Ross S. Berkowitz
Donald P. Goldstein
• Complete molar pregnancies are generally diploid and all chromosomes are of paternal origin.
• Partial molar pregnancies are triploid and the extra set of chromosomes is paternal.
• Complete moles are diagnosed earlier in pregnancy and less frequently present with the classic signs and symptoms.
• Single-agent chemotherapy achieves a high remission rate in nonmetastatic and low-risk metastatic gestational trophoblastic neoplasia.
• After achieving remission with chemotherapy, patients with gestational trophoblastic neoplasia can anticipate normal reproduction in the future.
Gestational trophoblastic disease (GTD) is the term used to describe the heterogeneous group of interrelated lesions that arise from abnormal proliferation of placental trophoblasts. GTD lesions are histologically distinct and can be benign or malignant. Benign lesions consist of hydatidiform moles, complete and partial, whereas malignant lesions consist of invasive mole, placental-site trophoblastic tumor (PSTT), and choriocarcinoma. This subset of malignant lesions that have varying propensities for local invasion and metastasis is referred to as gestational trophoblastic neoplasia (GTN). GTNs are among the rare human tumors that can be cured even in the presence of widespread dissemination (1,2). Although GTNs commonly follow a molar pregnancy, they can occur after any gestational event, including induced or spontaneous abortion, ectopic pregnancy, or term pregnancy.
Hydatidiform Mole
Epidemiology
Estimates of the incidence of molar pregnancy vary dramatically in different regions of the world. For example, the incidence of molar pregnancy in Japan (2:1,000 pregnancies) is reported to be about threefold higher than the incidence in Europe or North America (about 0.6 to 1.1 per 1,000 pregnancies) (3). In Taiwan, 1 in 125 pregnancies are molar, while in the United States the incidence is 1 in 1,500 live births. The incidences of choriocarcinoma and partial hydatidiform mole in Ireland were investigated by reviewing all products of conception from first- and second-trimester abortions (4). Based on a thorough pathologic review, the incidence of choriocarcinoma and partial hydatidiform mole was 1:1,945 and 1:695 pregnancies, respectively.
While variations in the worldwide incidence of molar pregnancy may result in part from reporting population-based versus hospital-based data, a number of studies suggest that the high incidence in some populations can be attributed to socioeconomic and nutritional factors. The decreasing incidence of molar pregnancy in South Korea is attributed to a more Western diet and improved standard of living (5). Case-control studies from Italy and the United States show that the rate of choriocarcinoma increases with decreasing consumption of dietary carotene (vitamin A precursor) and animal fat (6,7). Maternal age and reproductive history influence the rate of molar pregnancy. Women older the 40 years have a 5- to 10-fold greater risk of having a choriocarcinoma, while one in three pregnancies in women older than 50 years results in a molar gestation (8,9). These findings suggest that ova from older women may be more susceptible to abnormal fertilization, resulting in a complete hydatidiform mole.
Limited information is available concerning risk factors for partial molar pregnancy. The epidemiologic characteristics of complete and partial mole appear to differ significantly (8–11). The risk for partial mole is associated with the use of oral contraceptives and a history of irregular menstruation, but not with dietary factors (10). Nor does there appear to be an association between maternal age and the risk for partial mole.
Pathology and Cytogenetics
Hydatidiform moles may be categorized as either complete or partial moles on the basis of gross morphology, histopathology, and karyotype (Table 39.1).
Table 39.1 Features of Complete and Partial Hydatidiform Moles
|
Features |
Complete Mole |
Partial Mole |
|
Fetal or embryonic tissue |
Absent |
Present |
|
Hydatidiform swelling of chorionic villi |
Diffuse |
Focal |
|
Trophoblastic hyperplasia |
Diffuse |
Focal |
|
Scalloping of chorionic villi |
Absent |
Present |
|
Trophoblastic stromal inclusions |
Absent |
Present |
|
Karyotype |
46,XX (90%); 46,XY |
Triploid |
Complete Hydatidiform Mole
Complete hydatidiform moles exhibit characteristic swelling and trophoblastic hyperplasia (Fig. 39.1). They usually have a 46,XX karyotype, but about 10% have a 46,XY karyotype (12,13). The molar chromosomes are entirely of paternal origin, with mitochondrial DNA of maternal origin (Fig. 39.2) (14). Complete moles usually arise from an ovum fertilized by a haploid sperm, which duplicates its own chromosomes. The ovum nucleus may be absent or inactivated (15).
Figure 39.1 Photomicrograph of complete mole demonstrating enlarged villous with central cavitation and surrounding trophoblastic hyperplasia.
Figure 39.2 The karyotype of complete hydatidiform mole.
Partial Hydatidiform Mole
Partial hydatidiform mole is characterized by the following pathologic features (16) (Fig. 39.3):
Figure 39.3 Photomicrograph of partial mole showing marked disparity in villous size, trophoblastic inclusions (center), and mild trophoblastic hyperplasia. (From Berkowitz RS, Goldstein OP. Gestational trophoblastic diseases. In: Ryan KJ, BerkowitzR, Barbieri R, eds. Kistner’s gynecology principles and practice, 5th ed. Chicago: Year Book Medical Publishers, 1990:433, with permission.)
1. Chorionic villi of varying size with focal hydatidiform swelling, cavitation, and trophoblastic hyperplasia
2. Marked villous scalloping
3. Prominent stromal trophoblastic inclusions
4. Identifiable embryonic or fetal tissues
Partial moles have a triploid karyotype (69 chromosomes); the extra haploid set of chromosomes usually is derived from the father (Fig. 39.4) (17). It is possible that nontriploid partial moles do not exist (18). When a fetus is present in conjunction with a partial mole, it generally exhibits the stigmata of triploidy, including growth retardation and multiple congenital malformations such as syndactyly and hydrocephaly (Fig. 39.5).
Figure 39.4 The karyotype of partial hydatidiform mole.
Figure 39.5 Photomicrograph of a fetal hand demonstrating syndactyly. The fetus had a triploid karyotype, and the chorionic tissues were a partial mole.
Advances in Pathologic Diagnosis
When molar pregnancy is diagnosed early in the first trimester, the pathologist can have difficulty distinguishing complete hydatidiform mole from partial hydatidiform mole or hydropic abortions because of smaller villi, less trophoblastic hyperplasia, more primitive villous stroma, and less global necrosis (19,20). Accurate diagnosis can be facilitated through the use of flow cytometry to determine ploidy (i.e., diploid vs. triploid moles) (21) and through assessment of biomarkers of paternally imprinted and maternally expressed gene products (22). Biomarkers that take advantage of imprinted genes to distinguish complete mole and hydropic abortions from other gestations are identified. Because complete moles generally have no maternal chromosomes, paternally imprinted gene products normally expressed only by maternal chromosomes, should be absent. In complete moles, the nuclei of the villous stroma and cytotrophoblastic cells do not express p57, whereas all other gestations, including partial moles, are characterized by nuclear immunostaining in these cells. Thus, a complete mole is diploid and negative for p57, a hydropic abortion is diploid (sometimes triploid) and positive for p57, and a partial mole is triploid and positive for p57.
Familial Recurrent Molar Pregnancy
Evaluation of families with recurrent molar pregnancy suggests that dysregulation of normal parental imprinting of genes, with loss of maternally transcribed genes, is likely to contribute to the pathogenesis of molar pregnancy. Familial recurrent hydatidiform mole, is a rare occurrence, characterized by recurrent complete hydatidiform mole of biparental origin, rather than the more usual androgenetic origin (23). Genetic mapping shows that in most families the gene responsible is located in a 1.1 Mb region on chromosome 19q13.4. Mutations in the gene result in dysregulation of imprinting in the female germ line with abnormal development of both embryonic and extraembryonic tissue.
Clinical Features
Patients with complete molar pregnancy are diagnosed increasingly earlier in pregnancy and treated before they develop the classic clinical signs and symptoms. This is the result of many changes in clinical practice, such as the frequent use of human chorionic gonadotropin (hCG) measurement and transvaginal ultrasonography in early pregnancy for women with vaginal staining and for determining the gestational dates in asymptomatic women. The following is a description of the classic and current clinical features of complete molar pregnancy (24,25).
Complete Hydatidiform Mole
Vaginal Bleeding
Vaginal bleeding is the most common symptom causing patients to seek treatment for complete molar pregnancy. It had been reported to occur in 97% of cases, whereas currently it is reported to occur in 84% of patients. Molar tissues may separate from the decidua and disrupt maternal vessels, and large volumes of retained blood may distend the endometrial cavity. Because vaginal bleeding may be considerable and prolonged, one-half of these patients had anemia (hemoglobin <10 g/100 mL). Anemia is present in only 5% of patients.
Excessive Uterine Size
Excessive uterine enlargement relative to gestational age is one of the classic signs of a complete mole, although it was present in only about half of patients. Currently, excessive uterine size occurs in only 28% of patients. The endometrial cavity may be expanded by both chorionic tissue and retained blood. Excessive uterine size is generally associated with markedly elevated levels of hCG, because uterine enlargement results in part from trophoblastic overgrowth.
Preeclampsia
Preeclampsia was observed in 27% of patients with a complete hydatidiform mole. Preeclampsia is now reported in only 1 of 74 patients with complete mole at the initial visit. Although preeclampsia is associated with hypertension, proteinuria, and hyperreflexia, eclamptic convulsions rarely occur. Preeclampsia develops almost exclusively in patients with excessive uterine size and markedly elevated hCG levels. Hydatidiform mole should be considered whenever preeclampsia develops early in pregnancy.
Hyperemesis Gravidarum
Hyperemesis requiring antiemetic or intravenous replacement therapy occurred in one-fourth of women with a complete mole, particularly those with excessive uterine size and markedly elevated hCG levels. Severe electrolyte disturbances may develop and require treatment with parenteral fluids. Currently, only 8% of patients have hyperemesis.
Hyperthyroidism
Clinically evident hyperthyroidism was observed in 7% of patients with a complete molar gestation. These women may have tachycardia, warm skin, and tremor, and the diagnosis can be confirmed by detection of elevated serum levels of free thyroxine (T4) and tri-iodothyronine (T3). Clinical evidence of hyperthyroidism with complete mole is rare.
Anesthesia or surgery may precipitate thyroid storm. Thus, if hyperthyroidism is suspected before the induction of anesthesia for molar evacuation, β-adrenergic blocking agents should be administered. Thyroid storm may be manifested by hyperthermia, delirium, convulsions, tachycardia, high-output heart failure, or cardiovascular collapse. Administration of β-adrenergic blocking agents prevents or rapidly reverses many of the metabolic and cardiovascular complications of thyroid storm. After molar evacuation, thyroid function test results rapidly return to normal.
Hyperthyroidism develops almost exclusively in patients with very high hCG levels. Some investigators suggest that hCG is the thyroid stimulator in women with molar pregnancy because positive correlations between serum hCG levels and total T4 or T3 concentrations were observed. However, in one study in which thyroid function was measured in 47 patients with a complete mole, no significant correlation was found between serum hCG levels and serum values of free T4 index or free T3 index (26). Although some investigators speculated about a separate chorionic thyrotropin, this substance is not yet isolated.
Trophoblastic Embolization
Respiratory distress rarely occurs in patients with a complete mole. It is usually diagnosed in patients with excessive uterine size and markedly elevated hCG levels. These patients may have chest pain, dyspnea, tachypnea, and tachycardia and may experience severe respiratory distress during and after molar evacuation. Auscultation of the chest usually reveals diffuse rales, and chest radiographic evaluation may show bilateral pulmonary infiltrates. Respiratory distress usually resolves within 72 hours with cardiopulmonary support. In some circumstances, patients may require mechanical ventilation. Respiratory insufficiency may result from trophoblastic embolization and the cardiopulmonary complications of thyroid storm, preeclampsia, and massive fluid replacement.
Theca Lutein Ovarian Cysts
Prominent theca lutein ovarian cysts (6 cm in diameter) develop in about one-half of patients with a complete mole (27). Theca lutein ovarian cysts result from high serum hCG levels, which cause ovarian hyperstimulation (28). Because the uterus may be excessively enlarged, theca lutein cysts can be difficult to palpate during physical examination; however, ultrasonography can accurately document their presence and size. After molar evacuation, theca lutein cysts normally regress spontaneously within 2 to 4 months.
Prominent theca lutein cysts may cause symptoms of marked pelvic pressure, and they can be decompressed by laparoscopic or ultrasonographically directed aspiration. If acute pelvic pain develops, laparoscopy should be performed to assess possible cystic torsion or rupture.
Partial Hydatidiform Mole
Patients with partial hydatidiform mole usually do not have the dramatic clinical features characteristic of complete molar pregnancy. These patients have the signs and symptoms of incomplete or missed abortion, and partial mole is diagnosed after histologic review of the tissue obtained by curettage (29).
In a survey of 81 patients with a partial mole, the main initial sign was vaginal bleeding, which occurred in 59 patients (72.8%) (30). Excessive uterine enlargement and preeclampsia were present in three patients (3.7%) and two patients (2.5%), respectively. No patient had theca lutein ovarian cysts, hyperemesis, or hyperthyroidism. The initial clinical diagnosis was an incomplete or missed abortion in 74 patients (91.3%) and hydatidiform mole in five patients (6.2%). Pre-evacuation hCG levels were measured in 30 patients and were higher than 100,000 mIU/mL in two patients (6.6%).
Natural History
Complete Hydatidiform Mole
Complete moles have a potential for local invasion and dissemination. After molar evacuation, local uterine invasion occurs in 15% of patients, and metastasis occurs in 4% (27).
A review of 858 patients with complete hydatidiform mole at the New England Trophoblastic Disease Center (NETDC) revealed that two-fifths of the patients had the following signs of marked trophoblastic proliferation at the time they sought treatment:
1. hCG level >100,000 mIU/mL
2. Excessive uterine enlargement
3. Theca lutein cysts 6 cm in diameter
In this review, patients with any one of these signs were considered at high risk for developing postmolar tumor. After molar evacuation, local uterine invasion occurred in 31%, and metastases developed in 8.8% of the 352 high-risk patients. For the 506 low-risk patients, local invasion was found in only 3.4%, and metastases developed in 0.6%.
Older patients are at increased risk of developing postmolar GTN. One study reported that persistent tumor developed after a complete molar pregnancy in 37% of women older than 40 years (27), whereas in another study this finding occurred in 60% of women older than 50 years (31).
Partial Hydatidiform Mole
Persistent tumor, usually nonmetastatic, develops in approximately 2% to 4% of patients with a partial mole, and chemotherapy is required to achieve remission (32). Patients who develop persistent disease have no distinguishing clinical or pathologic characteristics (33).
Diagnosis
Ultrasonography is a reliable and sensitive technique for the diagnosis of complete molar pregnancy. Because the chorionic villi exhibit diffuse hydropic swelling, complete moles produce a characteristic vesicular ultrasonographic pattern as soon as in the first trimester (Fig. 39.6).
Figure 39.6 Ultrasonogram of a uterus showing a typical pattern of a complete hydatidiform mole. Note the characteristic vesicular ultrasonographic pattern.
Ultrasonography may contribute to the diagnosis of partial molar pregnancy by demonstrating focal cystic spaces in the placental tissues and an increase in the transverse diameter of the gestational sac (34). When these criteria are present, the positive predictive value for partial mole is 90%.
Treatment
When molar pregnancy is diagnosed, the patient should be evaluated for the presence of associated medical complications, including preeclampsia, hyperthyroidism, electrolyte imbalance, and anemia. After the patient’s condition is stabilized, a decision must be made concerning the most appropriate method of evacuation.
Suction Curettage
Suction curettage is the preferred method of evacuation, regardless of uterine size, for patients who desire to preserve fertility (32). It involves the following steps:
1. Oxytocin infusion—This procedure is begun before the induction of anesthesia.
2. Cervical dilation—As the cervix is being dilated, uterine bleeding often increases. Retained blood in the endometrial cavity may be expelled during cervical dilation. Active uterine bleeding should not deter the prompt completion of cervical dilation.
3. Suction curettage—Within a few minutes of commencing suction curettage, uterine size may decrease dramatically, and the bleeding will be well controlled. The use of a 12-mm cannula is strongly advised to facilitate evacuation. If the uterus is larger than 14 weeks of gestation, one hand should be placed on top of the fundus, and the uterus should be massaged to stimulate uterine contraction and reduce the risk of perforation.
4. Sharp curettage—When suction evacuation is believed to be complete, gentle sharp curettage is performed to remove any residual molar tissue.
Because trophoblast cells express RhD factor, patients who are Rh negative should receive Rh immune globulin at the time of evacuation.
Hysterectomy
If the patient desires surgical sterilization, a hysterectomy may be performed with the mole in situ. The ovaries may be preserved at the time of surgery, even in the presence of prominent theca lutein cysts. Large ovarian cysts may be decompressed by aspiration. Hysterectomy does not prevent metastasis; patients still require follow-up with assessment of hCG levels.
Prophylactic Chemotherapy
The use of prophylactic chemotherapy at the time of molar evacuation is controversial. The debate concerns the wisdom of exposing all patients to potentially toxic treatment when only about 20% are at risk of developing persistent tumor.
In a study of 247 patients with complete molar pregnancy who prophylactically received a single course of actinomycin D (ActD) at the time of evacuation, local uterine invasion developed in 10 patients (4%), and no patients experienced metastasis (35). All 10 patients with local invasion achieved remission after one additional course of chemotherapy. Prophylactic chemotherapy, prevented metastasis and reduced the incidence and morbidity of local uterine invasion.
In two prospective randomized studies of prophylactic chemotherapy in patients with a complete mole, a significant decrease in persistent tumor was detected in patients with high-risk mole who received prophylactic chemotherapy (47% and 50% vs. 14%) (36–38). Prophylaxis may be particularly useful in the management of high-risk complete molar pregnancy, especially when hCG assessments for follow-up are unavailable or unreliable.
Follow-Up
Human Chorionic Gonadotropin
After molar evacuation, patients should be monitored with weekly determinations of β-subunit hCG levels until these levels are normal for 3 consecutive weeks, followed by monthly determinations until the levels are normal for 6 consecutive months (39). The average time to achieve the first normal hCG level after evacuation is about 9 weeks (40). After achieving nondetectable serum hCG levels, the risk of developing GTN approaches zero (41–43). If these findings are confirmed, it is possible that postmolar hCG surveillance could be safely abbreviated.
Contraception
Patients are encouraged to use effective contraception during the entire interval of hCG follow-up. Because of the potential risk of uterine perforation, bleeding, and infection, intrauterine devices should not be inserted until the patient achieves a normal hCG level. If the patient does not desire surgical sterilization, either oral contraceptives or barrier methods should be used.
Increased incidence of postmolar persistent tumor was reported among patients who used oral contraceptives before gonadotropin remission (44). However, data from a prospective trial and other centers indicate that oral contraceptive use does not increase the risk of postmolar trophoblastic disease (45–47). It appears that oral contraceptives may be used safely after molar evacuation during the entire interval of hormonal follow-up.
Gestational Trophoblastic Neoplasia
Nonmetastatic Disease
Locally invasive GTN develops in about 15% of patients after evacuation of a complete mole and infrequently after other gestations (1). These patients usually present with the following symptoms:
1. Irregular vaginal bleeding
2. Theca lutein cysts
3. Uterine subinvolution or asymmetric enlargement
4. Persistently elevated serum hCG levels.
The trophoblastic tumor may perforate the myometrium, causing intraperitoneal bleeding, or erode into uterine vessels, causing vaginal hemorrhage. Bulky, necrotic tumor may involve the uterine wall and serve as a nidus for infection. Patients with uterine sepsis may have a purulent vaginal discharge and acute pelvic pain.
After molar evacuation, persistent GTN may exhibit the histologic features of either hydatidiform mole or choriocarcinoma. After a nonmolar pregnancy, persistent GTN always has the histologic pattern of choriocarcinoma. Histologic characterization of choriocarcinoma depends on sheets of anaplastic syncytiotrophoblast and cytotrophoblast without chorionic villi.
Placental-Site Trophoblastic Tumor
Placental-site trophoblastic tumor is an uncommon but important variant of choriocarcinoma that consists predominantly of intermediate trophoblast (48). Relative to their mass, these tumors produce small amounts of hCG and human placental lactogen (hPL), and they tend to remain confined to the uterus, metastasizing late in their course. In contrast to other trophoblastic tumors, placental-site tumors are relatively insensitive to chemotherapy.
Metastatic Disease
Metastatic GTN occurs in about 4% of patients after evacuation of a complete mole, but it is seen more often when GTN develops after nonmolar pregnancies (1). GTN usually metastasizes as choriocarcinoma because of its tendency for early vascular invasion with widespread dissemination. Trophoblastic tumors often are perfused by fragile vessels and are frequently hemorrhagic. Symptoms of metastases may result from spontaneous bleeding at metastatic foci. The most common sites of metastases are lung (80%), vagina (30%), pelvis (20%), liver (10%), and brain (10%).
Pulmonary
At the time of diagnosis, lung involvement is visible by chest radiography in 80% of patients with metastatic GTN. Patients with pulmonary metastasis may have chest pain, cough, hemoptysis, dyspnea, or an asymptomatic lesion visible by chest radiography. Respiratory symptoms may be acute or chronic, persisting over many months.
GTN may produce four principal pulmonary patterns:
1. An alveolar or “snowstorm” pattern
2. Discrete rounded densities
3. Pleural effusion
4. An embolic pattern caused by pulmonary arterial occlusion.
Because respiratory symptoms and radiographic findings may be dramatic, the patient may be thought to have a primary pulmonary disease. Some patients with extensive pulmonary involvement have minimal, if any, gynecologic symptoms because the reproductive organs may be free of trophoblastic tumor. The diagnosis of GTN may be confirmed only after thoracotomy is performed, particularly in patients with a nonmolar antecedent pregnancy.
Pulmonary hypertension may develop in patients with GTN secondary to pulmonary arterial occlusion by trophoblastic emboli. The development of early respiratory failure requiring intubation is associated with a poor clinical outcome (49).
Vaginal
Vaginal metastases occur in 30% of the patients with metastatic tumor. These lesions are highly vascular and may bleed vigorously when biopsied. Metastases to the vagina may occur in the fornices or suburethrally and may produce irregular bleeding or a purulent discharge.
Hepatic
Liver metastases occur in 10% of patients with disseminated trophoblastic tumor. Hepatic involvement is encountered when there is a protracted delay in diagnosis and the patient has an extensive tumor burden. Epigastric or right upper quadrant pain may develop if metastases stretch the hepatic capsule. Hepatic lesions may be hemorrhagic, causing hepatic rupture and exsanguinating intraperitoneal bleeding.
Central Nervous System
Metastatic trophoblastic disease involves the brain in 10% of patients. Cerebral involvement is seen in patients with advanced disease; virtually all patients with brain metastasis have concurrent pulmonary or vaginal involvement or both. Because cerebral lesions frequently hemorrhage spontaneously, most patients develop acute focal neurologic deficits (50,51).
Staging and Prognostic Score
Staging
An anatomic staging system for GTN was adopted by the International Federation of Gynecology and Obstetrics (FIGO) (Table 39.2). It is hoped that this staging system will encourage the objective comparison of data from various centers (52).
Table 39.2 Staging of Gestational Trophoblastic Neoplasia
|
Stage I |
Disease confined to uterus |
|
Stage II |
GTN extending outside uterus but limited to genital structures (adnexa, vagina, broad ligament) |
|
Stage III |
GTN extending to lungs with or without known genital tract involvement |
|
Stage IV |
All other metastatic sites |
|
Format as Table 15.7 in Berek & Hacker’s 5th edition, page 602 |
|
Stage I: Patients have persistently elevated hCG levels and tumor confined to the uterine corpus.
Stage II: Patients have metastases to the genital tract.
Stage III: Patients have pulmonary metastases with or without uterine, vaginal, or pelvic involvement. The diagnosis is based on a rising hCG level in the presence of pulmonary lesions viewed by chest radiography.
Stage IV: Patients have advanced disease and involvement of the brain, liver, kidneys, or gastrointestinal tract. These patients are in the highest risk category because they are most likely to be resistant to chemotherapy. Choriocarcinoma is usually present, and the disease commonly follows a nonmolar pregnancy.
Prognostic Scoring System
In addition to anatomic staging, it is important to consider other variables to predict the likelihood of drug resistance and to assist in selecting appropriate chemotherapy (53). A prognostic scoring system proposed by the World Health Organization reliably predicts the potential for resistance to chemotherapy (Table 39.3).
Table 39.3 Scoring System Based on Prognostic Factorsa
When the prognostic score is higher than 6, the patient is categorized as high risk and requires multimodal therapy, which includes intensive combination chemotherapy, and may also include surgery and radiation to achieve remission. Patients with stage I disease usually have a low-risk score, and those with stage IV disease have a high-risk score. The distinction between low and high risk applies mainly to patients with stage II or III disease.
Diagnostic Evaluation
Optimal management of persistent GTN requires a thorough assessment of the extent of the disease before the initiation of treatment. All patients with persistent GTN should undergo a careful pretreatment evaluation, including the following:
1. Complete history and physical examination
2. Measurement of the serum hCG level
3. Hepatic, thyroid, and renal function tests
4. Determination of baseline peripheral white blood cell and platelet counts
The metastatic workup should include the following:
1. Chest radiograph or computed tomography (CT) scan
2. Ultrasonography or CT scan of the abdomen and pelvis
3. CT or magnetic resonance imaging (MRI) scan of the head
When the pelvic examination and chest radiographic findings are negative, metastatic involvement of other sites is uncommon.
Liver ultrasonography and CT or MRI scanning will disclose most hepatic metastases in patients with abnormal liver function tests. CT or MRI scan of the head facilitates the early diagnosis of asymptomatic cerebral lesions. Chest CT scans may detect micrometastases not visible on chest radiography. Chest CT will demonstrate pulmonary micrometastases in about 40% of patients with presumed nonmetastatic disease (54).
In patients with choriocarcinoma or metastatic disease, hCG levels may be measured in the cerebrospinal fluid (CSF) to exclude cerebral involvement if the results of CT scanning of the brain are normal. The ratio of plasma-to-CSF hCG tends to be lower than 60 in the presence of cerebral metastases (55). A single plasma-to-CSF hCG ratio may be misleading, because rapid changes in plasma hCG levels may not be reflected promptly in the CSF (56).
Pelvic ultrasonography appears to be useful in detecting extensive trophoblastic uterine involvement and may aid in identifying sites of resistant uterine tumor (57). Because ultrasonography can accurately and noninvasively detect extensive uterine tumor, it may help identify patients who would benefit from hysterectomy.
Management of GTN
A protocol for the management of GTN is presented in Table 39.4.
Table 39.4 Protocol for Treatment of GTN
|
Stage I |
|
|
Initial |
Single-agent chemotherapy or hysterectomy with adjunctive chemotherapy |
|
Resistant |
Combination chemotherapy |
|
Hysterectomy with adjunctive chemotherapy |
|
|
Local resection |
|
|
Pelvic infusion |
|
|
Stage II and III |
|
|
Low riska |
|
|
Initial |
Single-agent chemotherapy |
|
Resistant |
Combination chemotherapy |
|
High riska |
|
|
Initial |
Combination chemotherapy |
|
Resistant |
Second-line combination chemotherapy |
|
Stage IV |
|
|
Initial |
Combination chemotherapy |
|
Brain |
Whole-head irradiation (3,000 cGy) |
|
Craniotomy to manage complications |
|
|
Liver |
Resection to manage complications |
|
Resistanta |
Second-line combination chemotherapy |
|
Hepatic arterial infusion |
|
|
aLocal resection optional. |
|
Low-Risk Disease
Low-risk GTN includes patients with both nonmetastatic (stage I) and metastatic GTN whose prognostic score is less than 7. In patients with stage I disease, the selection of treatment is based primarily on whether the patient desires to retain fertility.
Hysterectomy Plus Chemotherapy
If the patient does not wish to preserve fertility, hysterectomy with adjuvant single-agent chemotherapy may be performed as primary treatment. Adjuvant chemotherapy is administered for three reasons:
1. To reduce the likelihood of disseminating viable tumor cells at surgery
2. To maintain a cytotoxic level of chemotherapy in the bloodstream and tissues in case viable tumor cells are disseminated at surgery
3. To treat any occult metastases that may be present at the time of surgery
Chemotherapy can be administered safely at the time of hysterectomy without increasing the risk of bleeding or sepsis. In a series of 31 patients treated with primary hysterectomy and a single course of adjuvant chemotherapy, all achieved complete remission with no additional therapy (58).
Hysterectomy is performed in all patients with stage I placental-site trophoblastic tumor. Because placental-site tumors are resistant to chemotherapy, hysterectomy for presumed nonmetastatic disease is the only curative treatment. Patients with metastatic placental site trophoblastic tumor may still achieve remission, but their tumors are less responsive to chemotherapy (59).
Chemotherapy Alone
Single-agent chemotherapy is the preferred treatment in patients with stage I disease who desire to retain fertility (60). At the NETDC from July 1965 through June 2008, primary single-agent chemotherapy was administered to 561 patients with stage I GTN and 434 patients (77.4%) attained complete remission. The remaining 127 patients with resistant disease subsequently achieved remission after combination chemotherapy or surgical intervention.
When a patient’s disease is resistant to single-agent chemotherapy and she desires to preserve fertility, combination chemotherapy should be administered. If the patient’s disease is resistant to single-agent and combination chemotherapy and she wants to retain fertility, local uterine resection may be considered. When local resection is planned, a preoperative ultrasonography, MRI, or arteriography may help to define the site of the resistant tumor.
Low-Risk Metastatic GTN (Stages II and III)
Vaginal and Pelvic Metastasis
Low-risk disease treated with primary single-agent chemotherapy has a high (approximately 80%) rate of remission in contrast to high-risk disease that usually does not achieve remission with single-agent treatment and require treatment with primary intensive combination chemotherapy.
Vaginal metastases may bleed profusely because they are highly vascular and friable. When bleeding is substantial, it may be controlled by packing the vagina or by wide local excision. Infrequently, arteriographic embolization of the hypogastric arteries may be required to control hemorrhage from vaginal metastases (61).
Pulmonary Metastasis
At the NETDC from July 1965 through June 2008, of the 139 patients with low-risk stages II or III disease, 114 (82%) attained complete remission with single-agent chemotherapy. The remaining 25 (18%) patients who had disease resistant to single-agent treatment subsequently achieved remission with combination chemotherapy.
Thoracotomy
Thoracotomy has a limited but important role in the management of pulmonary metastases. If a patient has a persistent viable pulmonary metastasis following intensive chemotherapy, thoracotomy may be indicated to excise the resistant focus. A thorough metastatic workup should be performed before surgery is undertaken to exclude other sites of persistent disease. It is important to realize that fibrotic pulmonary nodules may persist indefinitely on chest radiography, even after complete gonadotropin remission is attained. In patients undergoing thoracotomy for resistant disease, chemotherapy should be administered postoperatively to treat potential occult sites of micrometastasis.
Hysterectomy
Hysterectomy may be required in patients with metastatic disease to control uterine hemorrhage or sepsis. In patients with extensive uterine tumor, hysterectomy may substantially reduce the trophoblastic tumor burden and limit the need for multiple courses of chemotherapy (62).
Follow-Up
All patients with low-risk GTN (stages I through III) should undergo follow-up with:
1. Weekly measurement of hCG levels until they are normal for 3 consecutive weeks.
2. Monthly measurement of hCG values until levels are normal for 12 consecutive months.
3. Effective contraception during the entire interval of hormonal follow-up.
High-Risk Metastatic GTN (Stages II–IV)
All patients with high-risk GTN (stages II–IV) should be treated with primary intensive combination chemotherapy and the selective use of radiation therapy and surgery. Between July 1965 and June 2008, of the 103 patients with high-risk GTN stages II–IV treated at the NETDC, 83 (80.5%) achieved complete remission. Before 1975, when single agent therapy was used primarily to treat patients with stage IV GTN, only 6 of 20 patients (30%) attained complete remission. Since 1975, 17 of 21 patients (80.9%) achieved remission. This improvement in survival resulted from the use of multimodal therapy, including primary combination chemotherapy in conjunction with radiation and surgical treatment. Patients with stage IV disease are at the greatest risk of developing rapidly progressive and unresponsive tumors despite intensive multimodal therapy. They should be referred to centers with special expertise in the management of trophoblastic disease.
Hepatic Metastasis
The management of resistant hepatic metastasis is particularly difficult (63). If a patient becomes resistant to systemic chemotherapy, hepatic arterial infusion of chemotherapy may induce complete remission in selected cases. Hepatic resection may be required to control acute bleeding or to excise a focus of resistant tumor. New techniques of arterial embolization may reduce the need for surgical intervention.
Cerebral Metastasis
At the NETDC, cerebral metastases are treated with whole-brain irradiation (3,000 cGy in 10 fractions) in conjunction with combination chemotherapy. Because irradiation may be hemostatic and tumoricidal, the risk of spontaneous cerebral hemorrhage may be lessened by the concurrent use of combination chemotherapy and brain irradiation. Excellent remission rates (86%) were reported in patients with cranial metastases treated with intensive intravenous combination chemotherapy and intrathecal methotrexate (MTX) (64).
Craniotomy
Craniotomy may be required to provide acute decompression or to control bleeding. It should be performed to manage life-threatening complications so that the patient ultimately will be cured with chemotherapy. In a study of six patients (65), the use of craniotomy to control bleeding resulted in complete remission in three patients. Infrequently, cerebral metastases that are resistant to chemotherapy may be amenable to local resection (66). Patients with cerebral metastases who achieve sustained remission generally have no residual neurologic deficits.
Follow-Up
Patients with stage IV disease should receive follow-up with:
1. Weekly determination of hCG levels until they are normal for 3 consecutive weeks.
2. Monthly determination of hCG levels until they are normal for 24 consecutive months.
These patients require prolonged gonadotropin follow-up because they are at increased risk of late recurrence.
An algorithm for the management of persistent GTN is presented in Figure 39.7.
Figure 39.7 Management of gestational trophoblastic tumor. GTN, gestational trophoblastic neoplasia; hCG, human chorionic gonadotropin; RT, radiotherapy. (From Berkowitz RS, Goldstein DP. Gestational trophoblastic neoplasia. In: Berek JS, Hacker NF. Berek and Hacker’s Gynecologic Oncology,5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2009;607, with permission.)
Chemotherapy
Single-Agent Treatment
Single-agent chemotherapy with either actinomycin D (ActD) or MTX achieved comparable and excellent remission rates in both nonmetastatic and low-risk metastatic GTN (67). Several protocols using these agents are available. ActD can be given every other week as a 5-day regimen or in a pulsatile fashion; similarly, MTX can be given either in a 5-day regimen or pulsatile weekly (68,69). No study compared all of these protocols with regard to success. An optimal regimen should maximize the response rate while minimizing morbidity and cost.
An important phase III randomized trial examining MTX and ActD in the treatment of low-risk GTN was published by the Gynecologic Oncology Group (GOG) (70). Two hundred sixteen patients were randomized to receive either biweekly ActD 1.25mg/m2 intravenous (IV) bolus or weekly MTX 30 mg/m2 intramuscular (IM). The remission rate was 58% in the MTX arm and 73% in theActD arm. These results suggest that ActD is superior to the weekly MTX regimen in treating low-risk GTN. Before recommending pulse ActD as the primary modality in the treatment of patients with low-risk GTN, it is important to be aware of the potential for significant toxicity of this regimen compared to those receiving MTX. All patients with low-risk disease in this study ultimately achieved remission, regardless of their initial response. Regarding the true comparative effectiveness of these agents, it would be prudent to compare the biweekly ActD regimen to the more commonly used 5-day or 8-day MTX regimens, which offer a high initial remission rate with minimal toxicity.
The administration of methotrexate with folinic acid (MTX-FA) in GTN to limit systemic toxicity was first reported in 1964 (71).Subsequently, it has been confirmed that MTX-FA is both effective and safe in the management of GTN.
An evaluation of 185 patients treated with MTX-FA revealed that complete remission was achieved in 162 patients (87.6%); of these patients, 132 (81.5%) required only one course of MTX-FA to attain remission (72). MTX-FA induced remission in 147 of 163 patients (90.2%) with stage I GTN and in 15 of 22 patients (68.2%) with low-risk stages II and III GTN. Resistance to therapy was more common in patients with choriocarcinoma, metastasis, and pretreatment serum hCG levels higher than 50,000 mIU/mL. After treatment with MTX-FA, thrombocytopenia, granulocytopenia, and hepatotoxicity developed in 3 (1.6%), 11 (5.9%), and 26 (14.1%) patients, respectively. Thus, MTX-FA achieved an excellent therapeutic outcome with minimal toxicity and attained this goal with limited exposure to chemotherapy.
Technique of Single-Agent Treatment
The serum hCG level is measured weekly after each course of chemotherapy. The hCG regression curve serves as the primary basis for determining the need for additional treatment.
After the first treatment:
1. Further chemotherapy is withheld as long as the hCG level is falling progressively.
2. Additional single-agent chemotherapy is not administered at any predetermined or fixed interval.
A second course of chemotherapy is administered under the following conditions:
1. If the hCG level plateaus for more than 3 consecutive weeks or begins to rise again.
2. If the hCG level does not decline by 1 log within 18 days after completion of the first treatment.
If the patient’s response to the first treatment was adequate and a second course of MTX-FA is required, the dosage of MTX is unaltered. An adequate response is defined as a fall in the hCG level by 1 log after a course of chemotherapy.
If the response to the first treatment is inadequate, the dosage of MTX is increased from 1.0 mg/kg/day to 1.5 mg/kg/day for each of the 4 treatment days. If the response to two consecutive courses of MTX-FA is inadequate, the patient is considered to be resistant to MTX, and ActD is promptly substituted. If the hCG levels do not decline by 1 log after treatment with ActD, the patient is considered resistant to ActD as a single agent. She must be treated intensively with combination chemotherapy to achieve remission.
Combination Chemotherapy
Triple Therapy
Prior to the introduction of etoposide in combination with MTX, ActD, cyclophosphamide, and vincristine (EMA-CO), triple therapy with MTX, ActD, and cyclophosphamide was the treatment of choice as initial therapy for patients with low-risk disease resistant to single-agent therapy and as primary therapy for high-risk patients. Collectively, data from three centers indicate that triple therapy induced remission in 21 (49%) of 43 patients with metastasis and a high-risk score (score >6) (73–75). Triple therapy is no longer indicated in patients with high-risk disease. It maybe useful in selected patients with low-risk scores resistant to single agents.
EMA-CO
Etoposide induces complete remission in 56 (95%) of 60 patients with nonmetastatic and low-risk metastatic GTN (76). The use of EMA-CO induced an 83% remission rate in patients with metastasis and a high-risk score(77). Another study confirmed that primary EMA-CO induced complete remission in 76% of the patients with metastatic GTN and a high-risk score (78). Another study reported that EMA-CO induced complete sustained remission in 87 (90.6%) of 96 patients with high-risk (score >6) GTN (79). Remission occurred with EMA-CO in 30 (86%) of 35 patients with brain metastasis (65).
The EMA-CO regimen is well tolerated, and treatment seldom has to be suspended because of toxicity. The EMA-CO regimen is the preferred primary treatment in patients with metastasis and a high-risk prognostic score (score >6).
EMA-EP
Patients resistant to EMA-CO can be treated successfully by substituting etoposide and cisplatin on day 8 (EMA-EP). EMA-EP induced remission alone or with surgery in 16 (76%) of 21 patients who were resistant toEMA-CO (80).The optimal combination drug protocol will most likely include etoposide, MTX, and ActD and perhaps other agents administered in the most dose-intensive manner.
Management of Refractory GTN
Efforts continue to identify new agents and regimens effective in treating patients who prove resistant to all standard chemotherapy regimens. A combination of cisplatin, vinblastine, and bleomycin(PVB) was used effectively in patients with drug-resistant tumor (74,75,81). Although ifosfamide and paclitaxel were used successfully, further studies are needed to define their potential role in either primary or second-line therapy (82,83). Osborne et al. reported that a novel three-drug doublet regimen consisting of paclitaxel, etoposide, and cisplatin (TE/TP) induced complete remission in two patients with relapsed high-risk GTN (84). Wan et al. demonstrated that floxuridine(FUDR)-containing regimens induced complete remission in all of 21 patients with drug-resistant GTN (85). Matsui et al. found that 5-fluorouracil (5-FU) in combination with ActD induced remission in 9 of 11 (82%) patients with drug resistance (86). The potential role for autologous bone marrow transplantation or stem cell rescue in conjunction with ultra-high-dose chemotherapy has yet to be defined, although complete remissions was reported in patients with refractory GTN (87,88).
Duration of Therapy
Patients who require combination chemotherapy must be treated intensively to attain remission. Combination chemotherapy should be given as often as toxicity permits until the patient achieves three consecutive normal hCG levels. After normal hCG levels are attained, at least two additional courses of chemotherapy are administered to reduce the risk of relapse.
False-Positive hCG Tests
The concept of false-positive hCG tests caused by heterophile antibodies is critical to remember when following patients with molar gestation or GTN. Some assay systems used by commercial laboratories are particularly vulnerable to false-positive tests resulting from the presence of heterophilic antibodies in the test kits they were using (89). For the most part this problem was corrected by adding blocking antibodies to the test systems. Since the hCG molecules in GTN are significantly more degraded or heterogeneous than in normal pregnancy, with higher proportions of free B-hCG, nicked hCG, and B-core fragments, it is important to use an assay that detects both intact hCG and its metabolites and fragments in order to accurately assess the tumor burden (90–92). Additionally, cross-reactivity with luteinizing hormone (LH) can cause confusion when dealing with women in the perimenopausal age group whose hCG level may plateau above assay even when there is no longer active tumor. The use of hormone suppression will suppress LH and prevent unnecessary treatment. False-positive hCG tests caused by heterophile agglutinins or LH release may cause confusion in the diagnosis of early pregnancy, ectopic pregnancy, and so-called phantom choriocarcinoma. When there is concern about the possibility of a false-positive serum hCG test, a urine sample should be tested, because patients with phantom hCG generally have no measurable hCG in a parallel urine sample.
Persistent Low-Level “Real” hCG
Some patients with molar pregnancy and GTN have persistent (weeks to months) very low levels of real hCG (usually <500 mIU/mL). In these women, extensive radiologic and clinical evaluations fail to reveal any lesions, and chemotherapy is usually not effective. This condition of “real” low-level hCG, where hCG is not hyperglycosylated, is called “quiescent GTN.” These patients should be managed with careful follow-up, because 6% to 10% ultimately will relapse into active disease and rising hCG levels. The risk of relapse to active disease is correlated with the amount of hyperglycosylated hCG. If relapse does occur, chemotherapy usually proves effective (93).
Subsequent Pregnancies
Pregnancies After Uncomplicated Hydatidiform Mole
Patients with hydatidiform moles can anticipate normal reproduction in the future (94). At the NETDC from 1965 until 2007, patients with uncomplicated complete mole had 1,337 subsequent pregnancies that resulted in 912 term live births (68.1%), 101 premature deliveries (67%), 11 ectopic pregnancies (0.9%), 7 stillbirths (0.5%), and 20 repeat molar pregnancies (1.5%). First- and second-trimester spontaneous abortions occurred in 245 (39%) pregnancies. Major and minor congenital malformations were detected in 40 infants (3.9%), and primary cesarean delivery was performed in 81 of 414 (19.6%) term or preterm births from 1979 to 2007.
Although data regarding pregnancies after partial mole are limited (296 subsequent pregnancies), the information is reassuring (94). Patients with both complete and partial mole should be reassured that they are at no increased risk of complications in later gestations.
When a patient has had a molar pregnancy, either partial or complete, she should be informed of the increased risk of having a molar gestation in subsequent conceptions. After one molar pregnancy, the risk of having molar disease in a future gestation is about 1% to 1.5%. Of 35 patients with at least two documented molar pregnancies, every possible combination of repeat molar pregnancy was observed. After two molar gestations, these 35 patients had 39 later conceptions resulting in 24 (61.5%) term deliveries, 7 (17.9%) moles (6 complete, 1 partial), 3 spontaneous abortions, 3 therapeutic abortions, 1 intrauterine fetal death, and 1 ectopic pregnancy. In six patients, the medical records indicated that the patient had a different partner at the time of different molar pregnancies (95).
For any subsequent pregnancy, it seems prudent to undertake the following approach:
1. Perform pelvic ultrasonographic examination during the first trimester to confirm normal gestational development.
2. Obtain an hCG measurement 6 weeks after completion of the pregnancy to exclude occult trophoblastic neoplasia.
Pregnancies After GTN
Patients with GTN who are treated successfully with chemotherapy can expect normal reproduction in the future. Patients who were treated with chemotherapy at the NETDC from 1965 to 2007 had 631 subsequent pregnancies that resulted in 422 term live births (66.9%), 42 preterm deliveries (6.7%), 7 ectopic pregnancies (1.1%), 9 stillbirths (1.4%), and 9 repeat molar pregnancies (1.7%) (94). First- and second-trimester spontaneous abortions occurred in 114 (188%) pregnancies. Major and minor congenital malformations were detected in 10 infants (2.1%). Primary cesarean delivery was performed in 81 (21.8%) of 371 subsequent term and preterm births from 1979 to 2007. The frequency of congenital anomalies is not increased, although chemotherapeutic agents have teratogenic and mutagenic potential.
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