which agents specifically adversely affect gonadal function. Alkylating agents (such as cyclophosphamide and similar to cisplatin and carboplatin) have proven to be the most toxic to ovarian follicles, with antimetabolites (such as methotrexate) and vinca alkaloids (such as vincristine) being much less toxic. Gonadal function is more likely to be preserved if therapy occurs before puberty, and it is recommended that pediatric patients avoid pregnancy for at least 2 years following treatment for cancer, because recurrence is most likely in this period. Several strategies have evolved to preserve ovarian function. Cryopreservation of oocytes offers the advantage of preserving gametes before fertilization and is especially appropriate for young females, thereby circumventing the possible ethical issues that may arise from the freezing of embryos. Heterotopic transplantation of ovarian cortical tissue to the forearm is a recently described technique in which viable oocytes have been retrieved for subsequent fertilization and provides an attractive alternative for patients undergoing radiation therapy of the pelvis. Treatment with gonadotropin-releasing hormone analogs before and during multi- agent chemotherapy has been shown to preserve fertility in pre- and postpubertal adolescent patients [5].

With the identification of active chemotherapy regimens for the treatment of ovarian cancer, adjuvant radiation therapy is not used frequently. When radiation is planned, a strategy used with some success to prevent radiation-induced ovarian failure is ovarian transposition (oophoropexy), in which a patient’s ovaries are affixed to structures outside of the planned field of radiation. Extrapolating from data in women receiving radiation for cervical cancer, however, this technique leads to preservation of ovarian function in less than half of the patients.

Tumors originating from ovary

Germ cell tumors of the ovary

These tumors are presumed to share a common cell of origin, the primordial germ cell, yet they remain a heterogeneous group of tumors. Variations regarding age, sites of presentation, histopathology, and malignant potential stem from differences in the stage of germ cell development. Germ cell tumors (GCTs) are the most common ovarian histologic type diagnosed in children between the ages of birth to 1 year (78%) and between the ages 15 to 19 years (54%). Often, these tumors express specific tumor markers that can aid in the preoperative detection, such that a plan for appropriate management can be established before exploration. The World Health Organization (WHO) classification of ovarian germ cell tumors is presented in Box 1.

Box 1. The modified World Health Organization classification of ovarian germ cell tumors

Mature cystic teraloma, dermoid cyst

These tumors are the most common benign ovarian neoplasm (38.6%) in female children and adolescents of all lesions. They are bilateral in about 10% of cases. Approximately 50% of these lesions are discovered incidentally during surgery or imaging in otherwise asymptomatic girls. Patients may present with abdominal pain or a mass, as well as gastrointestinal (GI) symptoms.

If thyroid tissue is the major component (greater than 50%) of a dermoid, it is termed a struma ovarii; this tumor is rarely bilateral, and it infrequently leads to thyrotoxicosis. Up to one third of patients develop ascites, and some develop hydrothorax (Meigs’ syndrome). Although rare, between 1% and 3% of mature cystic teratomas present with ovarian torsion, and an additional 1% to 3% can rupture spontaneously.

Mature cystic teratomas are composed of mature representative tissues from all three germ layers: ectoderm, mesoderm, and endoderm. Although any tissue type may be seen, the most common are skin and skin appendages (including hair and teeth), adipose tissue, mature brain tissue, intestinal epithelium, and cystic structures lined by squamous, cuboidal, or flattened epithelium. They have no significant malignant potential themselves, but approximately 2% of cases will undergo malignant degeneration, almost exclusively the squamous cell component of the teratoma.

Ultrasound imaging of mature cystic teratomas usually reveals a complex adnexal mass with internal echogenic features that reflect the tissues present such as fat, hair, teeth, and bone. Echogenic foci are seen more often in postpubertal girls (70%) than in prepubertal 13% girls.

Resection of the cystic teratoma without spillage of tumor contents and ovarian preservation are required for optimal surgical therapy. If at all possible, an ovarian cystectomy is performed with close inspection of the contralateral ovary for evidence of bilateral disease. The use of a laparoscopic approach versus laparotomy is a point of professional controversy, but the rate of spilling of the contents of a cyst isreported to be higher laparoscopically.

Malignant ovarian germ cell tumors

Dysgerminoma (seminoma, germinoma)

Dysgerminomas are the most common malignant ovarian GCT, and they are the female equivalent of testicular seminomas, from which much of the information regarding treatment has been extrapolated. The presenting symptoms of this malignant tumor are similar to those for other ovarian masses, and include increasing abdominal girth, a palpable abdominal or pelvic mass, and pain, but with more rapid onset because of their rapid growth. Unlike the remainder of the GCTs, which are almost exclusively unilateral, dysgerminomas are bilateral in 10% to 20% of cases [6]. Conspicuous uniformity of cell and nuclear size and appearance is a microscopic hallmark of dysgerminomas.

Five percent to 10% of dysgerminomas occur in phenotypic females with abnormal gonads. They are associated with pure gonadal dysgenesis (46XY, bilateral streak gonads) or mixed gonadal dysgenesis (45X/46XY, unilateral streak gonad, contralateral testis), and with androgen insensitivity (46XY, testicular feminization). As such, premenarchal girls with a pelvic mass should undergo a preoperative karyotype, because gonadoblastomas can occur in dysgenetic ovaries. The serum level of LDH (specifically isoenzyme 1) correlates with tumor burden in dysgerminoma, and can be used to monitor response to therapy.

Management of ovarian dysgerminoma must include surgery to confirm the presumptive diagnosis and to evaluate for or resect metastatic disease. Pre-operative work-up should include drawing tumor markers for ovarian GCTs and chest radiography. Often, a CT of the abdomen and pelvis can be performed to evaluate for clinically apparent metastatic disease. Usually, pelvic masses in pediatric and adolescents are managed surgically by laparotomy, although laparoscopy is an acceptable alternative in most situations. The diagnosis of dysgerminoma must be established by oophorectomy (Fig. 1). In the absence of clinically apparent bilateral ovarian disease, the contralateral ovary is not biopsied or removed. If fertility is to be preserved, the uterus is also left. The abdominal and pelvic contents and surfaces should be inspected carefully and palpated, and any suspicious lesions should be biopsied. Comprehensive staging, including random peritoneal biopsies, omentectomy, and pelvic and aortic lymphadenectomy generally is performed also. There is no consensus as to whether unilateral or bilateral lymphadenectomy is appropriate in the management of ovarian dysgerminoma. In patients whose karyotype reveals a Y chromosome, a bilateral salpingo-oophorectomy is required. In patients discovered to have metastatic disease, a unilateral oophorectomy and removal of any readily resectable tumor masses is performed, usually followed by adjuvant combination chemotherapy with bleomycin, etoposide, and cisplatin (BEP). In general, radiation therapy is reserved for disease recurrence. Because of the exquisite chemotherapy and radiation sensitivity of these tumors, the 5-ycar survival rate for stage IA disease is 95%, and for all stages, the survival rate is 85%.

Fig. 1. 12 year-old girl undergoing laparotomy for an ovarian mass and elevated lactate dehydrogenase. A bulky, unresectable ovarian dysgerminoma was diagnosed, apparently arising from the left ovary (bottom of photograph) and densely adherent to the posterior uterus (left side of photograph) with metastasis to the posterior cul de sac (behind the uterus). Following initial chemotherapy with bleomycin, etoposide, and cisplatin, no residual carcinoma was identified at a second surgery. She remains without disease 4 years after the procedure.

Ovarian endodermal sinus tumors

Endodermal sinus tumors (ESTs) account for 5% of all malignant ovarian tumors. They occur at a median age of 18 years, and one third of patients are premenarchal. Thus, it is the most common ovarian malignant GCT in pediatric patients. Presenting symptoms included abdominal or pelvic pain or abdominal enlargement. An asymptomatic pelvic mass, however, is palpated in 10% of patients. These tumors are derived from the primitive gut and liver, and therefore secrete α-fetoprotein (AFP), affording a useful serum tumor marker. Endodermal sinus tumors are almost always large (most are 15 cm in diameter) and unilateral. Grossly, they are solid, variegated, tumors that are tan or gray in color with areas of necrosis and hemorrhage. Histologically, characteristic glomerulus- like structures known as Schiller- Duvall bodies are present in about 20% of tumors. These tumors grow quickly and spread early by means of lymphatic invasion to the retroperitoneal lymph nodes and hematogenously to the lungs, liver, peritoneum, and bowel.

Surgical treatment for ESTs consists of unilateral salpingo- oophorectomy and frozen section for diagnosis. Although comprehensive staging or tumor cytoreduction is performed for many patients with early or clinically advanced stage disease, respectively, these procedures are not necessary, given that all patients with ESTs receive postoperative chemotherapy with BEP because of the aggressive nature of this tumor. Whereas survival was uniformly poor before establishing this regimen, the disease-free survival rate for all stages now exceeds 80%.

Immature teratoma

Immature teratomas are the third most common ovarian GCT. They account for 48% of GCTs in the age group birth to 14 years, 35% of GCTs in the 15- to 19-year-old age group, and 40% of GCTs in the 20- to 24-year-old age group. Patients usually present with abdominal distension, pain, and a palpable mass. Elevated serum AFP levels have been found in up to 60% of patients. The tumors grow rapidly and are nearly always unilateral; however, a mature cystic teratoma is present on the contralateral ovary 5% to 10% of the time. Extraovarian spread is present at initial laparotomy in about one third of cases. Histologically, all three germ cell layers are present and graded from 1 to 3 based on the proportion of primitive neuroectodermal tissue present. Tumor grade is correlated inversely with prognosis and dictates the need for adjuvant therapy [7].

Diagnosis is established at the time of surgery, and this should include comprehensive surgical staging, including a unilateral salpingo-oophorectomy, lymphadenectomy, omentectomy, and peritoneal biopsies. The rationale behind comprehensive surgical staging is that of all of the malignant GCTs, only immature teratomas that are stage IA and grade 1 will not require adjuvant therapy after surgery. All patients with tumors that are higher grade or stage require postoperative chemotherapy with BEP (bleomycin, etoposide, and cisplatin). This regimen affords a 5-year survival rate of 95% for stage I disease and a 5-year survival rate of 75% for advanced stages. Radiation therapy is reserved for localized persistent disease after chemotherapy.

Embryonal carcinoma

Embryonal carcinoma (EC) accounts for 4% of ovarian GCTs and is the ovarian analog of embryonal testicular cancer. It is a highly malignant tumor that is diagnosed before puberty in 50% of patients. Presenting signs and symptoms include an abdominal mass (80%), abdominal pain (53%), or both. Most patients experience precocious pseudopuberty as a result of hormonal production by these tumors. Many of these tumors secrete βHCG and AFP, which may be useful clinical tumor markers. Sixty percent of patients present with stage IA disease, and treatment is similar to that for ESTs.

Polyembryoma

Polyembryomas are very rare, and fewer than 20 cases have been reported. They are very malignant cancers characterized by numerous embryo-like bodies that morphologically resemble normal 15- to 16- day embryos. These tumors are seen more often in malignant mixed GCTs. Most polyembryomas occur before puberty, with a median age at presentation of 12 years old. The symptoms associated with these tumors include isosexual precocious pseudopuberty, abdominal distension, and vaginal bleeding. Grossly, they are solid, gray- white in color, unilateral, and vary in size from 10 cm in diameter to large masses occupying most of the pelvis and abdomen. Human placental lactogen (HPL), AFP, and beta subunit of human chorionic gonadotropin (βHCG) may be useful tumor markers. Treatment is anecdotal and may consist of surgical therapy followed by combination chemotherapy.

Choriocarcinoma of the ovary

Choriocarcinoma of the ovary out of the context of a gestation is exceedingly rare. It has the same appearance as gestational Choriocarcinoma. Most patients are in the pediatric age group. Before puberty, 50% of patients present with elevated βHCG, isosexual precocious puberty, and abdominal mass, while after puberty vaginal bleeding and elevated βHCG are common symptoms that may mimic an ectopic pregnancy. These tumors usually are diagnosed at an advanced stage. Combination chemotherapy with BEP or methotrexate, actinomycin D, cyclophosphamide (MAC) has afforded complete responses.

Mixed germ cell tumors

Mixed GCTs have two or more GCT components and account for about 8% of malignant ovarian GCTs. Endodermal sinus tumors combined with dysgerminomas are the most common mixed tumors. The mean age at diagnosis is 16, with one third of tumors occurring before puberty. These girls often present with isosexual precocious pseudopuberty. Most patients have a palpable abdominal or pelvic mass and pain. An appropriate fertility-preserving staging operation followed by BEP chemotherapy is appropriate therapy. Survival is relative to the proportion of the high-risk germ cell component in the tumor.

Gonadoblastoma

Gonadoblastomas have both a germ cell and sex cord stromal component. They occur in girls and young women most often in their teens. Over 80% of patients with these tumors are phenotypically females who often are virilized, while 20% are phenotypic males with crypt\orchidism, hypospadias, and female internal secondary sex organs. Sixty percent of affected females are virilized, and over 95% have an abnormal karyotype with a Y chromosome. Grossly, over 30% of tumors are bilateral. In 50% of cases, the gonadoblastoma is overgrown by dysgerminoma or immature teratoma, and endodermal sinus tumor or choriocarcinoma in 10% of cases. Treatment of these tumors in the presence of a

Y chromosome requires bilateral oophorectomy with preservation of the uterus if desired. If invasive disease has developed, therapy appropriate to the particular GCT component is required.

Sex cord-stromal tumors of the ovary

Sex cord-stromal tumors (SCST) of the ovary comprise 5% to 8% of all ovarian malignancies and 10% of all ovarian malignancies in pediatric patients [8]. Although the incidence of SCSTs increases as a woman ages, the relative rarity of epithelial tumors in younger women and girls leads to SCST being a relative common malignant ovarian cancer in the pediatric and adolescent populations. These tumors arise from the sex cords and stroma (mesenchyme) of the embryonic ovary. They are made up of granulosa and theca cells, the testicular counterparts of Sertoli and Leydig cells, and fibroblasts in varying proportions and stages of differentiation. Most stromal tumors produce hormones. As such, pediatric and adolescent patients often will present with signs and symptoms relative to their production. Although the specific presentation of these tumors will be described later, it is important to recognize that both excess estrogen and androgen production can lead to precocious puberty and abnormal vaginal bleeding, and hormone- secreting tumors should be in the differential and evaluated in patients presenting with these signs. Excess androgen production by SCSTs often can lead to virilization, and should be considered when seeing a patient with clitoromegaly or male-pattern hair distribution. In these situations, imaging of the ovaries with transvaginal ultrasonography and evaluation of the total testosterone level should be among the initial workup. The World Health Organization classification of ovarian sex cord and stromal tumors is presented in Box 2.

Granulosa-stromal cell tumors

Granulosa cell tumors are rare, accounting for about 1% to 2% of all ovarian tumors. Adult granulosa cell tumors (AGCT) make up 95% of all granulosa cell tumors. They occur more commonly in postmenopausal women and have a peak incidence at 50 to 55 years of age. Because GCTs produce estrogen, many patients present with menstrual disturbances, including menorrhagia or secondary amenorrhea, as well as estrogen-induced endometrial hyperplasia or cancer. Rarely, they may cause androgenic manifestations. Granulosa cell tumors often secrete inhibin, which serves as a useful serum tumor marker. Grossly, these tumors vary in size from very small to vary large; they may be either mostly cystic (blood filled) or solid, and they are unilateral in more than 95% of cases. Histologically, they consist mainly of granulosa cells but may have a theca cell or fibroblast component. When the granulosa cells are arranged in a follicular pattern, characteristic Call-Exner bodies are seen.

Juvenile granulosa cell tumors (JGCT) account for 5% of all ovarian tumors in children, with more than 50% of tumors diagnosed in patients younger than 20 years, and 5% of tumors occurring before puberty [9]. These tumors usually are associated with isosexual precocious pseudopuberty. In postpubertal patients, JGCTs usually present with menorrhagia or secondary amenorrhea. JGCTs can be associated with other abnormalities, and are thus a component of various syndromes, including: Potters syndrome, when they occur with multiple congenital anomalies; Ollier’s disease, when they occur with endochondromatosis; and Maffuci’s syndrome, when they occur with enchondromatosis and hemangiomatosis. Microscopically, JGCTs consist of a predominately solid cellular tumor with focal follicle formation; thus, Call-Exner bodies are rare. Treatment of GCTs is surgery for diagnosis and to establish the distribution of disease. As such, unilateral salpingo-oophorectomy with staging is appropriate. If the uterus is to be left, dilatation and curettage is necessary to exclude concurrent endometrial hyperplasia or malignancy resulting from estrogen stimulation from the GCT (Fig. 2). In more advanced stages or recurrence of a GCT, combination chemotherapy with BEP is given. The tendency for late recurrence in these tumors is reflected in a 10-year survival of 90% and 20-year survival of about 75%.

Box 2. The modified World Health Organization classification of ovarian sex cord and stromal tumors

Sertoli-Leydig cell tumors

Sertoli-Leydig cell tumors are exceedingly rare tumors, comprising only about 1% of all sex cord-stromal tumors and 0.1% to 0.5% of all primary ovarian tumors. The average age of patients diagnosed with a Sertoli-Leydig cell tumor is 25 years old, with less than 5% of these tumors occurring before puberty. Forty percent to 50% of patients present with virilization; however, isosexual precocious pseudopuberty also can be encountered. Sertoli-Leydig cell tumors produce testosterone and androstenedione. These neoplasms may produce AFP with serum levels well below those seen for endodermal sinus tumors. In patients who desire to preserve their fertility, unilateral salpingo-oophorectomy and staging is appropriate. Only 2% of cases have tumor spread beyond the ovaries. Treatment of recurrent disease with radiation or chemotherapy is of unproven benefit; however, responses to these modalities have been reported. The 5-year survival rate is 70% to 90%. Poorly differentiated tumors account for most fatalities.

Fig. 2. 20 year-old woman with a history of irregular menses undergoing laparotomy for an ovarian mass. Intraoperatively, a large ovarian granulosa cell tumor replacing the normal ovary was discovered. Her uterus (shown at the bottom of the photograph in front of the ovarian tumor) was left at surgery. Following removal of the affected ovary, a dilatation and curettage was performed that ruled out concurrent uterine hyperplasia or endometrial cancer. No adjuvant therapy was required for this early-stage cancer.

Epithelial ovarian tumors

Epithelial ovarian tumors in the pediatric age group account for 19% of all ovarian tumors, with 16% of these being malignant. They occur almost exclusively after puberty, with a mean age at diagnosis reported to be from 14 to 19 years old. The duration of symptoms before diagnosis usually ranges from 10 days to 3.5 months, and the most common symptoms in one series in descending order were dysmenorrhea (100%), abdominal pain (68%), abdominal distension (26%), nausea and vomiting (16%), and vaginal discharge. Tumors of low malignant potential (also known as borderline tumors) are defined by their lack of stromal invasion into the ovary. They generally occur in younger women, with a median age of onset 10 years earlier than that of invasive ovarian cancers. As such, this tumor accounts for 30% of epithelial ovarian cancers in adolescents, and likely explains the prolonged survival in pediatric patients (10- year survival rate of 73%) with malignant epithelial ovarian cancer compared adult patients. For epithelial ovarian cancers in pediatric and adolescent patients, consideration of the conservation of a normal ovary can be entertained. Recent data suggest that unilateral salpingo-oophorectomy and staging leads to excellent survival and reproductive outcomes in younger patients with invasive stage I disease. The need for additional surgery beyond simple tumor resection (oophorectomy) in the case of tumors diagnosed at frozen section as borderline is somewhat controversial [10]. Given that patients with a borderline tumor do not benefit from adjuvant chemotherapy (even with advanced-stage disease), the role of comprehensive staging (with contralateral oophorectomy and subsequent infertility) is uncertain. It is estimated, however, that up to 10% of patients with a diagnosis of a borderline tumor at frozen section can have evidence of invasive disease on comprehensive review of the specimen. For this reason, it may be worthwhile to stage all patients with a borderline tumor (including lymphadenectomy, omentectomy, and peritoneal biopsies, while leaving the contralateral ovary and uterus) in the case of a change in the final pathologic diagnosis.

Gestational trophoblastic disease and pediatric uterine neoplasms

Gestational trophoblastic disease

Gestational trophoblastic disease (GTD) describes a group of interrelated neoplasms derived from the trophoblastic cells of the fetal chorion. They include trophoblastic lesions arising from the chorionic villi (hydatidiform mole [complete and partial]) and those trophoblastic lesions without villi (placental site trophoblastic tumor and choriocarcinoma). These tumors are known for a variable degree of malignant potential and their production of βHCG, a clinically useful tumor marker. The prognosis is excellent with these cancers [11].

Epidemiology

There is marked geographical and ethnic variation in the reported incidence of GTD. The frequency of molar pregnancies in the United States is approximately 1 per 1000 pregnancies, while the reported rates in East Asia are up to 10 times higher. In the adolescent population, some data support an increased risk of GTD in the immediate period following menarche. A history of a previous molar pregnancy increases the risk of a subsequent molar pregnancy by 10- fold. The consumption of dietary carotene and animal fat has been associated with decreased risk of molar pregnancy, while cigarette smoking and oral contraceptive use have been associated with an increased risk.

Genetics and etiology of gestational trophoblastic disease

A complete mole is produced when an oocyte that has lost its female pronucleusacquires two male pronuclei, either by insemination of an oocyte by two sperm or by the union of the two male pronuclei to form a diploid nucleus. These events usually result in a 46 XX karyotype. Partial moles arise when an oocyte is inseminated by two sperm (or an abnormal diploid sperm). The two male pronuclei then combine with the female pronucleus to form a triploid nucleus with a 69 XXX, 69 XXY, or 69 XYY karyotype.

Pathology

Molar pregnancies may be classified as complete or partial on the basis of gross morphology, histopathology, and karyotype. A well developed complete mole generally offers no diagnostic challenge. Multiple containers, even buckets, of markedly hydropic villi (resembling a cluster of grapes), admixed with blood are delivered to the surgical pathologist, often with the appropriate diagnosis on the requisition sheet. The villi are much larger than in a normal gestation, averaging 1.5 cm in diameter. More commonly, the uterine contents are evacuated in the first trimester, making gross identification difficult. Likewise the villi are not as large, and this often presents a diagnostic challenge to even the most experienced pathologist. The most important microscopic features are enlarged edematous villi and abnormal trophoblastic proliferation. At least some of the enlarged villi show a central acellular fluid- filled space, the central cistern. By definition, the presence of villi precludes the diagnosis of choriocarcinoma. DNA flow and image cytometric analysis of nuclear DNA content are helpful in distinguishing a partial mole from a complete mole. Partial moles have some but not all of the features of complete moles, and also have additional characteristics. Grossly, when fetuses are identified, they have the stigmata of triploidy, including multiple congenital anomalies and growth retardation. The villi of a partial mole are both large and small, with an occasional central cistern.

Gestational choriocarcinoma is a highly malignant germ cell tumor resulting from malignant transformation of molar tissue or a de novo lesion arising spontaneously from the placenta of a term pregnancy, abortion, or ectopic pregnancy. It develops in one of 20,000 to 40,000 term pregnancies and 5% of molar pregnancies. In contrast, nongestational choriocarcinoma is a malignant germ cell tumor and arises in extrauterine sites. About 50% of choriocarcinomas are preceded by a hydatidiform mole; 25% occur after a spontaneous abortion, 20% after normal pregnancy, and 5% after ectopic pregnancy. Histologically, choriocarcinomas consists of a biphasic mixture of mononuclear cells (cytotrophoblast and intermediate trophoblast) with patchy small foci of syncytiotrophoblast; villi are not present. These tumors are exquisitely sensitive to chemotherapy; cure rates exceed 95% even with widespread metastatic disease.

Diagnosis

Any reproductive aged women with vaginal bleeding should be evaluated with serum or urine βHCG to exclude pregnancy as a contributing factor. Although the presence of a positive pregnancy test does not define the location or quality of the pregnancy, the information is used to define the appropriate next steps in evaluation and management. With sensitive transvaginal ultrasonography, a normal intrauterine gestation is identified when the βHCG is above 2000. In the absence of a normal intrauterine pregnancy, consideration of ectopic pregnancy, abnormal intrauterine pregnancy (such as missed or incomplete abortion), or GTD must be entertained. With sensitive ultrasound, the previous conditions that would accompany exceedingly high βHCG levels such as hypertensive diseases of pregnancy, hyperemesis, and thyrotoxicosis are seen rarely. Often, theca lutein cysts are seen in the ovaries of women with GTD, and will resolve after uterine evacuation and decline in βHCG.

When an abnormal pregnancy is diagnosed, the usual treatment is dilatation and curettage. Pathologic review may suggest GTD, although this malignancy is unique in that histologic confirmation is not required to begin therapy.

Surveillance after diagnosis of gestational trophoblastic disease

Following uterine evacuation for a suspicion of GTD (even in the absence of histologie confirmation), surveillance with serial testing of serum βHCG is imperative. The level should be drawn within 48 hours after the surgical procedure, and then every week until three normal levels are recorded. Thereafter, βHCG levels are evaluated monthly for 6 to 12 months. Effective contraception is imperative during the surveillance period to avoid increasing βHCG production from pregnancy that could be interpreted as persistent or recurrent disease.

In patients who demonstrate plateau or increase in βHCG levels, malignant GTD is diagnosed, and additional therapy is required. In women with persistent unexplained vaginal bleeding or symptoms after a normal gestation, persistent GTD should be considered.

Malignant gestational trophoblastic disease

When a diagnosis of malignant GTD is made through plateauing or rising βHCG levels or the pathologic diagnosis of choriocarcinoma, imaging of the chest, abdomen, and pelvis with CT is performed to establish a baseline anatomic distribution of disease for prognostic and staging purposes. Recent evidence has demonstrated that the presence of human antimouse antibodies (HAMAs) may lead to a false-positive serum βHCG result (thus suggesting persistent GTD); this condition has resulted in unnecessary chemotherapy or hysterectomy in some patients. Given that HAMAs are not filtered in the urine, a negative urine βHCG in the presence of a positive serum βHCG should raise the suspicion of phantom βHCG syndrome [12].

Optimizing treatment

In 1973 Hammond et al described a clinical classification for malignant GTD. This classification system treats malignant GTD as a spectrum of disease and allows identification of high-risk (poor prognosis) and low-risk (good prognosis) metastatic disease so that therapy can be individualized and results compared. In the 1980s, the WHO proposed a prognostic scoring system based on risk factors, and more recently International Federation of Gynecology and Obstetrics (FIGO) proposed a combined scoring and staging system based on the anatomic distribution of disease and risk factors. The purpose of these systems is to determine the prognosis of patients with GTD and establish whether treatment with single- or multi- agent chemotherapy is recommended for initial therapy. In patients with low-risk disease, chemotherapy with either methotrexate or actinomycin D leads to cure in up to 90% of cases. In those patients who do not respond completely to this treatment, therapy with multi- agent chemotherapy with etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine (EMA-CO) is required for cure. Surgical therapy such as hysterectomy may be required to eliminate refractory foci of disease in the uterus, or for primary treatment of GTD in women who are not interested in further childbearing. Also, thoracotomy or craniotomy may be necessary for resection of metastasis not responding to chemotherapy. With treatment, the cure rate of patients with low-risk disease is greater than 90%, and in high-risk disease, the cure rate is greater than 75%. Follow-up for patients with malignant GTD after treatment includes weekly βHCG for 3 weeks, and then monthly until normal for 12 months. Contraception is imperative for 1 year following treatment. Placental site trophoblastic tumors (PSTT) are a rare subset of GTD that is relatively chemotherapy resistant and as such usually requires hysterectomy for treatment. Because these tumors express little if any βHCG, their diagnosis is challenging. Human placental lactogen (HPL), however, may be a useful serum marker in this disease.

Pediatric uterine neoplasms

Tumors of the uterine corpus are rare in pediatric patients; however, they are often malignant when discovered in this population. Vaginal bleeding is the usual presenting symptom. Whereas previous management of these tumors was radical surgery with a negative impact on body image, current practices attempt to incorporate less radical therapy, and in some cases this may result in the ability to preserve reproductive function.

Uterine sarcoma

These tumors typically are diagnosed in postmenopausal women who present with vaginal bleeding, abdominal pain, and a pelvic mass. In general, these malignancies are very rare in the pediatric age group [13]. Only previous pelvic radiation has been established as a definitive risk factor for uterine sarcomas. The three main classifications of uterine sarcomas are carcinosarcoma (mixed malignant mullerian tumors, MMMT), leiomyosarcoma (the malignant counterpart of leiomyoma, uterine fibroids), and endometrial stromal sarcoma. Carcinosarcomas are the most commonly reported sarcoma in adolescents. They are often soft, broad-based, fleshy, polypoidal masses that fill the uterine cavity. Reports of endometrial stromal sarcoma (ESS) and leiomyosarcoma (LMS) are exceedingly uncommon. These tumors generally are treated with hysterectomy, although given that endometrial stromal sarcomas are hormonally-responsive, oophorectomy should be considered. Postoperative adjuvant therapy generally is considered because of the high rate of recurrence, and this is usually in the form of chemotherapy, radiation, or hormonal therapy. Recent reports of local resection with conservation of fertility have suggested good outcomes, although this treatment has not been evaluated extensively.

Endometrial hyperplasia and carcinoma

Although endometrial cancer is the most common malignancy of the female genital tract, it is typically a disease of postmenopausal, obese women. It is estimated that less than 5% of all endometrial cancers are diagnosed in premenopausal women; as such, endometrialadenocarcinoma in the adolescent population is exceedingly rare. In pediatric-age females, endometrial cancer and its precursor lesion endometrial hyperplasia usually are associated with morbid obesity. This is seen in patients with Turner’s syndrome taking unopposed estrogen therapy, or with polycystic ovarian syndrome (PCOS). These patients generally present with irregular vaginal bleeding. Because of the rarity of this diagnosis in this population, there is often a significant delay in the diagnosis of adolescents with endometrial cancer. Generally, patients are thought to have either a primary disorder of ovulation, or a primary bleeding disorder, such as von Willebrand’s disease. Atypical glandular cells on a Papanicolaou smear and a thickened endometrial stripe on transvaginal ultrasound are also suggestive of an abnormal endometrium. Diagnosis is established with an office endometrial biopsy or at the time of dilatation and curettage in the operating room. There are only sporadic reports of endometrial hyperplasia with atypia, the precursor to endometrial cancer, in pediatric patients. This is an important diagnosis to establish, in that without treatment, progression to invasive cancer occurs in about 25% of patients. As such, in a patient in whom preservation of fertility is important, treatment with progestins (medroxyprogesterone acetate 10 mg daily) often leads to regression of the hyperplasia without sterilization. Adolescent patients with well differentiated endometrial adenocarcinoma also can be treated with high-dose progestins in an effort to normalize the endometrium. This management is successful in 50% of cases, and allows for fertility after treatment [14]. These patients should be followed with repeat biopsy in 3 to 6 months to ensure normalization of the hyperplasia or cancer. Persistent cancer or hyperplasia may require hysterectomy.

Pediatric malignancies of the cervix and vagina

Although uncommon, some gynecologic malignancies of the vagina and cervix have their greatest incidence in the pediatric population. These include pelvic rhabdomyosarcoma (RMS), endodermal sinus tumors, and diethylstilbestrol (DES)-related vaginal and cervical cancers. In addition, with the decreasing age of sexual debut, more often pediatric patients are being exposed to the human papillomavirus, with the potential risk for subsequent genital tract dysplasia and malignancy later in life.

Rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma found in children, accounting for 4% to 8% of all malignant disease in children younger than 15. Genitourinary sites comprise 20% of the primary locations of these tumors. They can arise in the perineum, vulva, uterus, and cervix. Embryonal RMS (also called sarcoma botryoides) is the most common RMS, and it is found in 66% of all genitourinary cases. In the female genital tract, sarcoma botryoides is usually found in the vagina during infancy and early childhood. The peak incidence has been reported to be at 3 years of age, and almost all occur in children younger than 5. Grossly, the tumor appears as a diffusely thickened and soft polypoid tumor resembling a bunch of grapes (botrys is Greek for grapes). The presenting signs and symptoms include a foul smelling or bloody discharge and a grape- like mass originating from the anterior vaginal wall and protruding from the introitus. Metastatic disease from RMS is seen in 26% of cases. Treatment requires biopsy for histologie confirmation; this usually is obtained at the time of an examination under anesthesia. In the past, radical pelvic exenteration (removal of bladder, colon, vagina, uterus and ovaries) was the primary therapy for these tumors. With this treatment, survival was poor, and significant physical and psychological morbidity was common. In an effort to increase survival and improve quality of life, the Intergroup Rhabdomyosarcoma Study Group (IRSG) was formed to evaluate the impact of chemotherapy and radiation in treating RMS. The current standard of care derived from the most recent IRSG trial demonstrates that less radical surgery (with preservation of the pelvic organs when feasible) with chemotherapy consisting of vincristine, actinomycin D, and cyclophosphamide (VAC) with or without radiation leads to survival rates of greater than 60% for all stages, and up to 90% for nonmetastatic disease.

Endodermal sinus tumors

Endodermal sinus (yolk sac) tumors (ESTs) of the vagina and cervix are extremely rare and locally aggressive GCTs. In virtually all cases, these tumors are diagnosed in infants and children younger than 4. Metastasis occurs often, and death has been reported within a few months if these tumors are left untreated. Patients typically present with vaginal bleeding, foul smelling discharge, and a polypoid mass that usually fills the vagina. Diagnosis in most cases requires exam under anesthesia for histologic confirmation. The presence of Schiller-Duval bodies, although rarely seen, may assist in diagnosis, but immunochemistry for AFP confirms the diagnosis of EST. Treatment consists of partial vaginectomy with combination chemotherapy with either BEP or VAC. Response to therapy is monitored with serum AFP levels. These tumors are radiosensitive; however, the toxicities of sterility and abnormal growth of the pelvic bones may be unacceptable in a pediatric patient. Prognosis is poor, with very few patients surviving beyond 5 years.

Clear cell adenocarcinoma of the vagina and cervix

Diethylstilbestrol (DES) is a synthetic nonsteroidal estrogen compound that resembles 17β- estradiol; it first was prepared in 1938. It was approved for use in the prevention of spontaneous abortion and preterm delivery from the 1940s until 1971, when Herbst and Scully reported seven cases of primary vaginal clear cell adenocarcinoma in young women exposed to DES in utero. Approximately 3 million women were exposed to DES in the United States. As of the new millennium, more than 715 cases of clear cell adenocarcinoma of the vagina and cervix diagnosed in females born after 1940 have been recorded in The Registry for Research on Hormonal Transplacental Carcinogenesis, with estimates that 25 to 50 new cases develop each year [15]. About 60% of the patients in the registry have known exposure to DES; 30% are known not to have been exposed, and 10% are uncertain of their exposure. Despite the strong association of drug and tumor, clear cell adenocarcinoma develops only rarely in exposed women, with a cumulative incidence of 1 case per 1000 women exposed. Clear cell cancers of the vagina and cervix related to DES occur in patients at a median age of 19 years old. Early exposure to DES also is associated with vaginal adenosis (endocervical glands in the vaginal mucosa), and biopsy of any lesions in exposed patients is imperative.

Grossly, clear cell adenocarcinoma may involve any portion of the vagina or cervix. Most vaginal tumors arise on the anterior vaginal wall, usually in the upper third of the vagina (60%), corresponding to the most frequent site of adenosis. Clear cell adenocarcinoma of the vagina and cervix often presents with vaginal bleeding and discharge, although these cancers often are detected by cervicovaginal cytology. The diagnosis is established by biopsy. Women exposed to DES in utero should be examined at menarche or by age 14 and yearly thereafter, with particular emphasis on palpation and visualization of the entire vagina and cervix. In addition, cervicovaginal cytology should be obtained, followed by colposcopy and biopsy of any visible abnormalities.

The treatment of clear cell adenocarcinoma of the vagina or cervix is similar to that for squamous cell cancer, although consideration of preservation of fertility may be entertained when medically appropriate. For early-stage disease (90% of cases), radical hysterectomy and vaginectomy, lymphadenectomy, with or without vaginal reconstruction are appropriate. For smaller, minimally invasive tumors, cervical cone biopsy or local vaginal resection with radiation may allow for uterine preservation and the potential for fertility. The overall 5-year survival rate all for registry patients is 78%, with the survival for stage I patients approaching 90%.

Squamous cell carcinomas of the cervix

With the increasing prevalence of human papillomavirus (HPV) exposure in pediatric and adolescent populations, a higher incidence of cervical dysplasia is being diagnosed in these populations. As such, it is anticipated that a subsequent increase in the incidence of HPV-related cervical cancers will result in the future. Although not within the scope of this article, it is imperative that, when appropriate, the pdiatrie and adolescent populations undergo regular screening for cervical dysplasia and cancer to prevent or diagnose these diseases early. The reader should refer to reviews of cervical cytology and the management of an abnormal Papanicolaou smear for this information [16,17].

Pediatric vulvar neoplasms

Vulvar malignancies in the pediatric and adolescent age groups are exceedingly rare. Only a few papers document invasive vulvar cancer in women younger than 20, the youngest being 13. High-grade vulvar intraepithelial neoplasia, a precursor lesion to squamous cell cancer of the vulva, is being diagnosed with increased frequency in younger women because of sexual exposure to HPV, suggesting that younger women may be diagnosed with vulvar cancer in the future.

Vulvar malignancies

Surgical management of vulvar malignancies in pediatric and adolescent populations should optimize the chances for cure while minimizing disfiguring radical procedures. Vulvar sarcoma botryoides and endodermal sinus tumors are also very rare tumors. Multi- modality therapy, including limited resection of the tumor mass, combined with chemo- and radiation therapy is the standard of care.

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Marshall Stepanian, MD, PhD, David E. Cohn, MD*

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The Ohio State University College of Medicine and Public Health, 320 West 10th Avenue, M-210 Starling Loving Hall, Columbus, OH 43210, USA

* Corresponding author.

E-mail address: cohn-1@medctr.osu.edu (D.E. Cohn).

Copyright Hanley & Belfus, Inc. Oct 2004