Berek and Hacker's Gynecologic Oncology, 5th Edition
Gestational Trophoblastic Neoplasia
Ross S. Berkowitz
Donald P. Goldstein
Gestational trophoblastic neoplasia (GTN) is among the rare human malignancies that can be cured even in the presence of widespread metastases (1,2,3). GTN includes a spectrum of interrelated tumors—including hydatidiform mole, invasive mole, placental-site trophoblastic tumor, and choriocarcinoma—that have varying propensities for local invasion and metastasis. Although persistent GTN most commonly ensues after a molar pregnancy, it may follow any gestational event, including therapeutic or spontaneous abortion and ectopic or term pregnancy. Dramatic advances have been made in the diagnosis, treatment, and follow-up of patients with GTN since the introduction of chemotherapy in 1956.
Complete Versus Partial Hydatidiform Mole
Hydatidiform moles may be categorized as either complete or partial moles on the basis of gross morphology, histopathology, and karyotype (Table 15.1).
Complete Hydatidiform Mole
Pathology Complete moles lack identifiable embryonic or fetal tissues, and the chorionic villi exhibit generalized hydatidiform swelling and diffuse trophoblastic hyperplasia.
Chromosomes Cytogenetic studies have demonstrated that complete hydatidiform moles usually have a 46XX karyotype, and the molar chromosomes are entirely of paternal origin(4). Complete moles appear to arise from an ovum that has been fertilized by a haploid sperm, which then duplicates its own chromosomes, and the ovum nucleus may be either absent or inactivated (5). Although most complete moles have a 46XX chromosomal pattern, approximately 10% have a 46XY karyotype (6). Chromosomes in a 46XY complete mole also appear to be entirely of paternal origin, but in this circumstance, an apparently empty egg is fertilized by two sperm.
Table 15.1 Features of Complete and Partial Hydatidiform Moles
Partial Hydatidiform Mole
Pathology Partial hydatidiform moles are characterized by the following pathologic features (7):
- Chorionic villi of varying size with focal hydatidiform swelling and cavitation
- Marked villous scalloping
- Focal trophoblastic hyperplasia with or without atypia
- Prominent stromal trophoblastic inclusions
- Identifiable embryonic or fetal tissues
Chromosomes Partial moles usually have a triploid karyotype (69 chromosomes), with the extra haploid set of chromosomes derived from the father (8). When a fetus is present in conjunction with a partial mole, it usually exhibits the stigmata of triploidy, including growth retardation and multiple congenital malformations. In a careful review of our pathologic material, Genest et al. concluded that nontriploid partial moles probably do not exist (9).
The presenting symptoms and signs of patients with complete and partial molar pregnancy are presented in Table 15.2 (10,11,12).
Complete Hydatidiform Mole
Vaginal Bleeding Vaginal bleeding is the most common presenting symptom in patients with complete molar pregnancy and occurs in 97% of cases. Molar tissues may separate from the decidua and disrupt maternal vessels, and large volumes of retained blood may distend the endometrial cavity. As intrauterine clots undergo oxidation and liquefaction, “prune juice”-like fluid may leak into the vagina. Because vaginal bleeding may be considerable and prolonged, half of these patients present with anemia (hemoglobin <10 g/100 mL).
Table 15.2 Presenting Symptoms and Signs in Patients with Complete and Partial Molar Pregnancy
Excessive Uterine Size Excessive uterine enlargement relative to gestational age is one of the classic signs of a complete mole, although it is present in only about half of the patients. The endometrial cavity may be expanded by both chorionic tissue and retained blood. Excessive uterine size is usually associated with markedly elevated levels of human chorionic gonadotropin (hCG) because uterine enlargement results in part from exuberant trophoblastic growth.
Toxemia Preeclampsia is observed in approximately 27% of patients with a complete hydatidiform mole. Although preeclampsia is often associated with hypertension, proteinuria and hyperreflexia, and eclamptic convulsions rarely occur. Toxemia develops almost exclusively in patients with excessive uterine size and markedly elevated hCG levels. The diagnosis of hydatidiform mole should be considered whenever preeclampsia develops early in pregnancy.
Hyperemesis Gravidarum Hyperemesis requiring antiemetic and/or intravenous replacement therapy occurs in one-fourth of the patients with a complete mole, particularly those with excessive uterine size and markedly elevated hCG levels. Severe electrolyte disturbances may develop occasionally and require treatment with parenteral fluids.
Hyperthyroidism Clinically evident hyperthyroidism is observed in approximately 7% of patients with a complete molar gestation. These patients may present with tachycardia, warm skin, and tremor, and the diagnosis can be confirmed by detection of elevated serum levels of free thyroxine (T4) and triiodothyronine (T3).
Laboratory evidence of hyperthyroidism is commonly detected in asymptomatic patients with hydatidiform moles. Galton et al. (13) reported 11 patients whose thyroid function test values were elevated before molar evacuation, and the thyroid function test values rapidly returned to normal in all patients after evacuation.
If hyperthyroidism is suspected, it is important to administer β-adrenergic blocking agents before the induction of anesthesia for molar evacuation because anesthesia or surgery may precipitate a thyroid storm. The latter may be manifested by hyperthermia, delirium, convulsions, atrial fibrillation, 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 a thyroid storm.
Some investigators have suggested that hCG is the thyroid stimulator in patients with a hydatidiform mole because positive correlations between serum hCG and total T4 or T3 concentrations have sometimes been observed. However, Amir et al. (14) measured thyroid function in 47 patients with a complete mole and reported no correlation between serum hCG levels and the serum free T4 index or free T3 index. Thus, the identity of a thyrotropic factor in hydatidiform mole has not been clearly delineated. Although some investigators have speculated about a separate chorionic thyrotropin, this substance has not yet been isolated.
Trophoblastic Embolization Respiratory distress develops in approximately 2% of patients with a complete mole. These patients may have chest pain, dyspnea, tachypnea, and tachycardia and may experience severe respiratory distress after molar evacuation. Auscultation of the chest usually reveals diffuse rales, and the chest radiograph may demonstrate bilateral pulmonary infiltrates. The signs and symptoms of respiratory distress usually resolve within 72 hours with cardiopulmonary support. Respiratory insufficiency may result not only from trophoblastic embolization, but also from the cardiopulmonary complications of thyroid storm, toxemia, and massive fluid replacement.
Theca Lutein Ovarian Cysts Prominent theca lutein ovarian cysts (>6 cm in diameter) develop in approximately half the patients with a complete mole. These cysts contain amber-colored or serosanguineous fluid and are usually bilateral and multilocular. Their formation may be related to increased serum levels of hCG and prolactin (15). Ovarian enlargement occurs almost exclusively in patients with markedly elevated hCG values. Because the uterus may also be excessively enlarged, theca lutein cysts may be difficult to palpate on 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 frequently cause symptoms of marked pelvic pressure, and they may be decompressed by laparoscopic or transabdominal aspiration to relieve such symptoms. If acute pelvic pain develops, laparoscopy should be performed to assess possible cystic torsion or rupture, and laparoscopic manipulation may successfully manage incomplete ovarian torsion or cystic rupture (16).
Although in the 1960s, 1970s, and early 1980s, complete moles were usually diagnosed in the second trimester, in more recent years the diagnosis has commonly been made in the first trimester (17). Because of this, the diagnosis of complete mole is now often made before the classic clinical signs and symptoms develop. With earlier diagnosis, excessive uterine size, hyperemesis, anemia, and preeclampsia were observed at presentation in only 28%, 8%, 5%, and 1% of our patients, respectively. Between 1988 and 1993, none of our 74 patients with complete mole had respiratory distress or hyperthyroidism. However, patients continue to present with vaginal bleeding and markedly elevated hCG levels.
The histopathologic characteristics of complete mole are different in the first trimester (18). First trimester complete moles have less circumferential trophoblastic hyperplasia and smaller villi and their more subtle morphologic alterations may lead to misclassification as partial moles or nonmolar spontaneous abortions. Immunohistochemistry for p57(paternally imprinted, maternally expressed gene product) is useful for confirming the diagnosis of a complete mole (19). Nuclei of decidual cells (maternally derived tissue) and extra villous trophoblast of all types of gestations stain positively for p57. Almost all complete moles have absent (or nearly absent) villous stromal and cytotrophoblastic nuclear activity for p57, while all other types of gestations (including partial moles) show nuclear reactivity in more than 25 percent of cases. Fisher et al. (20) showed that maternal chromosomal 11 is retained in the rare case of complete mole exhibiting p57 staining. This helps to explain the rare occurrence of recurrent complete hydatidiform moles of biparental origin.
Partial Hydatidiform Mole
Patients with a partial hydatidiform mole usually do not have the clinical features characteristic of complete molar pregnancy. In general, these patients present with the signs and symptoms of incomplete or missed abortion, and the diagnosis of partial mole may be made only after histologic review of the curettings (21).
The main presenting symptom among 81 patients with a partial mole seen at the New England Trophoblastic Disease Center (NETDC) was vaginal bleeding, which occurred in 59 patients (72.8%). There was absence of a fetal heart beat in 12 patients (14.8%). Excessive uterine enlargement and preeclampsia were present in only three (3.7%) and two (2.5%) patients, respectively. No patient presented with theca lutein ovarian cysts, hyperemesis, or hyperthyroidism. The clinical diagnosis was incomplete or missed abortion in 74 patients (91.4%) and hydatidiform mole in only 5 patients (6.2%). Pre-evacuation hCG levels were measured in 30 patients and were greater than 100,000 mIU/mL in only 2 patients (10).
Complete Hydatidiform Mole
Complete moles are well recognized to have a potential for local invasion and distant spread. After molar evacuation, local uterine invasion occurs in 15% of patients and metastases in 4% (11,12).
A review of 858 patients with complete hydatidiform mole revealed that two-fifth of the patients had the following signs of marked trophoblastic proliferation at the time of presentation:
- Human chorionic gonadotropin level greater than 100,000 mIU/mL
- Excessive uterine enlargement
- Theca lutein cysts larger than 6 cm in diameter
Patients with any of these signs are at high risk for postmolar persistent tumor. The sequelae of 858 patients with low- and high-risk complete hydatidiform moles are shown in Table 15.3. 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 women are also at increased risk of postmolar GTN. Tsukamoto et al. reported that 56% of women older than 50 years developed persistent GTN after molar evacuation (22).
Table 15.3 Sequelae of Low- and High-Risk Complete Hydatidiform Moles
Partial Hydatidiform Mole
Approximately 2% to 4% of patients with a partial mole have persistent postmolar tumor and require chemotherapy to achieve remission (23). Those patients in whom persistent disease develops have no distinguishing clinical or pathologic characteristics.
Ultrasonography is a reliable and sensitive technique for the diagnosis of complete molar pregnancy. Because the chorionic villi exhibit diffuse hydatidiform swelling, complete moles produce a characteristic vesicular sonographic pattern, usually referred to as a “snowstorm” pattern. Ultrasonography continues to be useful in the detection of first trimester complete moles (24).
Ultrasonography may also 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 (25).
After molar pregnancy is diagnosed, the patient should be evaluated carefully for the presence of associated medical complications, including preeclampsia, hyperthyroidism, electrolyte imbalance, and anemia. After the patient has been stabilized, a decision must be made concerning the most appropriate method of evacuation.
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 though theca lutein cysts are present. Prominent ovarian cysts may be decompressed by aspiration. Although hysterectomy eliminates the risks associated with local invasion, it does not prevent distant spread.
Suction curettage is the preferred method of evacuation, regardless of uterine size, in patients who desire to preserve fertility. It involves the following steps:
- Oxytocin infusion—This is begun in the operating room before the induction of anesthesia.
- Cervical dilatation—As the cervix is being dilated, the surgeon frequently encounters increased uterine bleeding. Retained blood in the endometrial cavity may be expelled during cervical dilatation. However, active uterine bleeding should not deter the prompt completion of cervical dilatation.
- Suction curettage—Within a few minutes of commencing suction curettage, the uterus may decrease dramatically in size, and the bleeding is usually well controlled. If the uterus is more than 14 weeks in size, one hand may be placed on top of the fundus and the uterus massaged to stimulate uterine contraction and reduce the risk of perforation.
Table 15.4 Prophylactic Actinomycin D (Act-D) After Evacuation for Molar Pregnancy
- Sharp curettage—When suction evacuation is thought to be complete, sharp curettage is performed to remove any residual molar tissue.
The specimens obtained on suction and sharp curettage should be submitted separately for pathologic review.
The use of prophylactic chemotherapy at the time of evacuation of a complete mole is controversial (26). The debate concerns the wisdom of exposing all patients to potentially toxic treatment when only approximately 20% are at risk for development of persistent GTN.
In a study of 247 patients with complete molar pregnancy who received a single course of actinomycin D (Act-D) prophylactically at the time of evacuation, local uterine invasion subsequently developed in only 10 patients (4%), and in no case did metastases occur (Table 15.4). Furthermore, all 10 patients with local invasion achieved remission after only one additional course of chemotherapy. Prophylactic chemotherapy, therefore, not only prevented metastases, it reduced the incidence and morbidity of local uterine invasion. Kim et al. (27) and Limpongsanurak (28) performed prospective, randomized studies of prophylactic chemotherapy in patients with a complete mole and observed a significant decrease in persistent GTN in patients with high-risk mole who received prophylactic chemotherapy. Therefore, prophylaxis may be particularly useful in the management of high-risk complete molar pregnancy, especially when hormonal follow-up is unavailable or unreliable.
Human Chorionic Gonadotropin
Human chorionic gonadotropin is a predictable secretory product of the trophoblastic cell. Like the other glycoprotein hormones—luteinizing hormone (LH), follicle-stimulating hormone, and thyroid-stimulating hormone—hCG is composed of two polypeptide chains (α and β) attached to a carbohydrate moiety. There is considerable cross-reactivity between hCG and LH because they share indistinguishable α chains. Each of the β chains of these four glycoprotein hormones is biochemically unique and confers biologic and immunologic specificity. The β-subunit radioimmunoassay is the most reliable assay available for the management of patients with GTN and is particularly useful in quantitating low levels of hCG without substantial interference from physiologic levels of LH.
After molar evacuation or hysterectomy with the mole in situ, patients should be followed by weekly determinations of β-subunit hCG levels until these are normal for 3 consecutive weeks and then by monthly determinations until the levels are normal for at least 3 consecutive months. The normal postmolar β-hCG regression curve is presented inFigure 15.1. When a patient with molar pregnancy, either partial or complete, achieves a nondetectable hCG level, the risk of developing tumor relapse is very low (29,30,31). Based on these findings, pregnancy is currently allowed after only three months of follow-up. This is particularly important for those older patients who feel that their window of opportunity for successful pregnancy is closing.
Figure 15.1 Normal regression curve of beta-subunit human chorionic gonadotropin (-hCG) after molar evacuation. (Reprinted from Morrow CP, Kletzky OA, DiSaia PJ, Townsend DE, Mishell DR, Nakamura RM. Clinical and laboratory correlates of molar pregnancy and trophoblastic disease. Am J Obstet Gynecol 1977;128:424-430, with permission.)
Patients are encouraged to use effective contraception during the entire interval of gonadotropin follow-up. Intrauterine devices should not be inserted until the patient achieves a normal hCG level because of the potential risk of uterine perforation, infection, and bleeding. If the patient does not desire surgical sterilization, the choice is to use either hormonal contraception or barrier methods.
The incidence of postmolar GTN has been reported to be increased among patients who use oral contraceptives before gonadotropin remission (32). However, data from both the NETDC and the Gynecologic Oncology Group (GOG) indicate that these agents do not increase the risk of postmolar trophoblastic disease (33,34). In addition, the contraceptive method does not influence the mean hCG regression time. It appears that oral contraceptives may be safely prescribed after molar evacuation during the entire interval of hormonal follow-up.
Gestational Trophoblastic Neoplasia
Locally invasive GTN develops in 15% of patients after evacuation of a complete mole and infrequently after other gestations (11,12). These patients usually present clinically with one or more of the following:
- Irregular vaginal bleeding
- Theca lutein cysts
- Uterine subinvolution or asymmetric enlargement
- Persistently elevated serum hCG levels
The trophoblastic tumor may perforate through 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, however, persistent GTN always has the histologic pattern of choriocarcinoma. Histologically, choriocarcinoma is characterized by sheets of anaplastic syncytiotrophoblast and cytotrophoblast with no preserved chorionic villous structure.
Placental-Site Trophoblastic Tumor Placental-site trophoblastic tumor is an uncommon but important variant of GTN that consists predominantly of intermediate trophoblast and a few syncytial elements (35). These tumors produce small amounts of hCG and human placental lactogen relative to their mass, and 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. High cure rates can be achieved with early diagnosis and surgical resection. Intensive combination chemotherapy may achieve complete remission in patients with metastatic disease, particularly when the interval from the antecedent pregnancy is less than four years (36).
Metastatic Disease and Choriocarcinoma
Metastatic GTN occurs in 4% of patients after evacuation of a complete mole and is infrequent after other pregnancies (11,12). Metastasis is usually associated with choriocarcinoma, although the precise histology is usually not determined because diagnosis and treatment are based on rising hCG levels. Approximately one-half of choriocarcinomas occur following a hydatidaform mole and one-half after other pregnancies, including normal ones. Choriocarcinoma has a tendency toward early vascular invasion with widespread dissemination. Because trophoblastic tumors are often perfused by a network of fragile vessels, they are frequently hemorrhagic. Symptoms of metastases may therefore result from spontaneous bleeding at metastatic foci. Sites of metastatic spread are shown in Table 15.5.
Pulmonary At the time of presentation, 80% of the patients with metastatic GTN show lung involvement on chest radiographs. Patients with pulmonary metastases may have chest pain, cough, hemoptysis, dyspnea, or an asymptomatic lesion on a chest radiograph. Respiratory symptoms may be of acute onset, or they may be protracted over many months.
Gestational trophoblastic neoplasia produces four principal radiographic patterns in the lungs:
- An alveolar or “snowstorm” pattern
- Discrete, rounded densities
- A pleural effusion
- An embolic pattern caused by pulmonary arterial occlusion
Table 15.5 Relative Incidence of Common Metastatic Sites
Because respiratory symptoms and radiographic findings may be dramatic, the patient may be thought to have primary pulmonary disease. Some patients with extensive pulmonary involvement have minimal or no gynecologic symptoms and the diagnosis of GTN may be confirmed only after thoracotomy has been performed. This occurs particularly in patients with a nonmolar antecedent pregnancy.
Pulmonary hypertension may develop in patients with GTN secondary to pulmonary arterial occlusion by trophoblastic emboli. Although patients with pulmonary hypertension may be very symptomatic, the chest film may reveal only minimal changes.
Vaginal Vaginal metastases are present in 30% of patients with metastatic tumor. These lesions are usually highly vascular and may appear reddened or violaceous. They can bleed vigorously if sampled for biopsy, so attempts at histologic confirmation of the diagnosis should be resisted. 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 almost exclusively in patients with protracted delays in diagnosis and extensive tumor burdens. Epigastric or right upper quadrant pain may develop if metastases stretch Glisson's capsule. Hepatic lesions are hemorrhagic and friable and may rupture, causing exsanguinating intraperitoneal bleeding.
Central Nervous System Ten percent of metastatic trophoblastic disease involves the brain. Virtually all patients with brain metastases have concurrent pulmonary and/or vaginal involvement. Because cerebral lesions may undergo spontaneous hemorrhage, patients may have acute focal neurologic deficits.
The current staging system for GTN (2000) combines both anatomic staging and a prognostic scoring system (Tables 15.6, 15.7). It is hoped that this staging system will encourage the objective comparison of data among various centers.
Table 15.6 Staging of Gestational Trophoblastic Neoplasia
Table 15.7 Scoring System Based on Prognostic Factors
Stage I includes all patients with persistently elevated hCG levels and tumor confined to the uterine corpus.
Stage II comprises all patients with metastases to the vagina and/or pelvis.
Stage III includes all patients with 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 on a chest film.
Stage IV patients have far advanced disease with 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. In most cases, their disease follows a nonmolar pregnancy and has the histologic pattern of choriocarcinoma.
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 selection of appropriate chemotherapy. A prognostic scoring system, based on one developed by Bagshawe, reliably predicts the potential for resistance to chemotherapy (3).
When the prognostic score is 7 or more, the patient is categorized as high risk and requires intensive combination chemotherapy 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, so that the distinction between low and high risk applies mainly to patients with stage II or III disease.
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:
- A complete history and physical examination
- Measurement of the serum hCG level
- Hepatic, thyroid, and renal function tests
- Determination of baseline peripheral white blood cell and platelet counts
The metastatic workup should include:
- A chest radiograph and/or chest computed tomographic (CT) scan
- An ultrasonogram or a CT scan of the abdomen and pelvis
- A CT or magnetic resonance imaging (MRI) scan of the head
- Selective angiography of abdominal and pelvic organs, if indicated
- Whole body 18 FDG-PET scan to identify occult disease (37)
Liver ultrasonography and/or CT scanning document most hepatic metastases in patients with abnormal liver function tests. CT or MRI of the head has facilitated the early diagnosis of asymptomatic cerebral lesions (38). In the absence of lung or vaginal metastasis, the risk of cerebral and hepatic spread is exceedingly low.
In patients with choriocarcinoma and/or metastatic disease, it has been traditional to measure hCG levels in the cerebrospinal fluid (CSF) to exclude cerebral involvement if the CT scan of the brain was negative (39,40). However, in this era of MRI and 18 FDG-PET scans, the need for csf hCG determination is limited.
Stool guaiac tests should also be routinely performed in patients with persistent GTN. If the guaiac test is positive or if the patient reports gastrointestinal symptoms, a complete radiographic evaluation of the gastrointestinal tract should be undertaken.
Pelvic ultrasonography appears to be useful in detecting extensive trophoblastic uterine involvement and may also aid in identifying sites of resistant uterine tumor (41). Because ultrasonography can accurately and noninvasively detect extensive uterine tumor, it may help to select patients who will benefit from hysterectomy. When the uterus contains large amounts of tumor, hysterectomy may substantially reduce the tumor burden and limit the requirement for chemotherapy, as well as eliminate the potential for hemorrhage or infection (42).
Management of Gestational Trophoblastic Neoplasia
The NETDC protocol for the management of stage I disease is presented in Table 15.8. The selection of treatment is based primarily on whether the patient wishes to retain fertility.
Hysterectomy Plus Chemotherapy
If the patient no longer wishes to preserve fertility, hysterectomy with adjuvant singleagent chemotherapy may be performed as primary treatment. Adjuvant chemotherapy is administered for three reasons:
- To reduce the likelihood of disseminating viable tumor cells at surgery.
- To maintain a cytotoxic level of chemotherapy in the bloodstream and tissues in case viable tumor cells are disseminated at surgery.
- To treat any occult metastases that may already be present at the time of surgery. Occult pulmonary metastases may be detected by CT scan in about 40% of patients with presumed nonmetastatic disease (43).
Chemotherapy can be administered safely at the time of hysterectomy without increasing the risk of bleeding or sepsis. At the NETDC, 32 patients with stage I disease have been treated with primary hysterectomy and a single course of adjuvant chemotherapy, and all have achieved complete remission with no additional therapy.
Table 15.8 Protocol for Treatment of Stage I Gestational Trophoblastic Neoplasia
Hysterectomy is also performed in all patients with a placental-site trophoblastic tumor. Because placental-site tumors are relatively resistant to chemotherapy, hysterectomy for nonmetastatic disease is most prudent.
Single-agent chemotherapy is the preferred treatment in patients with stage I disease who desire to retain fertility. Between July 1965 and June 2006, 502 patients were treated with primary single-agent chemotherapy at the NETDC. Of these patients, 419 (83.4%) achieved complete remission with sequential MTX/Act-D. The remaining 83 (16.6%) withMTX/Act-D resistant disease subsequently attained remission after combination chemotherapy or surgical intervention.
When patients are resistant to single-agent chemotherapy and wish to preserve fertility, combination chemotherapy should be administered. If the patient is resistant to both single-agent and combination chemotherapy and wants to retain fertility, local uterine resection may be considered. When local resection is planned, a preoperative ultrasonogram, MRI, arteriogram, or/and PET scan may help to define the site of the resistant tumor.
All patients with stage I lesions should be followed with:
- Weekly hCG levels until they are normal for 3 consecutive weeks
- Monthly hCG levels until levels are normal for 12 consecutive months
- Effective contraception during the entire period of hormonal follow-up
Stages II and III
Low-risk patients are treated with primary single-agent chemotherapy, and high-risk patients are managed with primary intensive combination chemotherapy. A protocol for the management of patients with stage II and III disease is presented in Table 15.9.
All twenty-eight patients with stage II disease treated at the NETDC between July 1965 and June 2006 achieved remission. Single-agent chemotherapy induced complete remission in 16 (80%) of 20 patients with low-risk GTN. Four patients with resistant disease were cured with combination chemotherapy. In contrast, only two of eight patients with high-risk GTN achieved remission with single-agent treatment, the others requiring combination chemotherapy and local resection.
Table 15.9 Protocol for Treatment of Stages II and III Gestational Trophoblastic
Vaginal metastases may bleed profusely because they are highly vascular and friable. Yingna et al. reported that 18 (35.3%) of 51 patients with vaginal metastases presented with vaginal hemorrhage (44). When bleeding is substantial, it may be controlled by packing of the hemorrhagic lesion or by wide local excision. Arteriographic embolization of the hypogastric arteries may also be used to control hemorrhage from vaginal metastases.
Of 161 patients with stage III disease managed at the NETDC between July 1965 and June 2006, 160 (99.3%) attained complete remission. Gonadotropin remission was induced with single-agent chemotherapy in 90 of 110 (81.7%) patients with low-risk GTN. The remaining twenty patients with low-risk GTN resistant to single agent chemotherapy subsequently achieved remission with combination chemotherapy and/or local pulmonary resection. Fifty of the 51 (98%) stage III patients with high-risk scores treated with primary combination chemotherapy were cured.
Thoracotomy Thoracotomy has a limited role in the management of stage III disease. However, if a patient has a persistent viable pulmonary metastasis despite intensive chemotherapy, thoracotomy may be used to excise the resistant focus (45). A thorough metastatic workup should be performed before surgery to exclude other sites of persistent disease. Fibrotic pulmonary nodules may persist indefinitely on radiographs of the chest, even after complete gonadotropin remission has been attained. In patients undergoing thoracotomy for resistant disease, postoperative chemotherapy should be administered to treat potential occult sites of micrometastases.
Hysterectomy may be required in patients with metastatic GTN to control uterine hemorrhage or sepsis. Furthermore, in patients with extensive uterine tumor, hysterectomy may substantially reduce the trophoblastic tumor burden and thereby limit the need for multiple courses of chemotherapy.
Follow-up monitoring for patients with stage II and III disease is the same as for patients with stage I disease.
A protocol for the management of stage IV disease is presented in Table 15.10. These patients are at greatest risk for development of rapidly progressive and unresponsive tumors despite intensive multimodal therapy. They should all be referred to centers with special expertise in the management of trophoblastic disease.
Table 15.10 Protocol for Treatment of Stage IV Gestational Trophoblastic Neoplasia
All patients with stage IV disease should be treated with primary intensive combination chemotherapy and the selective use of radiation therapy and surgery. Before 1975, only 6 of 20 patients (30%) with stage IV disease treated at the NETDC attained complete remission. Since 1975, however, 17 of 21 patients (80.9%) with stage IV tumors have achieved gonadotropin remission. This improvement in survival has resulted from the use of primary combination chemotherapy in conjunction with radiation and surgical treatment.
The management of hepatic metastases is particularly challenging and problematic. If a patient is resistant to systemic chemotherapy, hepatic arterial infusion of chemotherapy may induce complete remission in selected cases. Hepatic resection may also be required to control acute bleeding or to excise a focus of resistant tumor.
If cerebral metastases are diagnosed, whole-brain irradiation (3,000 cGy in ten fractions) should be instituted promptly. Alternatively, localized external beam radiation may be given. Yordan and colleagues reported that deaths as a result of cerebral involvement occurred in 11 of 25 patients (44%) treated with chemotherapy alone, but in none of 18 patients treated with brain irradiation and chemotherapy (46). The risk of spontaneous cerebral hemorrhage may be lessened by the concurrent use of combination chemotherapy and brain irradiation because irradiation may be both hemostatic and tumoricidal.
Craniotomy Craniotomy may be required to provide acute decompression or to control bleeding and should be performed to manage life-threatening complications in the hope that the patient ultimately will be cured with chemotherapy. Infrequently, cerebral metastases that are resistant to chemotherapy may be amenable to local resection. Fortunately, most patients with cerebral metastases who achieve sustained remission generally have no residual neurologic deficits (47).
Salvage Therapy for Drug Resistance
Despite the effectiveness of well-recognized regimens, there is a need to identify new agents that have the potential to treat resistant GTN. Although ifosfamide and paclitaxelhave been used successfully, further studies are needed to define their potential role as either first or second-line therapy (48,49). Osborne et al. reported that a novel three-drug doublet regimen consisting of paclitaxel, etoposide and cisplatin (TE/TO) induced complete remission in two patients with relapsed high risk GTN (50). Wan et al. demonstrated the efficacy of floxuridine (FUDR)-containing regimens in drug resistant patients (51). Matsui et al. found that 5FU in combination with actinomycin D could also be used effectively as salvage therapy (52).
There have been individual case reports of successful high-dose chemotherapy with autologous bone marrow or stem cell support in patients with otherwise refractory GTN (53,54).
Patients with stage IV disease should be followed with:
- Weekly hCG levels until they are normal for 3 consecutive weeks
- Monthly hCG levels until they are normal for 24 consecutive months
- Effective contraception during the interval of hormonal follow-up
These patients require prolonged gonadotropin follow-up because they are at increased risk of late recurrence.
An algorithm for the management of GTN is presented in Fig. 15.2.
Many hCG assays have some cross-reactivity with luteinizing hormone. Following multiple courses of combination chemotherapy, ovarian steroidal function may be damaged, leading to rising luteinizing hormone levels. Patients who receive combination chemotherapy should therefore be placed on oral contraceptives to suppress luteinizing hormone levels and prevent problems with cross-reactivity.
Figure 15.2 Management of gestational trophoblastic neoplasia. GTN, gestational trophoblastic neoplasia; hCG, human chorionic gonadotropin; RT, radiation therapy.
Some patients may have a false-positive elevation in serum hCG values due to circulating heterophilic antibody (55). Patients with phantom choriocarcinoma or phantom hCG often have no progressive rise in their hCG levels and no clear antecedent pregnancy. The possibility of false-positive hCG levels should be evaluated by sending both urine and serum samples to a reference hCG laboratory.
Single-agent chemotherapy with either actinomycin D (Act-D) or methotrexate (MTX) has achieved comparable and excellent remission rates in both nonmetastatic and low-risk metastatic GTN (56). There are several protocols available for the treatment of patients with MTX or Act-D (Table 15.11).
Actinomycin D can be given every other week in a 5-day regimen or in a pulse fashion, and MTX can be given similarly in a 5-day regimen or weekly in a pulse fashion. No study has compared all of these protocols with regard to success and morbidity. The selection of chemotherapy should be influenced by the associated systemic toxicity. An optimal regimen should maximize response rate while minimizing morbidity.
In 1964, Bagshawe and Wilde (57) first reported the administration of MTX with folinic acid (MTX-FA) in GTN to limit systemic toxicity, and subsequently it has been confirmed thatMTX-FA is both effective and safe in the management of GTN (58) (Table 15.12). Methotrexate with folinic acid has been the preferred single-agent regimen in the treatment of GTN at the NETDC since 1974 (58). An evaluation of 185 patients treated in this manner revealed that complete remission was achieved in 162 patients (87.6%), and 132 of the 162 patients (81.5%) required only one course of MTX-FA to attain remission. 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, metastases, and when pretreatment serum hCG levels exceeded 50,000 mIU/mL. After treatment with MTX-FA, thrombocytopenia, granulocytopenia, and hepatotoxicity developed in only 3 (1.6%), 11 (5.9%), and 26 (14.1%) patients, respectively. MTX-FAtherefore achieved an excellent therapeutic outcome with minimal toxicity and attained this goal with limited exposure to chemotherapy.
Table 15.11 Single-Drug Treatment
Table 15.12 Protocol for Therapy with Methotrexate and Folinic Acid “Rescue”
Administration of Single-Agent Treatment
The serum hCG level is measured weekly after each course of chemotherapy, and the hCG regression curve serves as the primary basis for determining the need for additional treatment.
After the first treatment:
- Further chemotherapy is withheld as long as the hCG level is falling progressively.
- Additional single-agent chemotherapy is not administered at any predetermined or fixed time interval.
A second course of chemotherapy is administered under the following conditions:
- If the hCG levels plateau for more than 3 consecutive weeks or begin to rise again
- If the hCG level does not decline by 1 log within 18 days after completion of the first treatment
If a second course of MTX-FA is required, the dosage of MTX is unaltered if the patient's response to the first treatment was adequate. 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 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 Act-D is promptly substituted in patients with nonmetastatic and low-risk metastatic GTN. If the hCG values do not decline by 1 log after treatment with Act-D, the patient is also considered resistant to Act-D as a single agent. She must then be treated intensively with combination chemotherapy to achieve remission.
In the past, the preferred combination drug regimen at the NETDC was MAC III (triple therapy), which included MTX-FA, Act-D, and cyclophosphamide (Cytoxan, CTX) (59). However, triple therapy proved to be inadequate as an initial treatment in patients with metastases and a high-risk prognostic score. Data from the GOG, M. D. Anderson Hospital, and the NETDC indicated that triple therapy induced remission in only 21 (49%) of 43 patients with metastases and a high-risk score (score 7 or >) (60,61,62).
Table 15.13 EMA-CO Regimen for Patients With Gestational Trophoblastic Neoplasia
Etoposide was reported to induce complete remission in 56 (93%) of 60 patients with nonmetastatic and low-risk metastatic GTN (63). In 1984, Bagshawe (64) first described a new combination regimen that included etoposide, MTX, Act-D, Cytoxan, and vincristine (EMA-CO; Table 15.13), and reported an 83% remission in patients with metastases and a high-risk score. Bolis et al. confirmed that primary EMA-CO induced complete remission in 76% of the patients with metastatic GTN and a high-risk score (65). Bower et al. updated the data from Charing Cross Hospital and reported that EMA-CO induced complete remission in 130 of 151 patients (86.1%) with high-risk metastatic GTN (66). Furthermore, Newlands et al. reported remission using EMA-CO with intrathecal MTX in 30 of 35 patients (86%) with brain metastases (67).
The EMA-CO regimen is usually well tolerated, and treatment seldom has to be suspended because of toxicity, particularly with the judicious use of marrow stimulants. It is now the preferred primary treatment in patients with metastases and a high-risk prognostic score. If patients become resistant to EMA-CO, remission may still be achieved by substitutingetoposide and cisplatin for cyclophosphamide and vincristine on day 8 (66). The optimal combination drug protocol will most likely include etoposide, MTX, and Act-D and perhaps other agents, administered in the most dose-intensive manner. Vinblastine, bleomycin, and cisplatin also effectively induced remission in four of seven patients who were resistant to triple therapy (68). Other regimens that have exhibited activity in patients with resistant GTN include the three-drug doublet regimen consisting of paclitaxel, etoposide andcisplatin (TE/TO) (50), floxuridine (FUDR)-containing regimens (51), and 5FU/Act-D (52), as well as autologous marrow transplantation or stem cell rescue (53,54).
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 undertaken as consolidation therapy to reduce the risk of relapse.
Investigators have reported an increased risk of secondary tumors, including leukemia, colon cancer, melanoma, and breast cancer, in patients treated with chemotherapy for gestational trophoblastic tumors (69). The increased risk of secondary tumors has been attributed to the inclusion of etoposide in combination chemotherapy. The increased incidence of colon cancer, melanoma, and breast cancer was not apparent until more than 5, 10, and 25 years after therapy, respectively, and was limited to those patients who received a total dose of at least 2 gm/M2.
Pregnancies After Hydatidiform Mole
Patients with hydatidiform moles can anticipate normal reproduction in the future (70). From July 1, 1965 to December 31, 2007, patients who were treated at the NETDC for complete molar gestation had 1,337 subsequent pregnancies that resulted in 912 full-term live births (68.1%); 101 premature deliveries (7.6%); 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 pregnancies (18.3%). There were 41 therapeutic abortions (3.1%). Major and minor congenital malformations were detected in 40 of 1,020 infants (3.9%). Primary cesarean section was performed in 81 of 414 (19.6%) term or premature births from 1979 to 2007. Therefore, patients with a complete molar pregnancy should be reassured that they are at no increased risk of prenatal or intrapartum obstetric complications in later pregnancies. Although data concerning subsequent pregnancies after a partial mole were available for only 294 pregnancies, the data were similarly reassuring.
When a patient has had a hydatidiform mole, she is at increased risk of molar pregnancy in subsequent conceptions. Approximately 1 in 100 patients has at least two molar gestations. Some patients with repetitive molar pregnancies have a molar pregnancy with different male partners (71). Later molar pregnancies are characterized by worsening histologic type and increased risk of postmolar GTN. After two episodes of molar pregnancy, patients may still achieve a normal full-term gestation in a later pregnancy.
Therefore, for any subsequent pregnancy, the patient should have:
- A pelvic ultrasonogram during the first trimester to confirm normal gestational development
- An hCG measurement 6 weeks post-partum to exclude occult trophoblastic neoplasia
Pregnancies After Persistent Gestational Trophoblastic Neoplasia
Patients with GTN who are treated successfully with chemotherapy can expect normal reproduction in the future (70). Patients who were treated with chemotherapy at the NETDC from 1965 to 2007 reported 631 subsequent pregnancies that resulted in 422 term live births (66.9%); 42 premature deliveries (6.7%); 7 ectopic pregnancies (1.1%); 9 stillbirths (1.4%); and 9 repeat molar pregnancies (1.4%). First- and second-trimester spontaneous abortions occurred in 132 pregnancies (22.4%). There were 28 therapeutic abortions (4.4%). Major and minor congenital anomalies were detected in only 10 of 473 infants (2.1%). Primary cesarean section was performed in 81of 371 (21.8%) subsequent term and premature births from 1979 to 2007. It is particularly reassuring that the frequency of congenital malformations was not increased, although chemotherapeutic agents are known to have teratogenic and mutagenic potential.
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