Gynecologic Oncology: Clinical Practice and Surgical Atlas, 1st Ed.

Gestational Trophoblastic Disease

Diljeet K. Singh

Gestational trophoblastic disease (GTD) represents a spectrum of cellular proliferations arising from the villous trophoblast of the placenta and encompasses 4 clinicopathologic entities: hydatidiform mole (complete and partial), invasive mole, choriocarcinoma (CCA), and placental site trophoblastic tumor (PSTT). The last 3 conditions are associated with more significant clinical sequelae and together comprise the general term gestational trophoblastic neoplasia (GTN). In the absence of GTD, a normal pregnancy involves functioning trophoblast that invades the endometrium and recruits a robust vasculature to develop the placenta, which supports intrauterine fetal development. In healthy trophoblastic tissue, these “cancer simulating” behaviors are highly regulated; however, in GTD, normal control mechanisms fail, leading to invasive, vascular tumors with a tendency to metastasize.1

Historically, GTD has been associated with significant morbidity and mortality. Hydatidiform moles were typically accompanied by serious bleeding and other medical complications before the development of early detection and effective uterine evacuation in the 1970s. Over the past 50 years, advances in this field have transformed GTN from a high mortality condition to one of the most treatable of all human cancers, with a cure rate exceeding 90%.2-4Collaborative global efforts and specialty care centers have promoted the development of highly predictive staging and prognostic scoring systems, which enhance individualization of therapy. Furthermore, several advances in chemotherapy afford ongoing refinement in treatment protocols.2-6 For women at highest risk of death, the application of multimodal therapy, including chemotherapy, radiation, and surgery, has led to high cure rates while minimizing disease and treatment-related morbidities. In this setting of potentially high cure rates, the onus to identify and appropriately treat GTD falls on the providers entrusted with the primary care of women.

EPIDEMIOLOGY

Key Points


1. The incidence of GTD is approximately 1 per 1000 pregnancies.

2. The most consistently defined risk factors for GTD include extremes of reproductive age and history of prior molar pregnancy. Of all the environmental factors associated with GTD, only low β-carotene and animal fat intake is consistently associated with GTD.

3. Complete hydatidiform molar pregnancy typically results in 1 sperm fertilizing an empty ovum, with subsequent genetic duplication; in contrast, incomplete hydatidiform molar pregnancy typically develops from dispermic fertilization of a normal ovum.


In general, studies conducted in North America, Australia, New Zealand, and Europe indicate the incidence of hydatidiform mole ranges from 0.57 to 1.1 per 1000 pregnancies. In contrast, studies from Southeast Asia and Japan suggest an incidence as high as 2.0 per 1000 pregnancies. As a result of difficulties in obtaining reliable epidemiologic data, it is unclear whether these findings represent a true difference in prevalence or are related to discrepancies between hospital- and population-based data or disparities in the availability of central pathology review.7 Further complicating the identification of true incidence is the uncommon diagnosis of GTD and the unreliable documentation of early pregnancy loss. Epidemiologic studies do support wide regional variations in the incidence of hydatidiform moles.7However, attempts to attribute an increased incidence of hydatidiform mole among American Indians, Eskimos, Hispanics, and African Americans as well as various Asian populations to genetic traits, cultural factors, or differences in reporting have been unsuccessful.8 Furthermore, some data suggest a decline in the incidence of molar pregnancies, which may be attributed to improved socioeconomic conditions and improvements in diet, which is consistent with studies that show a decreased risk of molar pregnancy with increased consumption of dietary carotene and animal fat.9,10

The incidence of CCA and placental-site trophoblastic tumor are even less well known, because these lesions are exceedingly uncommon and because of the difficulty in clinically distinguishing postmolar CCA from invasive mole. In Europe and North America, CCA affects approximately 1 in 40,000 pregnancies, with 1 in 160,000 term pregnancies and 1 in 40 hydatidiform moles. In Southeast Asia and Japan, CCA rates are higher, at 9.2 and 3.3 per 40,000 pregnancies, respectively.8,11 In the United Kingdom, CCA develops in 1 in 50,000 deliveries, and placental-site trophoblastic tumor accounts for approximately 0.2% of cases of GTD.12,13 The incidence rates of both hydatidiform mole and CCA have declined over the past 30 years in all populations.11

The most consistently documented risk factors for the development of GTD include extremes of reproductive age and history of prior molar pregnancy. Advanced or very young maternal age consistently correlates with higher rates of complete hydatidiform mole. Compared with women aged 21 to 35 years, the risk of complete mole is doubled for those older than 35 years and/or younger than 21 years and is 7.5 times higher for women older than 40 years.14 A diagnosis of a previous hydatidiform mole confers approximately a 1% risk of repeat molar pregnancy.15 Although this is 10 times the risk of the general population, most women with history of a molar conception will have normal subsequent pregnancies. If a woman has had more than 2 prior molar pregnancies, the risk for recurrence in latter gestations increases to 15% to 28%, and the risk is not influenced by change of partner.15-21 Although many possible environmental etiologies for complete mole have been studied, the only consistent association is an inverse relationship between β-carotene and animal fat dietary intake and the incidence of molar pregnancy.9,10

Risk factors for CCA include prior complete hydatidiform mole, ethnicity, and advanced maternal age. GTN (invasive mole or CCA) follows a complete molar pregnancy in 15% to 20% of cases.22-24 CCA is approximately 1000 times more likely after a complete mole than after another pregnancy event. Fewer than 5% of partial moles will develop postmolar GTN; metastases occur rarely, and a histopathologic diagnosis of CCA has never been confirmed after a partial mole.22,25 The risk of CCA is also increased in women of Asian and American Indian descent and among African Americans. Similar to molar pregnancies, the median age of women with CCA is higher than that for normal pregnancies.11

Reproductive factors may play a role in the development of GTD. Women with a history of spontaneous abortion have a 2- to 3-fold increased risk of a molar pregnancy as compared with women without a history of miscarriage.26Other studies have suggested that women with menarche after 12 years of age, light menstrual flow, and previous use of oral contraceptives are at increased risk for GTN.27,28

Much of the pathogenesis of GTD is well known. In 90% of cases, complete hydatidiform mole occurs when an ovum without maternal chromosomes or with inactive chromosomes is fertilized by 1 sperm that duplicates its DNA, resulting in a 46, XX androgenetic (entirely paternally derived) karyotype.29 The other 10% of complete moles are 46, XY, or 46, XX, as a result of fertilization of an empty ovum by 2 sperms (dispermy). Although nuclear DNA is entirely paternal, mitochondrial DNA remains maternal in origin.30 In contrast, partial molar pregnancies demonstrate a triploid karyo-type (usually 69, XXY), resulting from the fertilization of an apparently normal ovum by 2 sperms.22

Evidence that recurrent molar pregnancies occur even in the setting of different male partners suggests a poorly understood role of maternal factors in the development of molar pregnancy.31 Some researchers have suggested that ova from older women are more susceptible to abnormal fertilizations than are those from younger women.1 In addition, there appears to be a relationship between excessive paternal chromosomes and trophoblastic hyperplasia.24

DIAGNOSIS

Key Points


1. Classic presenting signs of molar pregnancy include first trimester vaginal bleeding and uterine size greater than expected for gestational dates.

2. Ultrasonography is the imaging modality of choice when GTD is suspected.

3. Markedly elevated human chorionic gonadotropin levels above those of normal pregnancy are a hallmark of hydatidiform moles.


A high index of suspicion on the part of the general obstetrician-gynecologist is essential to the timely diagnosis of GTD and GTN. Clinical features, ultrasound, and serum and urine tests for human chorionic gonadotropin (hCG) aid in the diagnostic process.

In 80% to 90% of cases, complete hydatidiform mole presents with vaginal bleeding, usually at 6 to 16 weeks of gestation (Table 8-1). Other classic clinical signs suggestive of a diagnosis of molar pregnancy include uterine size greater than expected for gestational dates, hyperemesis gravidarum, and pregnancy-induced hypertension. Because the diagnosis of molar disease has shifted earlier in the pregnancy with increasing application of ultrasound technology, these findings are seen much less frequently.32 To a lesser extent, women with molar disease may also present with pelvic pain due to enlarged theca-lutein cysts and/or clinical signs of hyperthyroidism.

Table 8-1 Differential Diagnosis

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Partial moles present slightly later in pregnancy because they do not grow as rapidly as complete moles. Most (90%) present with symptoms of incomplete or missed abortion, and vaginal bleeding occurs in approximately 75% of patients.33 The other signs and symptoms seen with complete mole, such as excessive uterine enlargement, hyperemesis, pregnancy-induced hypertension, hyperthyroidism, and theca lutein cysts, are significantly less common.33

Presentation of gestational trophoblastic neoplasia depends on the antecedent pregnancy event, extent of disease, and histopathology. Most often postmolar GTN (invasive mole or CCA) presents as irregular bleeding after evacuation of a hydatidiform mole. Clinical signs of postmolar GTN include an enlarged, irregular uterus and persistent bilateral ovarian enlargement. Occasionally, the diagnosis is made at the time of evacuation when a metastatic vaginal lesion is found. Biopsy of suspected vaginal metastases is discouraged because of the risk of substantial bleeding.34 In patients with postpartum uterine bleeding and subinvolution, the differential should include GTN as well as retained products of conception, endomyometritis, primary or metastatic tumors of other organ systems, or a new pregnancy event (Table 8-1).35

Diagnosis of GTN is often made when metastases induce symptoms. The vascular nature of these lesions can lead to bleeding, including intra-abdominal and/or intracerebral hemorrhage, melena, or hemoptysis. Brain metastases and bleeding from these lesions can cause increased intracranial pressure, leading to headaches, seizures, or hemiplegia. Extensive lung metastases can also cause dyspnea, cough, and chest pain. PSTTs and epithelioid trophoblastic tumors almost always cause irregular uterine bleeding, often distant from a preceding nonmolar gestation, and rarely virilization or nephrotic syndrome. The uterus is usually symmetrically enlarged, and serum hCG levels are only slightly elevated.36,37

Several diagnostic tests aid in the diagnosis and evaluation of GTD. Ultrasonography has virtually replaced all other means of preoperative diagnosis of both complete and partial mole.38-40 Characteristic ultrasonographic scans of complete mole show a uterine cavity filled with a heterogeneous mass (snowstorm pattern), without associated fetal development and with theca lutein ovarian cysts, although these features are not always visible in the first trimester41 (Figure 8-1). Ultra-sonography may also facilitate the early diagnosis of a partial mole by demonstrating focal cystic spaces within the placenta and an increase in the transverse diameter of the gestational sac.39 Although previous work suggested that ultrasound was diagnostic of complete mole in early pregnancy, larger, more recent studies have shown that only 40% to 60% of cases are detected as molar by sonography in routine clinical practice.39,40,42,43 In addition, 10% of “molar pregnancies” diagnosed by ultrasound were found to be nonmolar hydropic abortions on histologic review.42,44 In the United Kingdom, the Royal College of Obstetrics and Gynaecologists recommends that all products of conception from non-viable pregnancies should undergo histologic examination irrespective of ultrasonographic findings, and other authors have recommended routine follow-up of hCG after elective termination.45,46 The American Congress of Obstetrics and Gynecology suggests pathologic evaluation of tissue after spontaneous and therapeutic abortions, although regulations vary by state.

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FIGURE 8-1. Pelvic ultrasound of a complete hydatidiform mole with the characteristic vesicular pattern of multiple echoes, holes within the placental mass, and no fetus.

hCG is a disease-specific tumor marker produced by hydatidiform moles and GTNs. hCG assays are readily available, and levels are easily measured quantitatively in both urine and blood. hCG is made up of an α subunit that is shared with pituitary glycoprotein hormones, including thyroid-stimulating hormone and luteinizing hormone (LH) and a β subunit unique to the placenta that confers specificity. Assays that are designed to detect hCG target the β subunit. In healthy pregnancy, hCG is intact and is hyperglycosylated during the first trimester. However, in GTD, many other subtypes of β-hCG can exist, including free β-hCG, β-core, nicked free β, or c-terminal peptide.47,48Because the hCG molecules in GTD are more heterogenous and degraded than those in normal pregnancy, an assay that detects all forms of hCG and its multiple fragments should be used to follow patients with GTD. Most institutions currently use rapid, automated, radiolabeled monoclonal antibody “sandwich” assays that measure different mixtures of hCG-related molecules. hCG assays are susceptible to false-positive results, usually caused by cross-reacting heterophile antibodies that are found in 3% to 4% of healthy people.49 These cross-reacting heterophile antibodies are present only in serum and do not pass into the urine. In most cases a negative urine hCG test can confirm that the serum value is a false positive, although referral to a specialty laboratory may be required. These so-called phantom hCG results, with levels reported as high as 800 mIU/mL, have led to treatment of healthy patients with unnecessary surgery and chemotherapy.50 Additionally, there is some cross-reactivity of hCG with LH, which may lead to falsely elevated low levels of hCG. Measurement of LH to identify this possibility and suppression of LH with oral contraceptive pills prevents this problem.51

Markedly elevated hCG levels above those of normal pregnancy are a hallmark of hydatidiform moles, and approximately half of patients with complete mole have pre-evacuation hCG levels greater than 100,000 mIU/mL.52However, the differential diagnosis of a significantly elevated hCG level includes the multiple causes of an enlarged placenta, such as misjudged gestational age, multiple gestation, and erythroblastosis fetalis (Table 8-1). Partial molar pregnancies, in contrast, typically do not demonstrate elevated hCG levels; fewer than 10% have hCG levels exceeding 100,000 mIU/mL.38

A clinical diagnosis of postmolar GTN is most often made by the finding of rising or plateauing hCG levels after evacuation of a hydatidiform mole. Chorio-carcinoma is usually diagnosed by the finding of an elevated hCG level, frequently in conjunction with the discovery of metastases, after other pregnancy events. PSTT is commonly associated with only slightly raised hCG levels; human placental lactogen may be elevated in this variant of trophoblastic disease.

When a diagnosis of GTN is suspected, a metastatic work-up should be conducted. Most patients who develop GTN after a molar pregnancy are detected early by hCG monitoring, so detailed investigation is rarely needed. Diagnostic testing should be guided by findings on complete history and physical examination and laboratory studies including complete blood count, serum chemistries including renal and liver functions panels, blood type and antibody screen, and quantitative serum hCG level. Pulmonary metastases are most common, so chest radiography (CXR) is essential.2 Chest computed tomography (CT) is not needed when CXR is normal, because discovery of micrometastases, which can be seen in approximately 40% of patients, does not affect outcome.53 However, if lesions are noted on CXR, CT of the chest, abdomen, and pelvis and brain magnetic resonance imaging (MRI) are obtained to exclude more widespread disease such as the brain or liver metastases, which would substantially change management. Pelvic ultrasound or MRI may also be useful in detecting extensive uterine disease for which hysterectomy may be of benefit.

Several procedures are critical in the diagnosis and management of GTD. A diagnosis of GTD is usually confirmed by cervical dilatation and suction curettage of uterine contents. Some patients who do not desire future fertility may elect to undergo primary hysterectomy for evacuation of the molar gestation, with concurrent sterilization. Due to risks of hemorrhage at the time of evacuation, hysterotomy or induction of labor is not recommended.

Repeat curettage after hydatidiform mole evacuation is not recommended unless there is excessive uterine bleeding and radiologic evidence of substantial intracavitary molar tissue, because repeat curettage does not often induce remission or influence treatment and may result in uterine perforation and hemorrhage.54-56

PATHOLOGY

Key Points


1. Complete hydatidiform moles undergo early and uniform hydatid enlargement of villous trophoblast in the absence of a fetus or embryo.

2. Partial, or incomplete, hydatidiform moles demonstrate identifiable fetal tissue and chorionic villi with focal edema that vary in size and shape.

3. Approximately 10% to 17% of hydatidiform moles result in invasive mole, and approximately 15% of these metastasize; the most common site of meta-static spread is to the lungs or vagina.

4. Choriocarcinoma (CCA) is a malignant disease characterized by abnormal trophoblastic hyperplasia and anaplasia, absence of chorionic villi, hemorrhage, and necrosis, with direct invasion into the myometrium and vascular invasion resulting in spread to distant sites.


Molar pregnancies and gestational trophoblastic neoplasia all originate from the placental trophoblast. Hydatidiform moles and CCA arise from villous trophoblast and PSTT from intermediate trophoblast. Normal trophoblast is composed of cytotrophoblast, syncytiotrophoblast, and intermediate trophoblast, all 3 of which may result in GTD when they proliferate.57 Normal syncytiotrophoblast invades the endometrial stroma with implantation of the blastocyst and is the cell type that produces hCG. Cytotrophoblast functions to supply the syncytium with cells in addition to forming outpouchings that become the chorionic villi covering the chorionic sac. The villous chorion adjacent to the endometrium and basalis layer of the endometrium together form the functional placenta for maternal-fetal nutrient and waste exchange. Intermediate trophoblast is located in the villi, the implantation site, and the chorionic sac.

Hydatidiform mole is pathologically characterized by varying degrees of trophoblastic proliferation (both cytotrophoblast and syncytiotrophoblast) and vesicular swelling of placental villi associated with an absent or an abnormal fetus/embryo. There are 2 syndromes of hydatidiform mole, which are distinguished by their clinical behavior, morphology, and genetic make-up. Complete hydatidiform moles undergo early and uniform hydatid enlargement of villi in the absence of a fetus or embryo, the trophoblast is consistently hyper-plastic with varying degrees of atypia, and villous capillaries are absent (Figure 8-2). Partial, or incomplete, hydatidiform moles demonstrate identifiable fetal or embryonic tissue, chorionic villi with focal edema that vary in size and shape, scalloping and prominent stromal trophoblastic inclusions and a functioning villous circulation, and focal trophoblastic hyperplasia with mild atypia only (Figure 8-3). Invasive mole arises from myometrial invasion of a hydatidiform mole via direct extension through tissue or venous channels (Figure 8-4). Approximately 10% to 17% of hydatidi-form moles result in invasive mole, and approximately 15% of these will metastasize; the most common site of metastatic spread is to the lungs or vagina. Invasive moles are most often diagnosed clinically rather than pathologically based on persistent hCG elevation after molar evacuation and are frequently treated with chemotherapy without a histopathologic diagnosis. CCA is a malignant disease characterized by abnormal trophoblastic hyperplasia and anaplasia, absence of chorionic villi, hemorrhage, and necrosis, with direct invasion into the myometrium and vascular invasion resulting in spread to distant sites, including the lungs, brain, liver, pelvis and vagina, kidney, intestines, and spleen (Figure 8-5). CCA has been reported to occur in association with any pregnancy event. Approximately 25% of cases follow abortion or tubal pregnancy, 25% are associated with term or preterm gestation, and the remaining 50% arise from complete moles. Only 2% to 3% of complete moles progress to CCA. PSTT is an extremely rare disease that arises from the placental implantation site and consists predominantly of mono-nuclear intermediate trophoblast without chorionic villi infiltrating in sheets or cords between myometrial fibers (Figure 8-6). PSTT is associated with less vascular invasion, necrosis, and hemorrhage than CCA, and it has a propensity for lymphatic metastasis. Immunohistochemical staining reveals the diffuse presence of cytokeratin and human placental lactogen, whereas hCG is only focal. Cytogenic studies have revealed that PSTTs are more often diploid than aneuploid. Most PSTTs follow nonmolar gestations.37 Epithelioid trophoblastic tumor (ETT) is a rare variant of PSTT that simulates carcinoma. Based on morphologic and histochemical features, it appears to develop from neo-plastic transformation of chorionic-type intermediate trophoblast. Most ETTs present many years after a full-term delivery.36

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FIGURE 8-2. Complete hydatidiform mole with hydropic villi, absence of villous blood vessels, proliferation of hyperplastic cytotrophoblast, and syncytiotrophoblast.

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FIGURE 8-3. Partial hydatidiform mole with chorionic villi of varying size and shape with focal edema and scalloping, stromal trophoblastic inclusions, and functioning villous circulation, as well as focal trophoblastic hyperplasia.

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FIGURE 8-4. Invasive mole with direct extension of molar tissue, including hydropic villi and covering hyperplastic trophoblast, into the myometrium.

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FIGURE 8-5. Choriocarcinoma composed of abnormal cytotrophoblast and syncytiotrophoblast with hyperplasia and anaplasia, absence of chorionic villi, hemorrhage, and necrosis.

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FIGURE 8-6. Placental-site trophoblastic tumor with sheets of mononuclear intermediate trophoblast cells without chorionic villi infiltrating between myometrial fibers.

Pathologic diagnosis of complete and partial moles is made by examination of curettage specimens. In the setting of unclear diagnosis, additional testing can be helpful. Immunohistologic staining for p57 (a paternally imprinted, maternally expressed gene) can differentiate complete moles (absent immunostaining) from hydropic abortuses and partial moles (positively staining), and flow cytometry can distinguish diploid complete moles from triploid partial moles.58,59 Additionally, pathologic diagnosis of invasive mole, CCA, PSTT, and ETT can sometimes be made by curettage, biopsy of metastatic lesions, or examination of hysterectomy specimens or placentas. Biopsy of a vaginal lesion suggestive of a GTN is dangerous because of the massive bleeding that can occur.60

In 2002, the International Federation of Gynecology and Obstetrics (FIGO) defined criteria for the diagnosis of postmolar disease and adopted a combined anatomic staging and modified World Health Organization (WHO) risk-factor scoring system for GTN (Tables 8-2 and 8-3).61 The components needed to diagnose postmolar GTN include at least 1 of the following: (1) hCG plateau for 4 consecutive values over 3 weeks, (2) hCG rise of > 10% for 3 values over 2 weeks, (3) hCG persistence 6 months after molar evacuation, (4) histopathologic diagnosis of CCA, or (5) presence of metastatic disease (Figure 8-1). The FIGO stage is designated by a Roman numeral, followed by the modified WHO score designated by an Arabic numeral, separated by a colon. PSTTs and ETTs are classified separately.5

Table 8-2 FIGO Anatomic Staging for Gestational Trophoblastic Neoplasia1

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Table 8-3 Modified WHO Prognostic Scoring System as Adapted by FIGO

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Treatment is based on classification into risk groups defined by the stage and scoring system. Patients with nonmetastatic (stage I) and low-risk metastatic (stages II and III, score < 7) GTN can be treated with single-agent chemotherapy, with resulting survival rates approaching 100%. Patients classified as having high-risk metastatic disease (stage IV and stages II-III, score ≥ 7) should be treated in a more aggressive manner with multiagent chemotherapy and as needed adjuvant radiation or surgery to achieve cure rates of 80% to 90%. Use of the FIGO staging system is essential for determining initial therapy for patients with GTN to assure the best possible outcomes with the least morbidity.

TREATMENT

Key Points


1. Suction evacuation and curettage is the preferred treatment method for a hydatidiform mole, independent of uterine size, for patients who wish to maintain their fertility.

2. Definitive follow-up requires serial serum quantitative hCG measurements every 1 to 2 weeks until 3 consecutive tests show normal levels, after which hCG levels should be determined at 3-month intervals for 6 months after the spontaneous return to normal.

3. Patients with nonmetastatic (stage I) and low-risk metastatic (stages II and III, score < 7) GTN should be treated with single-agent methotrexate or actinomycin D chemotherapy.

4. Patients with high-risk metastatic GTN (FIGO stage IV and stages II-III score ≥ 7) should be treated initially with multiagent chemotherapy with or without adjuvant surgery or radiation therapy.

5. Definitive treatment of PSTT and ETT includes hysterectomy with lymphadenectomy.


Once the diagnosis of molar pregnancy is suspected by history, physical examination, hCG levels, and ultrasound findings, the patient should be evaluated for the presence of medical complications (anemia, preeclampsia, hyperthyroidism) and metastases by vital signs and diagnostic tests including complete blood counts, basic chemistry, hepatic and thyroid panels, urinalysis, and CXR. The preoperative evaluation should also include blood type and cross-match, serum hCG level, and electrocardiogram if appropriate.

Suction evacuation and curettage is the preferred treatment method for a hydatidiform mole, independent of uterine size, for patients who wish to maintain their fertility.51,62 Intraoperative ultrasonography can reduce the risk of uterine perforation. After anesthesia is achieved, the cervix is dilated to allow a 12- to 14-mm suction cannula to pass into the lower uterine segment, which is rotated as the intrauterine contents are removed.35 An intravenous (IV) oxytocin infusion should be started at the onset of suction curettage and continued for several hours postoperatively to enhance uterine contractility and to minimize blood loss. Suction evacuation should be followed by gentle sharp curettage. Because the risk of bleeding increases with uterine size, at least 2 units of blood should be immediately available when the uterus is greater than 16-week gestational size. Patient outcomes are improved by use of appropriate equipment, access to blood products, careful intraoperative monitoring, and early anticipation of complications. Patients who are rhesus-negative should receive rhesus immunoglobulin at the time of evacuation because rhesus D factor is expressed on trophoblast.51,62

Women who are nulliparous should not be given prostanoids to ripen the cervix because these drugs can induce uterine contractions and might increase the risk of trophoblastic embolization to the pulmonary vasculature.1Similarly, medical induction of labor or hysterotomy are not recommended for molar evacuation because they increase trophoblastic dissemination and the development of postmolar GTN requiring chemotherapy.63 In addition, these methods increase maternal morbidity, such as blood loss, incomplete evacuation ultimately requiring dilation and curettage, and the requirement for cesarean delivery in subsequent pregnancies. Hysterectomy may be considered for women who do not desire further child-bearing or have life-threatening hemorrhage.64 The adnexa may be left intact even in the presence of theca lutein cysts. In addition to evacuating the molar pregnancy, hysterectomy provides permanent sterilization and eliminates the risk of local myometrial invasion as a cause of persistent disease. Hysterectomy does not eliminate the risk of postmolar GTN, which remains at 3% to 5% because of the potential for metastatic disease. hCG surveillance should be continued as after any molar pregnancy (Table 8-4).

Table 8-4 Surveillance After Gestational Trophoblastic Disease

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Prophylactic administration of either methotrexate or actinomycin D chemotherapy at the time of or immediately after evacuation of a hydatidiform mole is associated with a reduction in incidence of postmolar GTN from approximately 15% to 20% to 3% to 8%. However, the use of prophylactic chemotherapy should be limited to situations in which the risk of postmolar GTN is much greater than normal or in which adequate hCG follow-up is not possible, as essentially all patients who are followed up with serial hCG testing after molar evacuation and found to have persistent GTN can be cured with appropriate chemotherapy.65

Follow-up after evacuation of a hydatidiform mole is essential to detect trophoblastic sequelae (invasive mole or CCA), which develop in 15% to 20% of women with complete mole and 1% to 5% of those with partial mole (Figure 8-1 and Table 8-4).62,66,67 Clinical findings of prompt uterine involution, ovarian cyst regression, and cessation of bleeding are all reassuring signs; however, definitive follow-up requires serial serum quantitative hCG measurements every 1 to 2 weeks until 3 consecutive tests show normal levels, after which hCG levels should be determined at 3-month intervals for 6 months after the spontaneous return to normal. More than half of patients will have complete regression of hCG to normal within 2 months of evacuation. Contraception is recommended for 6 months after the first normal hCG result to distinguish a rising hCG due to persistent or recurrent disease from a rising hCG associated with a subsequent pregnancy. The use of oral contraceptive pills is preferable because they have the advantage of suppressing endogenous LH, which may interfere with the measurement of hCG at low levels, and studies have shown that oral contraceptive pills do not increase the risk of postmolar trophoblastic neoplasia.68 Pathologic examination of the placenta and other products of conception as well as determination of a 6-week postpartum hCG level is recommended with all future pregnancies. The general obstetrician-gynecologist may be responsible for immediate surveillance after a molar pregnancy and will be essential to ensuring that appropriate studies are carried out after subsequent pregnancy events.

The likelihood of persistent disease developing after evacuation of a complete mole increases with evidence of marked trophoblastic growth, such as a pre-evacuation hCG level greater than 100,000 mIU/mL, excessive uterine growth (> 20 weeks size), and theca lutein cysts greater than 6 cm in diameter. Patients with ≥ 1 of these signs have approximately a 40% incidence of postmolar GTN compared with 4% for those without any of these signs. Patients with age greater than 40 years, a repeat molar pregnancy, an aneuploid mole, and medical complications of molar pregnancy, such as toxemia, hyperthyroidism, and trophoblastic embolization, are also at increased risk for postmolar GTN.62

Treatment of Low-Risk Disease

Patients with nonmetastatic (stage I) and low-risk metastatic (stages II and III, score < 7) GTN should be treated with single-agent methotrexate or actinomycin D chemotherapy.69,70 Several outpatient chemotherapy protocols may be used, including weekly intramuscular (IM) or intermittent intravenous (IV) infusion methotrexate, biweekly single-dose actinomycin D, 5-day methotrexate or actinomycin D, and 8-day methotrexate plus folinic acid. Increased risk of initial chemotherapy resistance is seen with older patient age, higher hCG levels, nonmolar antecedent pregnancy, histopathologic diagnosis of CCA, presence of metastatic disease, and higher FIGO score; these patients may benefit from the 5- or 8-day regimens. Although differences are seen in primary remission rates depending on initial chemotherapy, almost all patients are eventually cured, with most being able to preserve fertility.71

Methotrexate 0.4 mg/kg (maximum 25 mg) IM or IV push daily for 5 days every other week appears to be a highly effective treatment protocol. Review of 30 years of experience in treating nonmetastatic GTN at the Brewer Trophoblastic Disease Center (Northwestern University Feinberg School of Medicine, Chicago, IL) with 5-day methotrexate showed that 89% of patients achieved primary remission, 9% were placed into remission with subsequent single-agent actinomycin D, and only 2% required multiagent chemotherapy or hysterectomy for cure. Significant toxicity to methotrexate necessitating a change to another chemo-therapeutic agent occurred in 5% of patients, and no life-threatening toxicity occurred. Stomatitis was common, nausea was uncommon, and alopecia did not occur. Factors found to be associated with resistance to initial methotrexate chemotherapy were high pretreatment hCG level, nonmolar antecedent pregnancy, and clinicopathologic diagnosis of CCA. These results of approximately 90% complete response and 100% survival confirm other reports that single-agent methotrexate in a 5-day outpatient course every 2 weeks is a highly effective and well-tolerated treatment.71

An alternative methotrexate regimen consists of slightly higher doses of methotrexate (1.0-1.5 mg/kg) IM every other day alternating with folinic acid (0.1-0.15 mg/kg) IM over 8 days with at least a 1-week interval between courses. This methotrexate plus folinic acid protocol demonstrated decreased toxicity, but higher cost and inconvenience, and it more frequently required change in chemotherapy to achieve remission.72 High-dose methotrexate infusion (100 mg/m2 IV push followed by 200 mg/m2 IV 12-hour infusion with folinic acid rescue), with interval between doses based on post-treatment hCG trends, is another modified methotrexate dosage schedule used for treatment of low-risk GTN. This regimen also has increased need for second-line therapy and is expensive.73 Although methotrexate administered in single weekly IM doses of 30 to 50 mg/m2 is more convenient, less costly, and less toxic, it has the relatively lowest complete response rate of any regimen and is not appropriate therapy for metastatic disease or CCA.74

Actinomycin D (10-12 mg/kg IV daily for 5 days every other week or as a single 1.25 mg/m2 IV dose every 2 weeks) is a reasonable alternative to methotrexate, although it has a more toxic side-effect profile (nausea, alopecia) than methotrexate and produces local tissue injury with extravasation. Actinomycin D has mainly been used for methotrexate resistance or as primary therapy for patients with hepatic or renal compromise or effusions contraindicating the use of methotrexate.75,76

Several studies have compared different methotrexate and actinomycin D regimens for treatment of low-risk, mostly nonmetastatic GTN. Three randomized clinical trials have compared weekly IM methotrexate with biweekly actinomycin D and demonstrated lower primary remission rates for weekly IM methotrexate (49%-53%) than for pulsed actinomycin D (69%-90%).77-79 In a randomized trial of patients with nonmetastatic GTN, complete remission was achieved in 74% of the women in the methotrexate-folinic acid arm, versus 100% of the women in the actinomycin D arm.80 In a retrospective analysis of patients with low-risk, mostly nonmetastatic GTN treated with 5-day regimens of methotrexate and actinomycin D or a combination of methotrexate and actinomycin, complete remission rates were not significantly different at 69%, 61%, and 79%, respectively, though adverse side effect rate was much greater with combination therapy (62%) than with single-agent methotrexate (29%) or actinomycin D (19%).81

Patients categorized as having low-risk metastatic GTN (FIGO stages II and III, score < 7) may be treated successfully with initial single-agent chemotherapy with methotrexate or actinomycin D, as for nonmetastatic disease. The weekly methotrexate or biweekly actinomycin D single-dose protocols currently in use for nonmetastatic postmolar disease should not be used for treatment of metastatic disease.71The combined experience of 3 specialized trophoblastic disease centers in the United States with single-agent methotrexate or actinomycin D treatment of low-risk metastatic GTN revealed excellent outcomes, with 48% to 67% of patients achieving primary remission with the first single-agent chemotherapy regimen.82-84 Multiagent chemotherapy was used in 1% to 14% of patients after failed sequential single-agent chemotherapy with or without surgery to ultimately cure all of the patients. In low-risk metastatic GTN patients, risk factors for drug resistance to initial single-agent chemotherapy were pretherapy hCG level more than 100,000 mIU/mL, age greater than 35 years, FIGO score greater than 4, and large vaginal metastases.

In all treatment protocols, chemotherapy should be continued until 1 course has been administered past a normal hCG level. Indications to change treatment to an alternative single agent include a plateau in hCG above normal during treatment or toxicity that precludes an adequate dose or frequency of treatment. Multiagent chemotherapy should be initiated if there is a significant elevation in hCG level, development of metastases, or resistance to sequential single-agent chemotherapy. If fertility preservation is not desired, hysterectomy may be performed as adjuvant treatment at the initiation of chemotherapy to shorten the treatment duration. Hysterectomy may also be used to treat hemorrhage or persistent, chemotherapy-resistant disease in the uterus. Hysterectomy is the treatment of choice for PSTT and ETT.

In summary, cure rates for both nonmetastatic and low-risk metastatic GTN can approach 100% with the use of initial single-agent methotrexate or actinomycin D chemotherapy. Approximately 20% of low-risk patients will develop resistance to the initial chemotherapeutic agent, but more than 90% will be cured by the use of sequential single-agent chemotherapy. Eventually, approximately 10% of patients will require multiagent chemotherapy with or without surgery to achieve remission.

Treatment of High-Risk Metastatic Disease and Recurrence

Patients with high-risk metastatic GTN (FIGO stage IV and stages II-III score ≥ 7) should be treated initially with multiagent chemotherapy with or without adjuvant surgery or radiation therapy.70 Several groups have demonstrated the efficacy of the EMA-CO regimen (etoposide, high-dose methotrexate with folinic acid, actinomycin D, cyclophosphamide, and vincristine) as primary therapy for high-risk GTN, reporting complete response rates of 71% to 78% and long-term survival rates of 85% to 94%.85-89 The EMA-CO regimen is currently the initial treatment of choice for high-risk metastatic GTN because of relatively low toxicity, allowing adherence to treatment schedules, high complete response rates, and overall high resultant survival.1,71 Chemotherapy for high-risk disease is continued for at least 2 to 3 courses after the first normal hCG measurement.70

Central nervous system metastases may be treated with whole-brain radiation (3000 cGy in 200-cGy fractions) or surgical excision with stereotactic irradiation with simultaneously initiation of systemic chemotherapy. During radiotherapy, the methotrexate infusion dose in the EMA-CO protocol is increased to 1 g/m2, and 30 mg of folinic acid is given every 12 hours for 3 days starting 32 hours after the infusion begins. An alternative to brain irradiation is the use of intrathecal as well as high-dose IV methotrexate. Cure rates for brain metastases are 50% to 80%, depending on patient symptoms and size and location of the brain lesions.90

Hysterectomy, pulmonary resection, and other adjuvant surgical procedures may be used for chemotherapy-resistant disease and to control hemorrhage in patients with high-risk GTN. Surgery is used to achieve cure in approximately one-half of high-risk patients.91-94 Between 1986 and 2005, of 50 patients with high-risk GTN treated with EMA-CO as primary or secondary therapy at the Brewer Center, 24 patients underwent 28 adjuvant surgical procedures, and 21 patients were cured. Surgical procedures that helped to achieve cure included hysterectomy, lung resection, uterine artery embolization, small bowel resection, salpingectomy, and uterine wedge resection.93

Approximately 30% of high-risk GTN patients will have an incomplete response to first-line chemotherapy or relapse from remission.95,96 Multiple metastases to sites other than the lung and vagina and previous inadequate chemotherapy are common in these patients. The majority can be managed with chemotherapy regimens that include etoposide and a platinum agent, which are often combined with surgical excision of persistent tumor. The EMA-EP regimen, substituting etoposide and cisplatin for cyclophosphamide and vincristine in the EMA-CO protocol, is considered the most appropriate therapy for patients who have responded to EMA-CO but have plateauing low hCG levels or who have developed re-elevation of hCG levels after a complete response to EMA-CO.97,98 Finally, in patients with disease that is resistant to methotrexate-containing protocols, drug combinations containing etoposide and platinum with bleomycin, ifosfamide, or paclitaxel have all been found to be effective.70,99,100

In summary, intensive multimodality therapy with EMA-CO chemotherapy and adjuvant radiotherapy or surgery when indicated achieves cure in 80% to 90% of patients with high-risk GTN. Most of the 30% of high-risk patients who fail first-line therapy or relapse from remission can be effectively treated with salvage therapy that includes platinum-containing drug combinations in conjunction with surgical resection of persistent tumor.

Treatment of Placental Site Trophoblastic Tumors and Epithelioid Trophoblastic Tumors

PSTT and ETT differ from invasive mole and CCA in their relative resistance to chemotherapy and their propensity for lymphatic spread. Initial treatment should include hysterectomy with lymph node dissection. Chemotherapy should be used in patients with metastatic disease and in patients with nonmetastatic disease who have adverse prognostic factors, including prolonged interval from last known pregnancy (> 2 years), deep myometrial invasion, tumor necrosis and mitotic count greater than 6/10 high-power fields. Although the optimal chemotherapy regimen for PSTT and ETT remains to be defined, the current clinical approach is an etoposide and platinum-containing regimen, such as EMA-EP or a paclitaxel/cisplatin–paclitaxel/etoposide doublet.71 The survival rate is approximately 100% for nonmetastatic disease and 50% to 60% for metastatic disease.12,101,102

Surveillance After GTN

After hCG has returned to normal and chemotherapy has been completed, patients treated for GTN should have serum quantitative hCG levels measured at 1-month intervals for 12 months (Table 8-4). Relapse risk is approximately 3% in the first year after completing therapy and less than 1% after that.103 Physical examinations are performed every 6 to 12 months, but testing such as x-rays or CT scans are rarely indicated. Contraception, ideally with oral contraceptives, should be used during treatment and for 6 to 12 months after completion of chemotherapy. Because of the 1% to 2% risk of a second gestational trophoblastic disease event in subsequent pregnancies, pelvic ultrasound is recommended in the first trimester of a subsequent pregnancy to confirm a normal gestation, the products of contraception or placentas from future pregnancies should be carefully examined histopathologically, and an hCG level should be obtained 6 weeks after any pregnancy.

SURVIVAL AND PROGNOSIS

Key Points


1. The majority of patients with GTN will be cured with adjuvant therapy.

2. Patients who develop resistance to initial chemotherapy are likely to be cured with subsequent alternative regimens.

3. Future pregnancies should be carefully monitored for the development of a second episode of GTD.


Cure rates for both nonmetastatic and low-risk metastatic GTN approach 100% with the use of initial single-agent methotrexate or actinomycin D chemotherapy. Approximately 20% of low-risk patients will develop resistance to the initial chemotherapeutic agent, but more than 90% will be cured by the use of sequential single-agent chemotherapy. Roughly 10% of patients with low-risk GTN will require multia-gent chemotherapy with or without surgery to achieve remission; for high-risk GTN, cure rates are 80% to 90% with intensive multimodality therapy with multiagent chemotherapy, along with adjuvant radiotherapy or surgery when indicated. Approximately 30% of high-risk patients will fail first-line therapy or relapse from remission. Salvage therapy with platinum-containing drug combinations, sometimes in conjunction with surgical resection of sites of persistent tumor, will result in cure of most high-risk patients with resistant disease. Even those patients with metastatic disease to the brain, liver, and gastrointestinal tract now have 75%, 73%, and 50% survival rates, respectively.3 Survival rates for PSTT and ETT are highly dependent on the presence of metastatic disease, with cure rates of approximately 100% for nonmetastatic disease and 50% to 60% for metastatic disease.12,101,102

Curative treatment of GTN has allowed women to maintain their reproductive potential despite exposure to drugs that have ovarian toxicity and teratogenic potential. Most women resume normal ovarian function after chemotherapy and exhibit no increase in infertility. Many studies have reported successful pregnancies, without an increase in abortions, stillbirths, congenital anomalies, prematurity, or major obstetric complications.71 Although subsequent pregnancy does not cause “reactivation” of disease, patients who have had 1 episode of GTD are at greater risk for the development of a second episode in a subsequent pregnancy, regardless of whether or not they required chemotherapy. Patients should avoid conception for 6 to 12 months after chemotherapy to allow for disease surveillance via hCG and to theoretically allow for elimination of mature ova that may have been damaged by cytotoxic drugs (Table 8-4).15,104,105

The carcinogenic potential of chemotherapy in relatively young patients has led to concern for second malignancies among patients treated for GTN. Although single-agent treatment has not been associated with an increased risk for secondary malignancy, sequential therapy and etoposide-containing drug combinations have been associated with a slight increased risk of secondary malignancies, including acute myelogenous leukemia, colon cancer, melanoma, and breast cancer.106

SPECIAL MANAGEMENT PROBLEMS

Quiescent gestational trophoblastic disease is a highly uncommon, presumed inactive form of GTN that is characterized by persistent, unchanging low levels (< 200 mIU/mL) of “real” hCG for at least 3 months associated with a past history of GTD or spontaneous abortion but without clinically detectable disease. The hCG levels do not change with treatment, including chemotherapy or surgery. The International Society for the Study of Trophoblastic Disease 2001 provides several recommendations for managing this condition: (1) false-positive hCG level due to heterophile antibodies or LH interference should be excluded, (2) the patient should be thoroughly investigated for evidence of disease, (3) immediate chemotherapy or surgery should be avoided, and (4) the patient should be monitored long term with periodic hCG testing while avoiding pregnancy. Treatment should be undertaken only when there is a sustained rise in hCG or the appearance of overt clinical disease.107 Subanalysis of hCG in these patients reveals no hyperglycosylated hCG, which has been associated with cytotrophoblastic invasion. During follow-up of patients with presumed quiescent GTD, approximately one-quarter eventually develop active GTN, which is signaled by an increase in both hyperglycosylated hCG and total hCG.108,109

A twin pregnancy consisting of a complete mole and a coexisting normal fetus is estimated to occur once in every 22,000 to 100,000 pregnancies. It must be distinguished from a partial mole (triploid pregnancy with fetus). The diagnosis can usually be established by ultrasound, but cytogenetics may be used to differentiate between chromosomally normal, potentially viable fetuses and triploid nonviable fetuses. Patients with a twin normal fetus/complete mole pregnancy should be cautioned that they may be at increased risk for hemorrhage and medical complications. Suction evacuation and curettage in the operating room is recommended for patients who desire pregnancy termination or develop bleeding or other complications. Evidence from a case series of 77 pregnancies showed that approximately 40% will result in normal viable fetuses if allowed to continue.110,111

FUTURE DIRECTIONS

The joint efforts of vigilant primary care providers, obstetricians/gynecologists, and collaborative oncologic specialists have led to excellent short- and long-term outcomes for women with GTD, and the substantial reduction in worldwide mortality from GTN is a triumph of modern global medical efforts. Diagnostic and prognostic tests are still needed to allow earlier identification of GTD patients who will develop postmolar GTN and GTN patients who will require multiagent chemotherapy. These tools could minimize ultimately unnecessary testing and loss to follow-up and ultimately reduce morbidity and mortality by individualizing treatment and decreasing chemotherapy resistance. Finally, a mechanistic understanding of the identified causative gene for repetitive molar pregnancy would not only improve outcomes in the few women affected by this gene, but also would further our comprehension of GTD, making prevention possible.

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