Chapter 18: Gynecologic Malignancies

INCIDENCE AND PATHOLOGY

Cancer arising in or near the ovary is actually a collection of diverse malignancies. This collection of malignancies, often referred to as “ovary cancer,” is the most lethal gynecologic malignancy in the United States and other countries that routinely screen women for cervical neoplasia. In 2014, it was estimated that there were 21,980 cases of ovarian cancer with 14,270 deaths in the United States. The ovary is a complex and dynamic organ and, between the ages of approximately 11 and 50 years, is responsible for follicle maturation associated with egg maturation, ovulation, and cyclical sex steroid hormone production. These complex and linked biologic functions are coordinated through a variety of cells within the ovary, each of which possesses neoplastic potential. By far the most common and most lethal of the ovarian neoplasms arise from the ovarian epithelium or, alternatively, the neighboring specialized epithelium of the fallopian tube, uterine corpus, or cervix. Epithelial tumors may be benign (50%), malignant (33%), or of borderline malignancy (16%). Age influences risk of malignancy; tumors in younger women are more likely benign. The most common of the ovarian epithelial malignancies are serous tumors (50%); tumors of mucinous (25%), endometrioid (15%), clear cell (5%), and transitional cell histology or Brenner tumor (1%) represent smaller proportions of epithelial ovarian tumors. In contrast, stromal tumors arise from the steroid hormone–producing cells and likewise have different phenotypes and clinical presentations largely dependent on the type and quantity of hormone production. Tumors arising in the germ cell are most similar in biology and behavior to testicular tumors in males (Chap. 12).

Tumors may also metastasize to the ovary from breast, colon, appendiceal, gastric, and pancreatic primaries. Bilateral ovarian masses from metastatic mucin-secreting gastrointestinal cancers are termed Krukenberg tumors.

OVARIAN CANCER OF EPITHELIAL ORIGIN

Epidemiology and pathogenesis

A female has approximately a 1 in 72 lifetime risk (1.6%) of developing ovarian cancer, with the majority of affected women developing epithelial tumors. Each of the histologic variants of epithelial tumors is distinct with unique molecular features. As a group of malignancies, epithelial tumors of the ovary have a peak incidence in women in their sixties, although age at presentation can range across the extremes of adult life, with cases being reported in women in their twenties to nineties. Each histologic subtype of ovarian cancer likely has its own associated risk factors. Serous cancer, the most common type of epithelial ovarian cancer, is seen with increased frequency in women who are nulliparous or have a history of use of talc agents applied to the perineum; other risk factors include obesity and probably hormone replacement therapy. Protective factors include the use of oral contraceptives, multiparity, and breast-feeding. These protective factors are thought to work through suppression of ovulation and perhaps the associated reduction of ovulation associated inflammation of the ovarian epithelium or, alternatively, the serous epithelium located within the fimbriae of the fallopian tube. Other protective factors, such as fallopian tube ligation, are thought to protect the ovarian epithelium (or perhaps the distal fallopian tube fimbriae) from carcinogens that migrate from the vagina to the tubes and ovarian surface epithelium. Mucinous tumors are more frequent in women with a history of cigarette smoking, whereas endometrioid and clear cell tumors are more frequent in women with a history of endometriosis.

Considerable evidence now suggests that the precursor cell to serous carcinoma of the ovary might actually arise in the fimbria of the fallopian tube with extension or metastasis to the ovarian surface or capture of preneoplastic or neoplastic exfoliating tubal cells into an involuting ovarian follicle around the time of ovulation. Careful histologic and molecular analysis of tubal epithelium demonstrates molecular and histologic abnormalities, termed serous tubular intraepithelial carcinoma (STIC) lesions, in a high proportion of women undergoing risk-reducing salpingo-oophorectomies in the context of high-risk germline mutations in BRCA1 and BRCA2, as well as a modest proportion of women with ovarian cancer in the absence of such mutations.

Genetic risk factors

A variety of genetic syndromes substantially increase a woman’s risk of developing ovarian cancer. Approximately 10% of women with ovarian cancer have a germline mutation in one of two DNA repair genes: BRCA1 (chromosome 17q12-21) or BRCA2 (chromosome 13q12-13). Individuals inheriting a single copy of a mutant allele have a very high incidence of breast and ovarian cancer. Most of these women have a family history that is notable for multiple cases of breast and/or ovarian cancer, although inheritance through male members of the family can camouflage this genotype through several generations. The most common malignancy in these women is breast carcinoma, although women harboring germline BRCA1 mutations have a marked increased risk of developing ovarian malignancies in their forties and fifties with a 30–50% lifetime risk of developing ovarian cancer. Women harboring a mutation in BRCA2 have a lower penetrance of ovarian cancer with perhaps a 20–40% chance of developing this malignancy, with onset typically in their fifties or sixties. Women with a BRCA2 mutation also are at slightly increased risk of pancreatic cancer. Likewise women with mutations in the DNA mismatch repair genes associated with Lynch syndrome, type 2 (MSH2, MLH1, MLH6, PMS1, PMS2) may have a risk of ovarian cancer as high as 1% per year in their forties and fifties. Finally, a small group of women with familial ovarian cancer may have mutations in other BRCA-associated genes such as RAD51, CHK2, and others. Screening studies in this select population suggest that current screening techniques, including serial evaluation of the CA-125 tumor marker and ultrasound, are insufficient at detecting early-stage and curable disease, so women with these germline mutations are advised to undergo prophylactic removal of ovaries and fallopian tubes typically after completing childbearing and ideally before age 35–40 years. Early prophylactic oophorectomy also protects these women from subsequent breast cancer with a reduction of breast cancer risk of approximately 50%.

Presentation

Neoplasms of the ovary tend to be painless unless they undergo torsion. Symptoms are therefore typically related to compression of local organs or due to symptoms from metastatic disease. Women with tumors localized to the ovary do have an increased incidence of symptoms including pelvic discomfort, bloating, and perhaps changes in a woman’s typical urinary or bowel pattern. Unfortunately, these symptoms are frequently dismissed by either the woman or her health care team. It is believed that high-grade tumors metastasize early in the neoplastic process. Unlike other epithelial malignancies, these tumors tend to exfoliate throughout the peritoneal cavity and thus present with symptoms associated with disseminated intraperitoneal tumors. The most common symptoms at presentation include a multimonth period of progressive complaints that typically include some combination of heartburn, nausea, early satiety, indigestion, constipation, and abdominal pain. Signs include the rapid increase in abdominal girth due to the accumulation of ascites that typically alerts the patient and her physician that the concurrent gastrointestinal symptoms are likely associated with serious pathology. Radiologic evaluation typically demonstrates a complex adnexal mass and ascites. Laboratory evaluation usually demonstrates a markedly elevated CA-125, a shed mucin (Muc 16) associated with, but not specific for, ovarian cancer. Hematogenous and lymphatic spread are seen but are not the typical presentation. Ovarian cancers are divided into four stages, with stage I tumors confined to the ovary, stage II malignancies confined to the pelvis, and stage III tumors confined to the peritoneal cavity (Table 18-1). These three stages are subdivided, with the most common presentation, stage IIIC, defined as tumors with bulky intraperitoneal disease. About 60% of women present with stage IIIC disease. Stage IV disease includes women with parenchymal metastases (liver, lung, spleen) or, alternatively, abdominal wall or pleural disease. The 40% not presenting with stage IIIC disease are roughly evenly distributed among the other stages, although mucinous and clear cell tumors are overrepresented in stage I tumors.

Screening

Ovarian cancer is the fifth most lethal malignancy in women in the United States. It is curable in early stages, but seldom curable in advanced stages; hence, the development of effective screening strategies is of considerable interest. Furthermore, the ovary is well visualized with a variety of imaging techniques, most notably transvaginal ultrasound. Early-stage tumors often produce proteins that can be measured in the blood such as CA-125 and HE-4. Nevertheless, the incidence of ovarian cancer in the middle-aged female population is low, with only approximately 1 in 2000 women between the ages of 50 and 60 carrying an asymptomatic and undetected tumor. Thus effective screening techniques must be sensitive but, more importantly, highly specific to minimize the number of false-positive results. Even a screening test with 98% specificity and 50% sensitivity would have a positive predictive value of only about 1%. A large randomized study of active screening versus usual standard care demonstrated that a screening program consisting of six annual CA-125 measurements and four annual transvaginal ultrasounds in a population of women age 55–74 was not effective at reducing death from ovarian cancer and was associated with significant morbidity in the screened arm due to complications associated with diagnostic testing in the screened group. Although ongoing studies are evaluating the utility of alternative screening strategies, currently screening of normal-risk women is not recommended outside of a clinical trial.

TREATMENT

OVARIAN SEX CORD AND STROMAL TUMORS

Epidemiology, presentation, and predisposing syndromes

Approximately 7% of ovarian neoplasms are stromal or sex cord tumors, with approximately 1800 cases expected each year in the United States. Ovarian stromal tumors or sex cord tumors are most common in women in their fifties or sixties, but tumors can present in the extremes of age, including the pediatric population. These tumors arise from the mesenchymal components of the ovary, including steroid-producing cells as well as fibroblasts. Essentially all of these tumors are of low malignant potential and present as unilateral solid masses. Three clinical presentations are common: the detection of an abdominal mass; abdominal pain due to ovarian torsion, intratumoral hemorrhage, or rupture; or signs and symptoms due to hormonal production by these tumors.

The most common hormone-producing tumors include thecomas, granulosa cell tumor, or juvenile granulosa tumors in children. These estrogen-producing tumors often present with breast tenderness as well as isosexual precocious pseudopuberty in children, menometrorrhagia, oligomenorrhea, or amenorrhea in premenopausal women, or alternatively as postmenopausal bleeding in older women. In some women, estrogen-associated secondary malignancies, such as endometrial or breast cancer, may present as synchronous malignancies. Alternatively, endometrial cancer may serve as the presenting malignancy with evaluation subsequently identifying a unilateral solid ovarian neoplasm that proves to be an occult granulosa cell tumor. Sertoli-Leydig tumors often present with hirsutism, virilization, and occasionally Cushing’s syndrome due to increased production of testosterone, androstenedione, or other 17-ketosteroids. Hormonally inert tumors include fibroma that presents as a solitary mass often in association with ascites and occasionally hydrothorax also known as Meigs’ syndrome. A subset of these tumors present in individuals with a variety of inherited disorders that predispose them to mesenchymal neoplasia. Associations include juvenile granulosa cell tumors and perhaps Sertoli-Leydig tumors with Ollier’s disease (multiple enchondromatosis) or Maffucci’s syndrome, ovarian sex cord tumors with annular tubules with Peutz-Jeghers syndrome, and fibromas with Gorlin’s disease. Essentially all granulosa tumors and a minority of juvenile granulosa cell tumors and thecomas have a defined somatic point mutation in the FOXL2 gene at C134W generated by replacement of cysteine with a guanine at position 402. About 30% of Sertoli-Leydig tumors harbor a mutation in the RNA-processing gene DICER in the RNAIIIb domain.

TREATMENT

GERM CELL TUMORS OF THE OVARY

Germ cell tumors, like their counterparts in the testis, are cancers of germ cells. These totipotent cells contain the programming for differentiation to essentially all tissue types, and hence the germ cell tumors include a histologic menagerie of bizarre tumors, including benign teratomas and a variety of malignant tumors, such as immature teratomas, dysgerminomas, yolk sac malignancies, and choriocarcinomas. Benign teratoma (or dermoid cyst) is the most common germ cell neoplasm of the ovary and often presents in young woman. These tumors include a complex mixture of differentiated tissue including tissues from all three germ layers. In older women, these differentiated tumors can develop malignant transformation, most commonly squamous cell carcinomas. Malignant germ cell tumors include dysgerminomas, yolk sac tumors, immature teratomas, and embryonal carcinoma and choriocarcinomas. There are no known genetic abnormalities that unify these tumors. A subset of dysgerminomas harbor mutations in c-Kit oncogenes (as seen in gastrointestinal stromal tumors [GIST]), whereas a subset of germ cell tumors have isochromosome 12 abnormalities, as seen in testicular malignancies. In addition, a subset of dysgerminomas is associated with dysgenetic ovaries. Identification of a dysgerminoma arising in genotypic XY gonads is important in that it highlights the need to identify and remove the contralateral gonad due to risk of gonadoblastoma.

Presentation

Germ cell tumors can present at all ages, but the peak age of presentation tends to be in females in their late teens or early twenties. Typically these tumors will become large ovarian masses, which eventually present as palpable low abdominal or pelvic masses. Like sex cord tumors, torsion or hemorrhage may present urgently or emergently as acute abdominal pain. Some of these tumors produce elevated levels of human chorionic gonadotropin (hCG), which can lead to isosexual precocious puberty when tumors present in younger girls. Unlike epithelial ovarian cancer, these tumors have a higher proclivity for nodal or hematogenous metastases. As with testicular tumors, some of these tumors tend to produce AFP (yolk sac tumors) or hCG (embryonal carcinoma, choriocarcinomas, and some dysgerminomas) that are reliable tumor markers.

TREATMENT

Transport of the egg to the uterus occurs via transit through the fallopian tube, with the distal ends of these tubes composed of fimbriae that drape about the ovarian surface and capture the egg as it erupts from the ovarian cortex. Fallopian tube malignancies are typically serous tumors. Previous teaching was that these malignancies were rare, but more careful histologic examination suggests that many “ovarian malignancies” might actually arise in the distal fimbria of the fallopian tube (see above). These women often present with adnexal masses, and like ovarian cancer, these tumors spread relatively early throughout the peritoneal cavity and respond to platinum and taxane therapy and have a natural history that is essentially identical to ovarian cancer (Table 18-1).

GLOBAL CONSIDERATIONS

Cervical cancer is the second most common and most lethal malignancy in women worldwide likely due to the widespread infection with high-risk strains of human papillomavirus (HPV) and limited utilization of or access to Pap smear screening in many nations throughout the world. Nearly 500,000 cases of cervical cancer are expected worldwide, with approximately 240,000 deaths annually. Cancer incidence is particularly high in women residing in Central and South America, the Caribbean, and southern and eastern Africa. Mortality rate is disproportionately high in Africa. In the United States, 12,360 women were diagnosed with cervical cancer and 4020 women died in 2014. Developed countries have looked at high-technology screening techniques for HPV involving automated polymerase chain reaction in thin preps that identify dysplastic cytology as well as high-risk HPV genetic material. Visual inspection of the cervix coated with acetic acid has demonstrated the ability to reduce mortality from cervical cancer with potential broad applicability in low-resource environments. The development of effective vaccines for high-risk HPV types makes it imperative to determine economical, socially acceptable, and logistically feasible strategies to deliver and distribute this vaccine to girls and boys before their engagement in sexual activity.

HPV INFECTION AND PREVENTIVE VACCINATION

HPV is the primary neoplastic-initiating event in the vast majority of women with invasive cervical cancer. This double-strand DNA virus infects epithelium near the transformation zone of the cervix. More than 60 types of HPV are known, with approximately 20 types having the ability to generate high-grade dysplasia and malignancy. HPV-16 and -18 are the types most frequently associated with high-grade dysplasia and targeted by both U.S. Food and Drug Administration–approved vaccines. The large majority of sexually active adults are exposed to HPV, and most women clear the infection without specific intervention. The 8-kilobase HPV genome encodes seven early genes, most notably E6 and E7, which can bind to RB and p53, respectively. High-risk types of HPV encode E6 and E7 molecules that are particularly effective at inhibiting the normal cell cycle checkpoint functions of these regulatory proteins, leading to immortalization but not full transformation of cervical epithelium. A minority of woman will fail to clear the infection with subsequent HPV integration into the host genome. Over the course of as short as months but more typically years, some of these women develop high-grade dysplasia. The time from dysplasia to carcinoma is likely years to more than a decade and almost certainly requires the acquisition of other poorly defined genetic mutations within the infected and immortalized epithelium.

Risk factors for HPV infection and, in particular, dysplasia include a high number of sexual partners, early age of first intercourse, and history of venereal disease. Smoking is a cofactor; heavy smokers have a higher risk of dysplasia with HPV infection. HIV infection, especially when associated with low CD4+ T cell counts, is associated with a higher rate of high-grade dysplasia and likely a shorter latency period between infection and invasive disease. The administration of highly active antiretroviral therapy reduces the risk of high-grade dysplasia associated with HPV infection.

Currently approved vaccines include the recombinant proteins to the late proteins, L1 and L2, of HPV-16 and -18. Vaccination of women before the initiation of sexual activity dramatically reduces the rate of HPV-16 and -18 infection and subsequent dysplasia. There is also partial protection against other HPV types, although vaccinated women are still at risk for HPV infection and still require standard Pap smear screening. Although no randomized trial data demonstrate the utility of Pap smears, the dramatic drop in cervical cancer incidence and death in developed countries employing wide-scale screening provides strong evidence for its effectiveness. In addition, even visual inspection of the cervix with preapplication of acetic acid using a “see and treat” strategy has demonstrated a 30% reduction in cervical cancer death. The incorporation of HPV testing by polymerase chain reaction or other molecular techniques increases the sensitivity of detecting cervical pathology but at the cost of identifying many women with transient infections who require no specific medical intervention.

CLINICAL PRESENTATIONS

The majority of cervical malignancies are squamous cell carcinomas associated with HPV. Adenocarcinomas are also HPV-related and arise deep in the endocervical canal; they are typically not seen by visual inspection of the cervix and thus are often missed by Pap smear screening. A variety of rarer malignancies including atypical epithelial tumors, carcinoids, small cell carcinomas, sarcomas, and lymphomas have also been reported.

The principal role of Pap smear testing is the detection of asymptomatic preinvasive cervical dysplasia of squamous epithelial lining. Invasive carcinomas often have symptoms or signs including postcoital spotting or intermenstrual cycle bleeding or menometrorrhagia. Foul-smelling or persistent yellow discharge may also be seen. Presentations that include pelvic or sacral pain suggest lateral extension of the tumor into pelvic nerve plexus by either the primary tumor or a pelvic node and are signs of advanced-stage disease. Likewise, flank pain from hydronephrosis from ureteral compression or deep venous thrombosis from iliac vessel compression suggests either extensive nodal disease or direct extension of the primary tumor to the pelvic sidewall. The most common finding of physical exam is a visible tumor on the cervix.

TREATMENT

EPIDEMIOLOGY

Several different tumor types arise in uterine corpus. Most tumors arise in the glandular lining and are endometrial adenocarcinomas. Tumors can also arise in the smooth muscle; most are benign (uterine leiomyoma), with a small minority of tumors being sarcomas. The endometrioid histologic subtype of endometrial cancer is the most common gynecologic malignancy in the United States. In 2014, an estimated 52,630 women were diagnosed with cancer of the uterine corpus, with 8590 deaths from the disease. Development of these tumors is a multistep process, with estrogen playing an important early role in driving endometrial gland proliferation. Relative overexposure to this class of hormones is a risk factor for the subsequent development of endometrioid tumors. In contrast, progestins drive glandular maturation and are protective. Hence, women with high endogenous or pharmacologic exposure to estrogens, especially if unopposed by progesterone, are at high risk for endometrial cancer. Obese women, women treated with unopposed estrogens, or women with estrogen-producing tumors (such as granulosa cell tumors of the ovary) are at higher risk for endometrial cancer. In addition, treatment with tamoxifen, which has antiestrogenic effects in breast tissue but estrogenic effects in uterine epithelium, is associated with an increased risk of endometrial cancer. Events such as the loss of the PTEN tumor suppressor gene with activation and often additional mutations in the PIK-3CA/AKT pathways likely serve as secondary events in carcinogenesis. The Cancer Genome Atlas Research Network has demonstrated that endometrioid tumors can be divided into four subgroups: ultramutated, microsatellite instability hypermutated, copy number low, and copy number high subgroups. These groups have different natural histories; therapy for these subgroups may eventually be individualized. Serous tumors of the uterine corpus represent approximately 5–10% of epithelial tumors of the uterine corpus and possess distinct molecular characteristics that are most similar to those seen in serous tumors arising in the ovary or fallopian tube.

Women with a mutation in one of a series of DNA mismatch repair genes associated with the Lynch syndrome, also known as hereditary nonpolyposis colon cancer (HNPCC), are at increased risk for endometrioid endometrial carcinoma. These individuals have germline mutations in MSH2, MLH1, and in rare cases PMS1 and PMS2, with resulting microsatellite instability and hypermutation. Individuals who carry these mutations typically have a family history of cancer and are at markedly increased risk for colon cancer and modestly increased risk for ovarian cancer and a variety of other tumors. Middle-aged women with HNPCC carry a 4% annual risk of endometrial cancer and a relative overall risk of approximately 200-fold as compared to age-matched women without HNPCC.

PRESENTATIONS

The majority of women with tumors of the uterine corpus present with postmenopausal vaginal bleeding due to shedding of the malignant endometrial lining. Premenopausal women often will present with atypical bleeding between typical menstrual cycles. These signs typically bring a woman to the attention of a health care professional, and hence the majority of women present with early-stage disease with the tumor confined to the uterine corpus. Diagnosis is typically established by endometrial biopsy. Epithelial tumors may spread to pelvic or para-aortic lymph nodes. Pulmonary metastases can appear later in the natural history of this disease but are very uncommon at initial presentation. Serous tumors tend to have patterns of spread much more reminiscent of ovarian cancer with many patients presenting with disseminated peritoneal disease and sometimes ascites. Some women presenting with uterine sarcomas will present with pelvic pain. Nodal metastases are uncommon with sarcomas, which are more likely to present with either intraabdominal disease or pulmonary metastases.

TREATMENT

GLOBAL CONSIDERATIONS

Gestational trophoblastic diseases represent a spectrum of neoplasia from benign hydatidiform mole to choriocarcinoma due to persistent trophoblastic disease associated most commonly with molar pregnancy but occasionally seen after normal gestation. The most common presentations of trophoblastic tumors are partial and complete molar pregnancies. These represent approximately 1 in 1500 conceptions in developed Western countries. The incidence widely varies globally, with areas in Southeast Asia having a much higher incidence of molar pregnancy. Regions with high molar pregnancy rates are often associated with diets low in carotene and animal fats.

RISK FACTORS

Trophoblastic tumors result from the outgrowth or persistence of placental tissue. They arise most commonly in the uterus but can also arise in other sites such as the fallopian tubes due to ectopic pregnancy. Risk factors include poorly defined dietary and environmental factors as well as conceptions at the extremes of reproductive age, with the incidence particularly high in females conceiving younger than age 16 or older than age 50. In older women, the incidence of molar pregnancy might be as high as one in three, likely due to increased risk of abnormal fertilization of the aged ova. Most trophoblastic neoplasms are associated with complete moles, diploid tumors with all genetic material from the paternal donor (known as parental disomy). This is thought to occur when a single sperm fertilizes an enucleate egg that subsequently duplicates the paternal DNA. Trophoblastic proliferation occurs with exuberant villous stroma. If pseudopregnancy extends out past the 12th week, fluid progressively accumulates within the stroma, leading to “hydropic changes.” There is no fetal development in complete moles.

Partial moles arise from the fertilization of an egg with two sperm; hence two-thirds of genetic material is paternal in these triploid tumors. Hydropic changes are less dramatic, and fetal development can often occur through late first trimester or early second trimester at which point spontaneous abortion is common. Laboratory findings will include excessively high hCG and high AFP. The risk of persistent gestational trophoblastic disease after partial mole is approximately 5%. Complete and partial moles can be noninvasive or invasive. Myometrial invasion occurs in no more than one in six complete moles and a lower portion of partial moles.

PRESENTATION OF INVASIVE TROPHOBLASTIC DISEASE

The clinical presentation of molar pregnancy is changing in developed countries due to the early detection of pregnancy with home pregnancy kits and the very early use of Doppler and ultrasound to evaluate the early fetus and uterine cavity for evidence of a viable fetus. Thus, in these countries, the majority of women presenting with trophoblastic disease have their moles detected early and have typical symptoms of early pregnancy including nausea, amenorrhea, and breast tenderness. With uterine evacuation of early complete and partial moles, most women experience spontaneous remission of their disease as monitored by serial hCG levels. These women require no chemotherapy. Patients with persistent elevation of hCG or rising hCG after evacuation have persistent or actively growing gestational trophoblastic disease and require therapy. Most series suggest that between 15 and 25% of women will have evidence of persistent gestational trophoblastic disease after molar evacuation.

In women who lack access to prenatal care, presenting symptoms can be life threatening including the development of preeclampsia or even eclampsia. Hyperthyroidism can also be seen. Evacuation of large moles can be associated with life-threatening complications including uterine perforation, volume loss, high-output cardiac failure, and adult respiratory distress syndrome (ARDS).

For women with evidence of rising hCG or radiologic confirmation of metastatic or persistent regional disease, prognosis can be estimated through a variety of scoring algorithms that identify those women at low, intermediate, and high risk for requiring multiagent chemotherapy. In general, women with widely metastatic nonpulmonary disease, very elevated hCG, and prior normal antecedent term pregnancy are considered at high risk and typically require multiagent chemotherapy for cure.

TREATMENT