Chapter 34: Gestational Trophoblastic Disease

Gestational trophoblastic disease (GTD) comprises a wide spectrum of neoplastic disorders that arise from placental trophoblastic tissue after abnormal fertilization (Fig. 34-1). The spectrum includes benign disease (complete and partial hydatidiform moles) and malignant gestational trophoblastic neoplasia (GTN), which includes choriocarcinoma, placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT) (¹). Invasive moles may also occur and are best categorized as malignant, since they can metastasize. Gestational trophoblastic neoplasia is also described as gestational trophoblastic tumor (GTT) and is further designated as nonmetastatic or metastatic (²).

The hydatidiform mole is the most common type of GTD. It is essentially a benign condition with variable potential for malignant transformation. Most molar pregnancies resolve spontaneously after uterine evacuation, with no further events or adverse outcomes. At any time during or after gestation, approximately 20% undergo malignant transformation to invasive nonmetastatic or metastatic GTN and require further treatment (³). Nearly two-thirds of these lesions develop into persistent nonmetastatic GTN; the remaining one-third develop distant metastases (^2,4).

These tumors were first described around 400 B.C. by Hippocrates and subsequently termed “dropsy” of the uterus. During the 1950s, the 5-year survival of patients with choriocarcinoma was less than 5%. The treatment of these tumors has been revolutionized with effective chemotherapy, leading to a cure rate approaching 100% and fertility preservation in most patients (^1,5,6). Successful outcomes rely on individualized management based on careful staging and treatment planning by a multidisciplinary team.

The prevalence of GTD depends on geography, maternal age, previous GTD history, socioeconomic factors, dietary factors, and blood grouping. True estimates of the incidence of molar pregnancy are difficult to obtain because of the vast variation in presentation and management of normal and abnormal pregnancies around the world. In North America and in Europe, GTD develops in approximately 1 in 100 to 2,000 pregnancies (^1,7,8). A higher rate of 1.5 to 6 per 1,000 pregnancies has been reported in South America. Early observations comparing East and Southeast Asian countries with the United States suggest a 5- to 15-fold higher incidence, as high as 1 in 120 pregnancies in East Asia (^1,8,9). Native Alaskans have an incidence three- to fourfold that of white women. Native Americans had a higher incidence than other ethnic groups in New Mexico (¹⁰). Not all data confirm the importance of ethnic background. Recent analyses suggest that the incidence in Southeast Asia is similar to that in Europe, which may reflect modifications in diet, improved diagnosis, and improved capture of population statistics (^1,2,8).

Extremes of age at conception appear to influence the rate of GTD (^1,2,11). Women older than 40 years have a fivefold greater risk of molar pregnancy (¹¹); those younger than 20 years have a 1.5- to 2-fold relative risk (¹¹). Women with a history of hydatidiform mole have a 10-fold greater risk for a second molar pregnancy and a more than 1,000-fold greater risk of choriocarcinoma than women with normal pregnancies (¹¹). The New England Trophoblastic Disease Center demonstrated the increased risk of subsequent molar pregnancy to be 1% (¹²).

Women of lower socioeconomic status have a 10-fold greater rate of molar pregnancy than more affluent counterparts. This trend has been reported in East Asia, the Middle East, the United States, and Brazil (^2,13). This relationship between GTD incidence and geographic region, culture, and socioeconomic status suggests that diet and nutrition may contribute to the etiology. Low β-carotene and high animal fat consumption are associated with GTD. There is strong association between cigarette smoking and GTD.

Historically 80% of GTDs are hydatidiform moles, 15% are invasive moles, and 5% are choriocarcinomas. Placental site trophoblastic tumor occurs in 0.2% to 2% of all GTD but is responsible for the highest mortality rate of all GTD histologies (^14,15). Choriocarcinoma is associated with an antecedent complete hydatidiform mole in 50% of the cases, a history of abortion in 25%, term delivery in 20%, and ectopic pregnancy in 5%. Occurrence after partial mole is rare (^1,2). The precise rate of choriocarcinoma may be underreported because tissue is not recommended for the diagnosis based on the risk of hemorrhage with biopsy (^1,2).

In the United States, molar pregnancies are reported in approximately 3,000 patients per year, and malignant transformation occurs in 2% to 19% of these cases (^1,2,4). Complete molar pregnancies occur 1 in 15,000 abortions and 1 in 150,000 normal pregnancies. The estimated incidence of twin pregnancy consisting of a molar pregnancy and a normal fetus is 1 per 22,000 to 100,000 pregnancies.

A hydatidiform mole is confined to the uterine cavity. When a hydatidiform mole persists, it is termed malignant and may be designated GTT or GTN and may be metastatic or nonmetastatic. Most malignant GTDs occur after evacuation of a mole and exhibit the histologic features of either hydatidiform moles or choriocarcinomas. Choriocarcinomas are highly malignant and tend to metastasize extensively. Conversely, persistent GTD after a nonmolar pregnancy almost always has the histologic pattern of choriocarcinoma. Invasive moles and placental site tumors are locally invasive but rarely metastatic. Both tumors are rare, but they can be distinguished histologically (²). Specific pathologic criteria exist for each of these histologic subtypes.

Complete Mole

Based on morphologic and cytogenetic features, hydatidiform moles are divided into two unique syndromes: complete (classic) and partial (Table 34-1) (See Fig. 34-1). Complete hydatidiform mole is characterized by the lack of a fetus and a characteristic abnormal budding edematous villous structure with nonpatchy trophoblastic hyperplasia, stromal karyorrhectic debris, and collapsed, abnormal villous blood vessels (²). A complete mole is usually detected during the second trimester and is identified by total hydatidiform enlargement of the villi, which are enveloped by hyperplastic and atypical trophoblasts. There is a notable absence of any embryonic or amniotic remnant. In questionable cases, p57 immunohistochemistry can be useful in confirming the diagnosis (¹⁶). Approximately 20% of complete moles give rise to persistent trophoblastic disease.

Partial Mole

Partial moles, in contrast to complete moles, are typically accompanied by an identifiable embryo or amniotic membranes (Fig. 34-2). These moles are described as partial because the hydatidiform changes in the villi tend to be focal. They demonstrate patchy villous hydrops with scattered abnormally shaped and scalloped irregular villi with trophoblastic pseudo inclusions and patchy trophoblastic hyperplasia (²). The villous capillaries appear to be functional because they possess the same proportion of nucleated fetal erythrocytes as the embryo. In partial moles, hydatidiform change occurs at a slower rate, and the proportion of relatively normal villi appears to correlate with fetal survival rate.

Diagnosis of molar pregnancies based on histology alone can be problematic. Negative immunostaining for P57KIP2, an imprinted gene expressed by the maternal allele, is diagnostic of a complete mole, as the placenta of all other gestations demonstrates nuclear staining of cytotrophoblast and villous mesenchyme (^2,6). Ploidy analysis can help differentiate partial (triploid) from complete (diploid) mole, but cannot distinguish between this and other etiologies of triploidy. Selective molecular genotyping allows for definitive diagnosis when histologic review is equivocal, but the cost of such testing may prohibit widespread adoption of this technique.

Maturation of mesenchymal elements is only minimally delayed in partial moles, and there is a paucity of fibroblast karyorrhexis. Approximately 2% to 6% of partial moles undergo malignant degeneration (³). Because of this sporadic malignant potential, follow-up and treatment of patients with partial moles are the same as for patients with complete moles.

Invasive Mole

Locally invasive moles have the same histologic features as complete mole. In addition, they are characterized by myometrial invasion without involvement of intervening endometrial stroma. Invasive moles are typically diagnosed clinically approximately 6 months after molar evacuation when human chorionic gonadotropin (hCG) remains elevated. They tend to invade locally, causing hemorrhage and necrosis. Rarely, uterine perforation results. Hematogenous metastasis may occur, often to the lungs. Occasionally, metastatic deposits display hydropic villi rather than the sheets of anaplastic cells that typify metastatic choriocarcinoma. Invasive moles are scored using the World Health Organization (WHO) scoring system, and treatment is predicated based on the score. If childbearing is complete, hysterectomy is recommended, but if fertility preservation is desired, the appropriate form of chemotherapy based on the WHO score is administered.

Choriocarcinoma

Choriocarcinoma is a malignant tumor with a unique histology distinct from that of moles (²). The tumor is grossly red and granular and exhibits extensive necrosis and hemorrhage. On microscopic examination, the neoplasm is composed of a disordered array of syncytiotrophoblastic and cytotrophoblastic elements, absence of chorionic villi, frequent mitoses, and multinucleated giant cells. Direct myometrial and vascular invasion occur early, with resultant metastases to the lungs, vagina, brain, kidneys, liver, pelvis, spleen, and gastrointestinal tract (^1,2,6).

Placental Site Trophoblastic Tumor

Placental site tumors are rare and most often develop after nonmolar gestations but can occur after evacuation of a complete hydatidiform mole (¹⁴). These tumors occur at the placental implantation site and consist of numerous nodules in the endometrium or myometrium. Histologically, these consist of a homogeneous population of mononuclear intermediate trophoblast cells of the placenta infiltrating in sheets or cords between myometrial fibers, sometimes with a few syncytial elements (¹⁷). The intermediate trophoblastic cells have oval nuclei with abundant eosinophilic cytoplasm, and no chorionic villi are seen. Syncytiotrophoblastic and cytotrophoblastic populations are absent, and less vascular invasion, necrosis, and hemorrhage are seen than in choriocarcinoma (¹⁷). Lymphatic metastasis is common. Placental site trophoblastic tumor secretes placental lactogen and small amounts of β-hCG and is usually diploid (^1,2).

Epithelioid Trophoblastic Tumor

Epithelioid trophoblastic tumor is a rare variant of PSTT that mimics carcinoma but histologically is composed of chorionic-type intermediate trophoblast.

Pathologic characteristics alone generally do not allow adequate discrimination of molar pregnancies. With the advent of cytogenetic techniques, such as chromosomal banding and restriction fragment length polymorphism analysis of DNA, unique chromosomal patterns of molar pregnancies were discovered (¹⁸), allowing complete and partial moles to be distinguished from one another (¹⁹).

Cell Biology

Normal fertilization results from the union of a single sperm and an egg, followed by rapid cellular division and the creation of a diploid embryo (Fig. 34-3). Early embryonic differentiation gives rise to trophoblasts, specialized epithelial cells responsible for developing the placenta and the villi. Gestational trophoblastic tumors arise from abnormal unions of sperm with the ovum, resulting in distinct pathologic characteristics involving activated transcription factors, cytokines, hormone secretion, cell adhesion molecules, and immunologic activity (²⁰).

A complete mole contains nuclear chromosomes of paternal origin and mitochondrial DNA of maternal origin (^2,21). Chromosomal banding studies reveal that complete moles contain only paternal chromosomes. This finding has been confirmed by showing that when paternal heterozygotes for the human leukocyte antigen (HLA) locus give rise to a mole, the HLA expression of the molar tissue is homozygous (²²). Approximately 80% to 92% of complete moles have a 46,XX karyotype derived from fertilization of an empty egg, the chromosomes of which were lost during meiosis, by a haploid sperm (23X) that then undergoes duplication to create a diploid set of identical chromosomes (46,XX) (²³). Complete moles can also result from postzygotic diploidization of a triploid conception. Approximately 4% to 20% of complete moles result from dispermy, in which two spermatozoa (each of which may be 23X or 23Y) fertilize an empty ovum, resulting in a 46,XX or 46,XY karyotype containing all paternal nuclear chromosomes (^2,24). Most are 46,XY, but approximately 5% of all complete moles are heterozygous 46,XX resulting from such dispermy. A 46,YY mole has not been reported, suggesting that the X chromosome is required for survival. There is no strong evidence that dispermic or Y chromosome–containing moles have greater malignant potential than the monospermic 46,XX karyotype (²¹).

A partial mole results from the abnormal union of two spermatozoa with one ovum with intact chromosomes, resulting in a triploid karyotype. Occasionally, a normal ovum can be fertilized by an abnormal diploid sperm (²). Therefore, the classic partial mole has a triploid karyotype (69 chromosomes), and both paternal and maternal chromosomes are present. The most common sex chromosome arrangement is XXY, but XXX and XYY do exist (²). Of note, in triploid pregnancies, a partial mole results when the extra haploid chromosome is of paternal origin, and a fetus develops when the extra haploid chromosome is of maternal origin. In the event that a partial mole is reported as diploid, the diagnosis is usually a misdiagnosed complete mole, hydropic abortion, or twin pregnancy (²).

Rarely, familial recurrent hydatidiform mole syndrome may be present, leading to recurrent molar pregnancies. This is an autosomal recessive disorder with mutations in NLRP7 (70% of cases) or KHDC3L (5% of cases) resulting in diploid complete moles of biparental origin, as opposed to exclusively paternal origin. Live birth in these patients is rare, but egg donation from unaffected women may result in successful live birth (²⁵).

Growth Factors and Oncogenes

Our improved understanding of the activities of proto-oncogenes, tumor suppressor genes, cytokines, and growth factors is contributing to our understanding of GTN and tumor progression (²²).

The excess of paternal chromosomes in moles probably contributes to the induction of trophoblastic hyperplasia. The genomic imbalance may cause changes in expression of growth factor genes located on the paternal allele. Both normal placentas and molar pregnancies contain paternal antigens. Upon implantation, an immunologic response is initiated, with infiltration of lymphocytes and macrophages and secretion of cytokines.

The growth of choriocarcinomas may be related to the abundant expression of epidermal growth factor (EGF) receptor. Macrophage-derived cytokines—interleukin-1 (IL-1-α, IL-1-β) and tumor necrosis factor—can suppress cell growth and increase the expression of EGF receptor in choriocarcinoma cell lines, thus acting as paracrine mediators of cell growth (²⁶).

The contribution of several oncogenes to the malignant transformation of GTD has also been examined. Growth regulation in the trophoblast is associated with expression of the transcription factor Mash-2 (²⁷). Complete moles demonstrate increased expression of c-fms RNA compared with that in normal placentas (²⁸). In choriocarcinoma, increased expression of oncogenes has been observed, and progression of some tumors has been associated with inactivation of tumor suppressor genes (²⁹). The significance of these findings is uncertain. Because trophoblasts are by nature rapidly dividing and invasive, increased expression of these oncogenes may be essential for normal cell function. Table 34-2 lists other genes whose overexpression has been implicated in GTD (^30,31,32). Human placental growth hormone has recently been detected in all variants of GTD and may serve as a novel biomarker for diagnosis (³³).

Complete Moles

The most common presenting symptom of the complete mole is vaginal bleeding in the first or early second trimester of pregnancy, although the classic signs of a molar pregnancy include vaginal bleeding as well as absence of fetal heart sounds and physical evidence of a uterus that is larger than expected for the gestational age (²).

A constellation of symptoms and signs has historically been associated with molar pregnancy, but such events are becoming less common due to routine ultrasonography in early pregnancy and the resulting early diagnosis of molar pregnancy (³⁴). In the event that molar pregnancy is detected later in the first or early second trimester, patients may present with abdominal pain due to the enlarged uterus, which may be larger than expected for gestational age. Intrauterine blood clots may liquefy and produce the pathognomonic prune juice–like vaginal discharge. Because of recurrent bleeding, patients may also present with iron deficiency beyond that expected for a normal pregnancy. Symptoms of anemia have been noted in approximately 50% of patients at diagnosis (³⁵). Theca lutein cysts, caused by β-hCG–induced hyperstimulation of both ovaries in about 50% of patients, may result in a sensation of pelvic pressure or fullness. Usually, these cysts regress spontaneously after uterine evacuation, although their rupture or tension can cause acute abdominal symptoms occasionally requiring surgery (³⁵).

In the past, 20% to 30% of patients have presented with early pre-eclampsia, thought to be precipitated by the release of large amounts of vasoactive substances from necrotic trophoblastic tissue, but seizures are rare (¹²). Ten percent of patients have presented with hyperemesis gravidarum, and 7% have presented with hyperthyroidism, presumably due to the structural similarities of β-hCG to thyroid-stimulating hormone (^36,37). Thyroid storm has been reported. Other rare presentations include respiratory distress, disseminated intravascular coagulation, and microangiopathic hemolytic anemia (³⁵).

Partial Moles

Unlike complete moles, fewer than 10% of patients with partial moles present with an enlarged uterus. An intact fetus can coexist with a partial mole, though this occurs in fewer than 1 in 100,000 pregnancies. Patients with partial moles typically do not have the hormonal symptoms experienced by patients with complete moles, and pre-eclampsia is rare. Among 81 patients with partial moles, none had prominent theca lutein cysts, hyperthyroidism, or respiratory insufficiency and only one had toxemia (³⁷). Patients with partial moles present with signs and symptoms of a missed or incomplete abortion, and the diagnosis of a partial mole is made only after histologic review of curettage specimens.

Malignant Gestational Trophoblastic Disease

Although spontaneous remission occurs in approximately 80% of patients with GTD after evacuation, malignant GTD is most commonly diagnosed after evacuation of a molar pregnancy when serum β-hCG titers plateau or rise (^2,15). Patients treated surgically for molar pregnancy should be monitored closely for malignant transformation with symptoms, signs, and serum evaluation. Previously referred to as persistent trophoblastic disease, a plateaued or rising β-hCG level (three consecutive measurements) indicates malignant change and the development of GTN.

Fifty percent of all malignant GTNs follow molar pregnancy, 25% follow normal pregnancy, and the remaining 25% follow ectopic pregnancy or abortion. Persistent invasive nonmetastatic GTN usually presents with recurrence of symptoms or signs such as irregular vaginal bleeding, theca lutein cysts, asymmetric uterine enlargement, or persistently elevated serum β-hCG levels. The tumor may even perforate the myometrium causing intraperitoneal bleeding, or the tumor may invade into uterine vessels causing vaginal hemorrhage. Irregular vaginal bleeding may be due to a vascular uterine mass or a vaginal metastasis. Patients can also present with sepsis and abdominal pain, as the uterine tumor presents a nidus for infection (²). Placental site trophoblastic tumor and ETT present in the same manner as invasive moles and nearly always present with abnormal vaginal bleeding, because the disease remains localized to the uterus prior to metastasis (¹⁴). Only small amounts of β-hCG are produced relative for their size, and in some cases, the β-hCG is normal (²).

Metastatic GTN occurs in about 20% of patients who have undergone molar evacuation (³⁵). Metastatic GTN most often arises from choriocarcinoma. Molar pregnancy is the most common antecedent of choriocarcinoma, but this tumor may also occur after normal pregnancy, ectopic pregnancy, or abortion. These highly vascular tumors tend to metastasize extensively and may cause spontaneous hemorrhage at the metastatic foci, causing symptoms. The metastases are sometimes histologically identical to molar disease, but the vast majority are choriocarcinomas. Metastatic spread is hematogenous. Because of its extensive vascular network, metastatic GTN often produces local spontaneous bleeding. Common metastatic sites of GTN as reported by the New England Trophoblastic Disease Center are summarized in Table 34-3 (³⁸).

Pulmonary metastases are common, occurring in 80% of patients with metastatic disease (³⁸), and result when trophoblastic tissue enters the circulation via uterine venous sinuses. Most often, this happens spontaneously, but it may also occur after molar evacuation. Because choriocarcinoma is a vascular tumor, hemoptysis is frequent with lung involvement. Other symptoms include chest pain, dyspnea, and cough.

Pulmonary hypertension and pleural effusions may develop. An asymptomatic lesion on a chest x-ray or computed tomography (CT) scan may be the only sign of pulmonary involvement. Radiologic features may be subtle and include alveolar, nodular, and miliary patterns (³⁹). Pulmonary metastases (Fig. 34-4) can be extensive and can cause respiratory failure and death.

Patients may experience right-upper-quadrant pain when hepatic metastases stretch the Glisson capsule. Gastrointestinal lesions can result in severe hemorrhage or perforation with peritonitis, either of which requires emergency intervention. Vaginal examination may reveal bluish metastatic deposits. Biopsy of these and other metastatic sites is contraindicated because severe uncontrolled bleeding may occur (³⁵).

Central nervous system (CNS) involvement from metastatic GTN suggests widespread disease. Central nervous system metastases occur in 7% to 28% of patients with metastatic choriocarcinoma (^38,39). The presenting neurologic symptoms include headache, hemiparesis, vomiting, dizziness, coma, grand mal seizure, visual disturbances, aphasia, and slurred speech. Weight loss and anorexia may also occur. In one-third of cases with cerebral metastases, there is no vaginal bleeding (²). Cerebral metastases tend to respond favorably to both radiotherapy and chemotherapy (Fig. 34-5).

The diagnosis of molar pregnancy is usually made by the histologic examination of curettage specimens. The diagnosis of persistent GTN or malignant GTN is most often indicated by plateauing or rising hCG titers after evacuation during surveillance. Histologic diagnosis of invasive mole, choriocarcinoma, or metastatic deposits should never be attempted because a biopsy of these neoplasms can cause massive, life-threatening hemorrhage. The hCG level in this setting is sensitive enough to make the diagnosis of malignant GTN without histologic confirmation. Beause PSTT and ETT do not typically arise after molar pregnancy, their diagnosis is usually made upon examination of the curettage, biopsy, or hysterectomy specimens (²). Presenting symptoms of PSTT are most commonly irregular vaginal bleeding, amenorrhea, and a pelvic mass (¹⁷).

Radiologic Imaging

Ultrasonography is useful for the confirmation of molar pregnancy but is not diagnostic, because diagnosis depends on histologic examination of evacuated material. Ultrasonography is the first modality of radiographic imaging used when GTD is considered and may reveal the classic “snowstorm” appearance, which is due to the numerous chorionic villi exhibiting diffuse hydatidiform swelling (⁴⁰) (see Fig. 34-5; Figs. 34-6 and 34-7). Such a classic appearance is less common now, because the diagnosis is often made in the first trimester prior to the development of significant hydropic change. More common is a mixed echogenic vascular mass. In the setting of partial mole, fetal parts may also be detected (¹).

A chest x-ray should be performed in all patients because 70% to 80% of patients with metastatic GTN have lung involvement (³⁵) (see Fig. 34-4). Brain imaging is not routinely warranted in the absence of symptoms or pulmonary abnormalities, because 97% to 100% of patients with CNS disease from choriocarcinoma have concomitant pulmonary metastases (⁴¹).

An abnormal chest x-ray associated with a β-hCG level that plateaus or rises during treatment is an indication for a more extensive evaluation for metastatic disease. Computed tomography scans of the brain, abdomen, and pelvis should be performed to evaluate other likely sites of metastatic spread.

Magnetic resonance imaging (MRI) is the preferred modality for localized disease to delineate invasiveness and tumor vascularity (Fig. 34-8) (⁴²).

Laboratory Tests

Chorionic gonadotropin is a glycoprotein hormone secreted by the syncytiotrophoblast: it is essential for the maintenance of normal function of the corpus luteum during pregnancy. This hormone has an α subunit identical to the α subunit of the pituitary hormones and a β subunit (β-hCG) unique to trophoblastic tissue that confers its specific biologic activity. The hormone becomes detectable 8 days after ovulation, and its level doubles every 2 to 4 days, reaching its peak at 10 to 12 weeks of gestation. After that, the β-hCG level declines steadily. Because all trophoblastic tumors secrete β-hCG, its level serves as an excellent marker for tumor activity in the nonpregnant patient (^2,43).

In normal pregnancy, hCG exists intact with both subunits and is hyperglycosylated in the first trimester. In GTD, hCG can exist as a free β subunit, nicked free β subunit, c-terminal peptide, β-core, or hyperglycosylated forms (⁴⁴). The assay used to detect or follow hCG in the setting of GTD must recognize all of these forms; for this reason, home pregnancy tests should be avoided in favor of commercial assays (^1,2). Even some commercial assays only work well for pregnancy-related hCG. These assays may be unreliable for detecting hCG isoforms, occasionally leading to false-negative readings, or may cross-react with heterophile antibodies leading to false-positive results (^1,2). Because the heterophile antibodies are large, they are filtered in the renal glomerulus and do not pass through into the urine. Therefore, urine pregnancy tests may be useful to exclude a false-positive result (serum positive, urine negative) but are not sufficient for making the diagnosis of GTD, only for excluding a false-positive result.

Monitoring of the serial β-hCG levels is mandatory during therapy for GTD to ensure adequate treatment. The level of β-hCG can be considered approximately proportional to the tumor burden and inversely proportional to therapeutic outcome. The 10% to 20% of patients with hydatidiform mole who are not cured by local therapy or do not achieve a spontaneous remission can be identified by a rising or plateaued β-hCG titer on serial determinations after evacuation of a mole. These patients may have persistent trophoblastic disease and require additional therapy, as outlined later. A new pregnancy should be excluded by correlating the hCG level with the ultrasound findings prior to assuming malignant GTD; that is, once the hCG level rises to a level where a fetal pole should be identified, an ultrasound should exclude conception.

At one time, the ratio of β-hCG in serum to that in cerebrospinal fluid (CSF) was used to detect brain metastases in GTD. A serum:CSF β-hCG ratio of less than 60:1 was considered a positive predictor for brain metastases (⁴¹). With the availability of MRI, this test is rarely used. CA-125 may also have a role as a marker for GTD. In at least one study of patients with hydatidiform mole, the CA-125 level was elevated; more significant was the association of the degree of CA-125 elevation with the development of persistent GTD (⁴⁵).

The complete blood count usually reveals anemia and thrombocytopenia. Clotting times may be prolonged, and consumption of coagulation factors may be unusually high in patients with disseminated intravascular coagulation. Hepatic or renal impairments are rare. Thyroid function studies are mandated in patients with a clinical history or physical examination findings suggestive of hyperthyroidism.

Phantom hCG or phantom choriocarcinoma syndrome is also called pseudohypergonadotropinemia. It refers to persistent mild elevation of hCG when no true hCG or trophoblastic tissue is present. This may result in the patient being treated further by her physician during the follow-up period either after primary surgery for molar pregnancy or chemotherapy for metastatic disease. It is mentioned here because clinicians may encounter this problem during the follow-up period and should rule out this syndrome before deciding to label a patient as having persistent disease.

Human chorionic gonadotropin is a glycoprotein whose two subunits, α and β, are held together by charge and hydrophobic interactions. Over 40 different professional laboratory tests are available for assaying the level of serum hCG. Most of these work through the multiantibody “sandwich assay,” using the labeled-enzyme or chemoimmunoassay (radioimmunoassay) method developed in the 1950s. The mechanism by which heterophilic antibodies cause false-positive results relates to the nature of this immunometric assay. One antibody, commonly a mouse monoclonal immunoglobulin (IgG), immobilizes hCG by binding one site on the molecule. A second antibody, commonly a polyclonal antibody labeled with an enzyme or chemiluminescent agent, marks the first antibody. Heterophilic antibodies usually bind the assay of IgG at sites common to humans and other species. They are bivalent and therefore link the capture and tracer antibodies, mimicking hCG immunoactivity. Binding of human antibodies to mouse IgG is the most common form of interference. The positivity of this test in the serum, however, is not correlated with positivity in the urine. These large heterophile antibodies are filtered out at the level of the glomerulus, and the urine hCG test is therefore negative in the setting of heterophile antibodies. Therefore, a simple urine hCG test can support or refute a “phantom hCG” test result. If both the urine test and the serum test results are positive, this likely represents true malignant GTD, and searching for occult disease is prudent. If the urine test is negative, assuming that no clear radiologic sites of disease are identified, different assay systems can then be used to confirm the first serum result, which may indicate heterophile antibodies and exclude true malignant GTD (⁴⁶). It is recommended that the serum be tested by a reference laboratory in these cases.

Phantom hCG emphasizes the clinical dilemma that arises when patient care is based primarily on laboratory data. It is the clinician’s responsibility to interpret test results with caution. The prevalence of false-positive hCG results is not well recognized. It has been found to be 3.4% of healthy individuals.

There are many staging and prognostic systems in GTD. Each of these systems attempts to define prognostic groups in order to identify patients most likely to become resistant to single-agent methotrexate or dactinomycin and direct a rational therapeutic strategy, thereby optimizing treatment and achieving the highest possible cure rate (²). Patients are classified into different prognostic groups based on factors such as tumor histologic subtype, extent of disease, human gonadotropin titer, duration of disease, nature of the antecedent pregnancy, and extent of prior treatment. The staging system of the International Federation of Gynecology and Obstetrics (FIGO 2000) is the most commonly used system (Table 34-4). This staging system was developed from the WHO scoring system, shown in Table 34-5 (^47,48). Patients with a score of 0 to 6 have a low risk of developing resistance to single-agent therapy and may be appropriately treated with dactinomycin or methotrexate. Patients scoring greater than 6 have a higher risk of developing disease resistant to treatment with a single chemotherapy agent and are best treated with combination chemotherapy (^2,48,49).

The FIGO 2000 system is not universally predictive of individual patient outcome. Patients with a score of 0 to 3 will almost all be cured with single-agent chemotherapy, but 70% of patients who score 5 to 6 will fail single-agent treatment and require combination chemotherapy. Because almost all failures can be cured by transitioning to combination chemotherapy, single-agent therapy is still used initially for patients who score 5 to 6 to spare the 30% of responders the more toxic effects of combination chemotherapy (⁶).

Certain other factors can be used to predict and identify early development of resistance to therapy. Pulsatility index, measured with Doppler ultrasonography, can measure uterine vascularity and predict methotrexate-resistant disease (⁶). Additionally, hCG regression nomograms and kinetics may predict early onset of resistant disease during treatment with a single agent, although this is not yet in common practice (⁵⁰). Patients infected with human immunodeficiency virus who have CD4 counts less than 200 cells/μL do not tolerate chemotherapy and have poor outcomes with higher mortality (⁵¹).

Although outcomes for patients treated with GTD are favorable, the mortality rate for patients primarily treated at a trophoblast center is lower than that in patients referred after failure of primary treatment, prompting the recommendation for early referral to a trophoblast center when possible (^3,52).

Using the FIGO 2000 scoring system, each patient is considered individually and treated by a multidisciplinary team. Figure 34-9 outlines the general diagnostic and therapeutic approaches used at the University of Texas MD Anderson Cancer Center.

Molar Pregnancy

Primary Treatment

Hydatidiform mole is curable. The treatment is mainly surgical (⁵³), but optimal management is dependent on the desire to preserve reproductive capability. All patients are evaluated for any medical condition secondary to the mole and treated appropriately before surgery. Most patients are of reproductive age, wish to maintain fertility, and are treated with suction dilation and curettage, often with ultrasound guidance to remove all molar tissue and avoid uterine perforation (^1,53). The procedure has less than a 1% incidence of mortality (¹⁵). If the uterus is greater than 16 weeks in size, there is a risk of pulmonary embolization of molar tissue, and care in a referral center is warranted (²). Depending on the trophoblastic elements, the amount of bleeding can vary. Oxytocin is often infused immediately prior to surgery to limit the volume of blood lost, although caution is necessary in patients with medical complications due to the risk of hyponatremia and fluid overload (⁵⁴). Specimens from surgery are sent for pathologic evaluation. Labor induction and hysterectomy are not recommended due to the increased incidence of post-molar GTN requiring chemotherapy (³⁸). Patients maintaining fertility should be counseled with regard to the possibility of another molar pregnancy and of malignant transformation. Patients with partial moles should be given anti-D immunoglobulin prophylaxis.

In the rare patient who has completed childbearing and no longer desires fertility, hysterectomy to remove the uterus with the mole intact is reasonable. The ovaries may be preserved, even in the setting of theca lutein cysts. After hysterectomy, patients must be followed with hCG levels.

Postsurgical Care and Indications for Chemotherapy

After primary surgical treatment, all patients undergo weekly serum β-hCG tests until the level returns to normal on three consecutive assays (ie, 3 consecutive weeks). Three consecutive normal β-hCG levels define complete remission.

Urine pregnancy tests alone are considered inadequate for monitoring. The level of β-hCG typically normalizes within 8 weeks, but this may take up to 14 to 16 weeks in 20% of patients. In patients with complete moles, the β-hCG should be checked monthly for 6 months. Patients with partial moles have less than 1 in 3,000 risk of subsequent GTD, but rates in the literature range up to 6% (^2,3). Although international guidelines do not require follow-up serum hCG testing, this is still performed at our institution (^2,6).

Contraception should be used for 6 months, but no increased risk of recurrent molar pregnancy has been demonstrated in the 6-month period (²). Because luteinizing hormone (LH) interferes with the detection of β-hCG at low levels, the use of oral contraceptives may be useful, because they suppress endogenous LH. Historically, oral contraceptive use prior to normalization of hCG was linked to GTD, but modern oral contraceptives do not appear to pose this risk (^2,6).

Eighty percent of patients need no further treatment (^4,55). The other 20% who develop malignant sequelae are treated as appropriate for their status, as either low- or high-risk patients as defined by the FIGO 2000 criteria (see Table 34-5) (¹⁵). These patients are considered to have malignant GTN rather than molar pregnancies. The initial pathologic results of the previous gestation were complete mole in 78%, partial mole in 9%, and choriocarcinoma in 8% (¹⁵). Of these patients, 81% had low-risk disease, 18% had high-risk disease, and 1% had PSTT. Risk factors include a preevacuation hCG level >100,000 IU/L, excessive uterine growth, theca lutein cysts over 6 cm in diameter, and age over 40 years (^56,57). These patients are identified through the following events (^2,3,49):

• Rising or plateaued β-hCG level for 2 weeks measured over three separate intervals

• Tissue diagnosis of choriocarcinoma

• Evidence of metastatic disease

• Elevation of β-hCG level after a normal result

• Postevacuation bleeding not due to retained tissues

An elevated but falling hCG 6 months after molar evacuation does not mandate chemotherapy because hCG levels eventually normalize in patients (⁵⁸). However, a serum hCG level greater than 20,000 IU/L more than 4 weeks after evacuation prompts chemotherapy because of the risk of uterine perforation and hemorrhage (^1,2). Patients who receive treatment for molar pregnancy are encouraged to use effective contraception with hormonal or barrier methods during the 6-month interval of β-hCG follow-up. Intrauterine devices are not used because of the potential for uterine perforation. It is essential to exclude a new pregnancy in a patient under surveillance, rather than assume GTD. This is done by correlating the rise in β-hCG levels and ultrasonic findings based on the hCG level.

Prophylactic Chemotherapy

Prophylactic adjuvant chemotherapy after molar evacuation is controversial and usually not advised. The postevacuation risk of developing GTN is 15% to 20% after complete mole and 0.5% to 1% after partial mole. In one study, administering dactinomycin intravenously for 5 days starting 3 days after molar evacuation reduced the risk of GTN to 3% to 8% (⁵⁹). However, such prophylaxis exposes approximately 80% of women to unnecessary chemotherapy and its attendant side effects, as the hCG levels would have been expected to decline without chemotherapy. Additionally, surveillance is still required after chemotherapy, and unnecessary chemotherapy may induce drug resistance (⁶⁰). Because the vast majority of patients with GTN are detected and cured with hCG surveillance and directed chemotherapy without prophylaxis, prophylactic chemotherapy has not improved survival. Thus, the benefit of prophylaxis is outweighed by the risk, except in unique circumstances where compliant patient follow-up is not possible (^2,61).

A minority of patients who have undergone removal of a complete hydatidiform mole may develop the unusual complication of intermediate trophoblastic disease (¹⁹). They usually present with vaginal bleeding and a slightly elevated β-hCG titer. Examination of the uterus may reveal multiple nodules involving the endometrium and myometrium. Surgical intervention is warranted because progressive disease tends to develop, and the disease does not readily respond to chemotherapy.

Malignant Gestational Trophoblastic Disease

For malignant GTD, the treatment depends on the cell type, stage, level of serum β-hCG, duration of the disease, specific sites of metastases, and extent of prior treatment. Patients should be stratified for risk prior to initiating a treatment plan. The FIGO 2000 system incorporating the modified WHO scoring system is the most commonly used risk stratification system (see Table 34-4) (^47,48,49). A score of 0 to 6 indicates a low risk of developing resistance to single-agent chemotherapy; a score over 6 indicates a high risk of resistance to single-agent chemotherapy and mandates combination chemotherapy.

To assign a risk category and stage, patients must undergo history, physical, and directed imaging. Patients who are detected early by hCG monitoring are evaluated by history, examination, serum hCG, pelvic ultrasound (excludes pregnancy, measures uterine size, and excludes pelvic extension), and chest x-ray. If the chest x-ray suggests lung metastasis, a chest CT may be ordered, but only lesions visible on chest x-ray should be scored (^2,49). If a patient is found to have lung metastasis, an MRI of the brain is obtained to exclude brain metastasis (⁶). If a patient has choriocarcinoma or suspected GTN following a nonmolar pregnancy, imaging should include a CT of the chest and abdomen, MRI of the brain and pelvis, and a pelvic ultrasound to evaluate for metastases to the lung, liver, pelvis, and brain (²). Positron emission tomography (PET)/CT may be useful in imaging patients with recurrent disease prior to consideration of surgical resection (⁶). Lumbar puncture to measure the CSF:serum hCG ratio is of historical interest but is not routinely used since the advent of MRI.

Low-Risk Disease, Nonmetastatic

Hysterectomy is the treatment of choice for patients who do not wish to maintain fertility. Posthysterectomy chemotherapy may be considered but is not routine. The rationale behind chemotherapy is to reduce the likelihood of disseminating viable tumor cells at surgery and during the immediate postoperative period as well as to eliminate any occult metastases. Outcomes data are not convincing. Patients who wish to retain fertility should receive chemotherapy as primary treatment for low-risk disease. Each patient must be stratified for risk prior to initiating chemotherapy.

Acceptable chemotherapy regimens are listed in Table 34-6. Either methotrexate, with or without folinic acid rescue, or dactinomycin is acceptable with the schedules as outlined. The differences in inclusion criteria in studies comparing these regimens make determining superiority of one regimen over another difficult, although dactinomycin may result in superior outcomes. The only published randomized trial compared low-dose methotrexate (30 mg/m²) with dactinomycin and found dactinomycin to be superior (⁶²). Advocates of methotrexate cite less toxicity, no hair loss, less nausea, less vomiting, and less myelosuppression. Advocates of dactinomycin cite the above trial and less frequent infusion schedule (²). An ongoing trial conducted by the Gynecologic Oncology Group compares pulsed dactinomycin with intravenous methotrexate. Regardless, patient outcome for low-risk nonmetastatic GTN is cure.

Response to treatment is determined by monitoring serum β-hCG levels every 1 to 2 weeks during treatment (²). Persistent elevation over three consecutive samples or an increase in titer of β-hCG over two consecutive samples over more than 2 weeks indicates disease resistant to first-line therapy and requires restaging (²). Phantom hCG syndrome must be excluded in the setting of low-level persistent positive results. Assuming this represents a true result, if the tumor is still limited to the uterus and the patient is older than 40 years and/or has no wish to retain fertility, hysterectomy is offered. If the patient prefers to retain fertility and belongs to the low-risk category, she can be treated with other chemotherapy. Patients who are initially treated with methotrexate but fail with hCG levels less than 300 IU/L can often be cured with dactinomycin administered as a single agent. Patients with higher levels of hCG should be treated with combination EMA-CO chemotherapy (etoposide, methotrexate, dactinomycin, cyclophosphamide, and vincristine) (^2,6). Despite a high rate of resistance to first-line chemotherapy, a cure rate of almost 100% is achieved with combination chemotherapy. In the rare instances of tumor resistance to combination chemotherapy in a patient who wishes to retain fertility, localized resection should be offered after careful evaluation by perioperative MRI, ultrasonography, and/or arteriography.

Once the serum hCG has normalized, three additional treatments of chemotherapy past normal are administered to minimize the chance of recurrence (²). A comparison of two versus three cycles of methotrexate past normalization of hCG level showed a doubling in recurrence rates in patients receiving only two consolidation courses, so it is important to administer three cycles past titer normalization (⁶³).

Low-Risk Disease, Metastatic

More than 50 years ago, metastatic GTD was not curable. Since then, treatments have improved such that the cure rate now exceeds 90% (⁵). This success is the result of a combination of factors:

• The discovery that these tumors are chemosensitive

• The ability to diagnose and monitor therapy by using β-hCG levels

• Identification of prognostic factors

• Use of combination therapy

• Referral of patients to specialized centers for treatment

Patients with metastatic low-risk disease as determined by the WHO prognostic scoring system have a high potential for cure with chemotherapy alone (^1,2). Single-agent chemotherapy with methotrexate or dactinomycin is indicated as in low risk nonmetastatic disease (see Table 34-6). Complete response occurs in 90% of patients with low-risk disease, with little short- or long-term toxicity (⁶⁴). In patients who fail single-agent therapy with methotrexate and have hCG levels less than 300 IU/L, dactinomycin can still result in cure (⁶). Patients who fail single-agent chemotherapy are still cured with combination regimens (⁶⁴).

Patients in whom treatment does not produce a complete response may have undetected metastatic disease. Mutch et al reported that at least 40% of patients with a negative chest radiograph result will have a positive chest CT scan and may be at higher risk of resistance to single-agent therapy (⁶⁵). The cure rate for patients with low-risk disease is essentially 100% (^2,6).

High-Risk Disease

High-risk disease is not likely to be cured by single-agent chemotherapy, and patients with high-risk disease are at the highest risk of treatment failure. These patients should be treated with combination chemotherapy, most commonly EMA-CO (Table 34-7) (^1,2,5). The ACE regimen (dactinomycin, cisplatin, and etoposide) has recently been reported to have outstanding efficacy but is not yet regarded as standard of care for upfront high-risk disease (⁶⁶).

Historically, a combination of MAC (methotrexate, dactinomycin, and cyclophosphamide) was used, producing cure rates of 63% to 80% (⁶⁷). In intermediate- or high-risk GTT, MAC is most effective when used as initial chemotherapy (65% survival) rather than second-line treatment (39% survival) following failed single-agent therapy (⁶⁷).

An older regimen, CHAMOCA (cyclophosphamide, hydroxyurea, dactinomycin, methotrexate with leucovorin rescue, vincristine, cyclophosphamide, and doxorubicin), resulted in a remission rate of 82%, but this regimen was inferior to MAC in terms of toxicity and efficacy and is not used in current practice (⁶⁸).

Because etoposide was identified to have activity against trophoblastic disease, Bagshawe developed the EMA-CO regimen and reported a survival rate of 83% in patients with high-risk choriocarcinoma (⁶⁹). The efficacy of this combination has been confirmed and this remains the preferred regimen for high-risk GTT (^70,71,72). It is generally well tolerated. Toxicity includes alopecia, mild anemia, neutropenia, and stomatitis. Reproductive function is preserved in 75% of patients. In patients with significant tumor volume, rapid tumor necrosis may result in hemorrhage, and consideration may be given to lower dose induction therapy. After normalization of hCG, three additional consolidation cycles (6 weeks) of EMA-CO are administered (²).

Metastases Requiring Special Care

In the setting of high-risk disease and bulky tumor in areas susceptible to massive hemorrhage or worsening organ failure, consideration may be given to induction chemotherapy followed by full-dose combination chemotherapy. Patients with massive pulmonary or liver metastases or brain metastases may benefit from a 25% dose reduction for the first two cycles, with monitoring in an intensive care unit setting until the disease shrinks enough to allow full-dose chemotherapy with less significant risk of hemorrhage. An alternative strategy is to use low-dose etoposide 100 mg/m² and cisplatin 20 mg/m² on days 1 and 2 every week up to three times prior to initiating standard EMA-CO. Additionally, consideration can be given to using EMA-EP (EMA with etoposide and cisplatin) rather than EMA-CO in patients with the worst prognosis, namely with liver and brain metastases.

Significant vaginal hemorrhage should prompt resuscitative transfusion but is expected to resolve within 3 to 4 days. Additional strategies for management may include embolization, hysterectomy, and arterial ligation. Nearly all patients experiencing hemorrhage can be expected to survive with appropriate resuscitation and management (⁷³). Twenty-five percent of patients with high-risk disease do not attain complete remission, in which case salvage chemotherapy is administered.

Pulmonary Metastases

Pulmonary metastases can be extensive and may cause respiratory failure and death (⁷⁴). Some factors that predict a worse outcome or early death from respiratory compromise include cyanosis, pulmonary hypertension, dyspnea, anemia, tachycardia, extensive (>50%) lung opacification, mediastinal involvement, bilateral pleural effusion, and a high WHO prognostic score (^75,76). In patients with extensive pulmonary metastases, reduced doses of initial chemotherapy have been suggested to abate the risk of respiratory failure, although this strategy does not protect completely against pulmonary failure and death (^75,76).

Central Nervous System Metastases

Like pulmonary metastases, CNS metastases pose a significant threat. Although clinically apparent in only 7% to 28% of patients with choriocarcinoma, CNS involvement is found in as many as 40% of patients on postmortem examination. Multimodality therapy seems to be optimal, yielding a remission rate of 50% (7 of 14 patients) with disease-free intervals of 12 to 120 months.

Athanassiou et al reported that 8.8% of 782 patients had CNS metastases (⁴¹). The overall survival rate of patients who had CNS metastases at diagnosis was 80%. The overall survival of patients who developed CNS metastases after initial diagnosis and treatment was only 25%. Two other studies found similar outcomes and concluded that CNS prophylaxis may improve prognosis (^77,78). However, Gillespie et al showed no benefit of CNS prophylaxis in 69 patients with lung metastases (⁷⁹). We do not advocate CNS prophylaxis in the absence of definite CNS disease.

Patients with known CNS disease benefit from chemotherapy and whole-brain irradiation. In a retrospective analysis of 70 patients, half died before therapy was initiated. Of the remaining patients, 24% of those given chemotherapy alone survived, but 50% of patients given concurrent chemotherapy plus whole-brain irradiation achieved long-term remission and none died of CNS disease (⁸⁰).

When patients present with CNS metastases, primary treatment of the brain with surgical resection or radiotherapy prior to EMA-CO chemotherapy is indicated to decrease the risk of hemorrhage. Surgical resection is appropriate only for patients with solitary metastasis. Surgical decompression should be considered for patients who have symptoms of raised intracranial pressure (⁸¹).

The optimal dose of radiation appears to be 30 Gy. Patients with less than 25 Gy had a lower cure rate (⁸⁰). The local control rate was 91% if >22 Gy was administered but 24% if <22 Gy was administered (⁸²). For CNS disease, it is prudent to administer 30 Gy over 10 fractions initiated simultaneously with the start of chemotherapy. Stereotactic radiotherapy or gamma-knife treatment has been advocated at the end of chemotherapy to treat any residual unresectable lesions as an alternative to whole-brain radiation, due to the toxicity and limited evidence of improvement with whole-brain irradiation (⁶).

The EMA-CO chemotherapy regimen should be administered following surgery or radiation (⁸³). The dose of methotrexate is escalated to 1,000 mg/m². Intrathecal methotrexate 12.5 mg may be given with the CO component of EMA-CO or with whole-brain radiotherapy (20-30 Gy in two daily fractions) concurrent with chemotherapy (^6,84). Extracranial sites of metastases at the time of CNS metastasis are common. Overall survival in patients with CNS metastases is 67% (⁸³).

Patients in First Remission

Patients in first remission thought to have a high risk of recurrence are observed closely with serum β-hCG levels and posttherapy baseline radiologic imaging. For patients who had lung metastases, a repeat high-resolution CT scan at the end of chemotherapy serves as a baseline for follow-up. Many patients who have had lung metastases have residual nodules in the lung field on CT scans or chest x-ray, signifying fibrous scar tissue. For patients who had brain metastases, an MRI of the head would be obtained. Likewise, for patients who had liver metastases, a CT scan of the liver would be obtained. If the uterus is in place and was a site of previous disease, consideration is also given to baseline MRI of the uterus. The rationale is that modest increases in the β-hCG level, signifying relapse, may be accompanied by subtle changes in “sterile” lesions noted on earlier images. This finding raises the issue of surgical resection of a chemotherapy-resistant site. If the imaging obtained after chemotherapy reveals suspicious nodules or masses and the β-hCG level is normal, a baseline PET-CT scan is sometimes obtained to serve as a baseline. If the β-hCG level rises during follow-up, a PET-CT scan would help identify active disease.

Salvage Therapy

One-quarter of patients with high-risk metastatic disease do not achieve complete remission with EMA-CO or experience relapse later. These patients require identification of chemotherapy-resistant sites for possible surgical resection and salvage therapy with alternative platinum-based regimens. These regimens may include EMA-EP (omitting day 2 etoposide and dactinomycin and alternating weekly with etoposide and cisplatin); TE/TP (paclitaxel and etoposide alternating weekly with paclitaxel and cisplatin); ACE (dactinomycin, cisplatin, and etoposide); VIP (etoposide, ifosfamide, and cisplatin); BEP (bleomycin, etoposide, and cisplatin); cisplatin, vincristine, and methotrexate; PVB (cisplatin, vinblastine, and bleomycin); PEBA (cisplatin, etoposide, bleomycin, and doxorubicin); and ICE (high-dose ifosfamide, carboplatin, and etoposide) (^{2,5,66,85,86,87,88,89,90,91,92,93,94,95}). Response rates range from 20% to 75%. The most commonly used regimens are EMA-EP, which is toxic but results in a cure rate greater than 75%, and TE/TP, which may be equally efficacious and less toxic (²).

Cure can also be achieved with surgery in a subset of chemoresistant patients who have one to three disease sites after combination chemotherapy. In this setting, PET-CT may be useful to detect metastatic sites (^6,96). Total or radical hysterectomy to remove the disease, with or without adnexectomy and lymphadenectomy, can be curative in 90% of patients with primary drug-resistant and relapsed GTN (^97,98).

Patients who fail these approaches may be candidates for high-dose chemotherapy. Limited outcomes data exist, but reports suggest that high-dose chemotherapy alone combined with surgical resection may lead to salvage in one-third of patients. The most common regimen is CarbopEC-T (carboplatin, etoposide, cyclophosphamide, and paclitaxel) (^2,6).

Placental Site Trophoblastic Tumor

Originally known as trophoblastic pseudotumor, these tumors have been designated as PSTT to better reflect their malignant potential. The median age at diagnosis is 33 years (range, 18-47 years). The most common presenting symptoms are irregular vaginal bleeding, amenorrhea, and a pelvic mass (¹⁷). The median interval from antecedent pregnancy is 3.4 years. These tumors present with lung metastases in 10% to 20% of cases, and 10% of patients develop metastases during the follow-up interval (¹⁷).

The FIGO scoring is not used to determine the treatment of PSTT (²). Hysterectomy is the preferred treatment for nonmetastatic disease, which is highly curable. Postoperative chemotherapy is indicated for patients with certain risk factors, including metastatic disease, mitotic index, hCG level, and time from antecedent pregnancy. The latter is the most prognostic factor (²). The long-term survival rate of patients presenting with PSTT within 4 years of antecedent pregnancy was 98%, compared with 100% mortality for patients presenting with PSTT more than 4 years after antecedent pregnancy, but these findings have been inconsistent (^14,17).

The general strategy is to perform hysterectomy for patients with nonmetastatic disease who present less than 4 years after antecedent pregnancy. Premenopausal patients with limited disease may preserve their ovaries, and lymphadenectomy is of limited utility (¹⁷). Patients with metastatic disease at presentation receive EMA-EP (^{2,14,94,99,100}) and, upon response, undergo resection of residual disease sites and hysterectomy. Recurrent disease not amenable to surgical resection may require radiation or combination chemotherapy with EMA-CO (^94,99). Patients who present more than 4 years after antecedent pregnancy have poor survival and should be considered for clinical trials or high-dose chemotherapy, even when the disease appears to be localized (^1,2,7). Patients with limited disease who desire fertility may be considered for focal uterine resection with or without chemotherapy, but this is investigational (^1,2).

Placental site trophoblastic tumor produces β-hCG inconsistently, so the serum β-hCG level is not uniformly helpful in diagnosis, treatment, or follow-up (^17,64). Placental site trophoblastic tumor is less responsive to chemotherapy than choriocarcinoma, but chemotherapy remains effective in many patients, and the prognosis depends on the extent of disease at presentation (^2,17). The overall mortality rate of PSTT is 16% to 21% (³). The median overall survival is 86 months; 88% of patients with early-stage disease and 11% of patients with advanced-stage disease were without evidence of disease 28 months after diagnosis (¹⁷).

Epithelioid Trophoblastic Tumor

This rare disease entity appears to be distinct from PSTT but is treated in a similar fashion. The International Society for the Study of Trophoblastic Disease database is collecting information on both of these tumor entities and will inform future treatment decisions (²).

The estimated incidence of twin pregnancy consisting of a molar pregnancy and a normal fetus is 1 per 22,000 to 100,000 pregnancies. This has been described in both spontaneous and in vitro fertilization (IVF) gestations, although the incidence may be greater in women undergoing assisted reproduction. Gestational trophoblastic tumors in such cases have been either molar pregnancies or malignant neoplasms.

A patient with this rare condition poses a therapeutic dilemma. Although some have suggested termination for these pregnancies due to a low successful birth rate and an increased risk of GTN, recent studies have reported that 38% to 57% of women deliver a healthy baby, with a slight increase in maternal complications but no increase in malignant transformation of molar pregnancy (¹⁰¹). The decision on any therapy is made after consultation with the patient, a perinatologist, and a gynecologic oncologist, with careful assessment of the risk to the mother and the fetus.

Women who have undergone effective treatment for molar pregnancy have a risk of future molar pregnancy of 1% to 2% (¹⁰²). Strict contraception is required during the surveillance period because pregnancy would obviate the usefulness of β-hCG as a tumor marker. Patients are advised to use effective hormonal or barrier contraception. Intrauterine devices are not employed as contraception for patients with intact uteri because of concerns of uterine perforation. In general, once a 6-month surveillance establishes disease-free status, conception is acceptable, although these women are always at higher risk for future molar disease and will require close observation during future pregnancies (¹⁰³). Previous studies suggested a 12-month conception-free period, but 6 months confers the same protection and allows the patient to pursue fertility earlier without an increased risk of GTD relapse. The recommendation to avoid pregnancy relates to the importance of hCG surveillance and does not relate to the risk of recurrence, as GTN-related outcomes, miscarriage, and the incidence of birth defects appear to be unrelated to conception (^6,56).

Standard chemotherapy has minimal impact on subsequent ability to reproduce (^104,105). In one study, 83% of women who received prior chemotherapy subsequently conceived (⁶). In general, no increase in adverse events such as first- or second-trimester abortions or stillbirths, prematurity, or need for cesarean section has been noted, except for one report documenting a slight increase in stillbirth in subsequent pregnancies after chemotherapy (¹⁰²). Similarly, their offspring have no increased risk of anomalies (⁵⁶). Patients are monitored closely throughout any subsequent pregnancy, especially in the first trimester, to confirm that gestation is normal (⁷⁹). Patients who have difficulty with conception are considered for fertility treatment but are at increased risk of repeat molar pregnancy.

Combination chemotherapy with EMA-CO induces menopause an average of 3 to 5 years earlier than otherwise anticipated (^6,105). The previously identified increased risk of second primary cancers (eg, acute myelogenous leukemia and thyroid cancer) after chemotherapy for choriocarcinoma was not observed in recent studies (¹⁰⁶). Issues of survivorship concern sexual dysfunction and reproductive quality of life and appear to be greater in socially disadvantaged patients (^2,107).

Gestational trophoblastic disease represents a wide spectrum of neoplastic disorders that arise from placental trophoblastic tissue after abnormal fertilization. Patients are classified into different prognostic groups based on factors such as tumor histologic subtype, extent of disease, human gonadotropin titer, duration of disease, nature of the antecedent pregnancy, and extent of prior treatment. Each patient should receive individualized management after careful prognostication under the care of a multidisciplinary team. Surgery and chemotherapy each play an important role in effective management. Patients with GTD are followed long term with regular laboratory tests of complete blood count and β-hCG. Survivors of GTD are also followed for management of psychosocial problems that may be associated with GTD and their treatment.