This chapter deals primarily with APGO Educational Topic Area:
TOPIC 50 GESTATIONAL TROPHOBLASTIC NEOPLASIA
Students should be able to outline a basic approach to diagnosis, management, and follow-up of patients with gestational trophoblastic neoplasia (GTN). They should identify risk factors, common presenting signs and symptoms, and physical examination findings. They should be able to contrast molar pregnancy and malignant GTN.
Clinical Case
A 27-year-old G1 presents to you with vaginal bleeding. She is 8 weeks pregnant based on her last menstrual period. She states that she is also having severe nausea and vomiting. You perform an ultrasound, which demonstrates a snowstorm pattern and no fetus in the uterus.
Gestational trophoblastic neoplasia (GTN) is a rare variation of pregnancy of unknown etiology and usually presents as a benign disease called hydatidiform mole (molar pregnancy). GTN is a clinical spectrum that includes all neoplasms that derive from abnormal placental (trophoblastic) proliferation. There are two varieties of molar pregnancies, complete mole (no fetus) and incomplete mole (fetal parts in addition to molar degeneration). Persistentor malignant disease will develop in approximately 20% of patients with molar pregnancy. Persistent or malignant GTN is responsive to chemotherapy.
Key clinical features of GTN include 1) clinical presentation as pregnancy; 2) reliable means of diagnosis by pathognomonic ultrasound findings; and 3) a specific tumor marker, human chorionic gonadotropin (hCG). Persistent GTN may occur with any pregnancy, although it most commonly follows molar pregnancy.
EPIDEMIOLOGY
The incidence of molar pregnancy varies among different national and ethnic groups. The highest incidence occurs among Asian women living in Asia (1 in 200 pregnancies). The incidence in the United States is approximately 1 in 1,500 pregnancies, with a recurrence rate of 1% to 2%. The risk of GTN is increased in women over age 35 years and under age 20 years, although the incidence is higher in women in between these age ranges because pregnancy is more common at these ages. It is associated with low dietary carotene consumption and vitamin A deficiency. Partial moles are associated with a history of infertility and spontaneous abortion.
HYDATIDIFORM MOLE
A hydatidiform mole includes abnormal proliferation of the syncytiotrophoblast and replacement of normal placental trophoblastic tissue by hydropic placental villi. Complete moles do not have identifiable embryonic or fetal structures. Partial moles are characterized by focal trophoblastic proliferation, degeneration of the placenta, and identifiable fetal or embryonic structures.
The genetic constitutions of the two types of molar pregnancy are different (Table 45.1). Complete moles have chromosomes entirely of paternal origin as the result of the fertilization of a blighted ovum by a haploid sperm that reduplicates or, rarely, fertilization of a blighted ovum with two sperm. The karyotype of a complete mole is usually 46XX. The fetus of a partial mole is usually a triploid. This consists of one haploid set of maternal chromosomes and two haploid sets of paternal chromosomes, the consequence of dispermic fertilization of a normal ovum. Complete moles are more common than partial moles and are more likely to undergo malignant transformation.
Clinical Presentation
Patients with molar pregnancy have findings consistent with a confirmed pregnancy as well as uterine size and date discrepancy, exaggerated subjective symptoms of pregnancy, and painless second-trimester bleeding. With the increased early prevalence of first-trimester ultrasound, moles are now frequently diagnosed in the first trimester of pregnancy before symptoms are present. Abnormal bleeding is the most characteristic presenting symptom which prompts evaluation for threatened abortion. Lack of fetal heart tones detected at the first obstetric appointment can also prompt evaluation (depending on the estimated gestational age). Ultrasound imaging confirms the diagnosis of molar pregnancy by its characteristic “snowstorm” appearance and absence of fetal parts (complete mole) as shown in Figure 45.1. In cases of partial mole, ultrasonography reveals an abnormally formed fetus (Fig. 45.2). Quantitative hCG levels are excessively elevated for gestational age, and the uterus is usually larger than expected.
BOX 45.1 Classification of Gestational Trophoblastic Neoplasia
Hydatidiform mole (primary nonmalignant nonmetastatic disease)
Complete mole
Partial mole
Malignant gestational trophoblastic neoplasia (GTN)
Persistent nonmetastatic GTN
Metastatic GTN
Good-prognosis metastatic disease
Poor-prognosis metastatic disease
Placental site tumors (malignant, usually nonmetastatic)
FIGURE 45.1. “Snowstorm” appearance of complete mole on ultrasound examination. The arrow points to intrauterine tissue. (From Soper JT. Gestational trophoblastic disease. Obstet Gynecol. 2006;108(1):178.)
FIGURE 45.2. Hydropic villi of partial mole on ultrasound examination. Arrows point to variable and focal villous edema. (Courtesy of Eric Blackwell, M.D.)
Molar pregnancies may present with other signs and symptoms, including severe nausea and vomiting; marked gestational hypertension; proteinuria; and, rarely, clinical hyperthyroidism. Most of these findings can be attributed to the high levels of hCG produced by the abnormal pregnancy. Some patients experience tachycardia and shortness of breath, arising from intense hemodynamic changes associated with acute hypertensive crisis. In these patients, physical examination reveals not only the date and size discrepancy of the uterine fundus and absent fetal heart tones but also changes associated with developing severe hypertension such as hyperreflexia. Bimanual pelvic examination may reveal large adnexal masses (theca lutein cysts; see Chapter 50), which represent marked enlargement of the ovaries secondary to hCG stimulation.
With earlier diagnosis, the medical complications of molar pregnancy are becoming less common. In any woman who presents with findings suggestive of severe hypertension prior to 20 weeks in pregnancy, a molar pregnancy should be immediately suspected.
Twin pregnancies with a normal fetus coexisting with a complete or partial mole are exceedingly rare. Women with these pregnancies should be treated in a tertiary hospital center with specialized care. Medical complications in molar twin gestations rarely allow these pregnancies to reach term. These pregnancies also have a higher risk of persistent metastatic or nonmetastatic GTN.
Whereas both partial and complete molar pregnancies present as abnormal pregnancies, partial mole most often presents as a missed abortion. Vaginal bleeding is less common in partial molar pregnancy than in complete molar pregnancy. Uterine growth is less than expected for the gestational age in partial molar pregnancy. Ultrasound reveals molar degeneration of the placenta and a grossly abnormal fetus or embryo. Medical complications, theca lutein cysts, and subsequent malignancies are rare (see Table 45.1).
BOX 45.2 Preoperative Evaluation of Molar Pregnancy
1. Baseline quantitative human chorionic gonadotropin level
2. Baseline chest x-ray to check for metastatic disease
3. Complete blood count
4. Blood type with type and screen
5. Clotting function studies
6. Other appropriate tests if clinical evidence of hyperthyroidism and/or gestational hypertension
Treatment
In most cases of molar pregnancy, the definitive treatment is prompt evacuation of the uterine contents. Uterine evacuation is done most often by dilation of the cervix and suction curettage followed by gentle sharp curettage. Because the evacuation of larger moles is sometimes associated with uterine atony and excessive blood loss, appropriate preparations should be made for uterotonic administration and blood transfusion, if needed. In rare cases of a late presenting partial molar pregnancy, there may be an additional need for larger grasping instruments to remove the abnormal fetus. In general, the larger the uterus, the greater the risk of pulmonary complications associated with trophoblastic emboli, fluid overload, and anemia.
This is particularly true in patients with severe associated gestational hypertension, who may experience concomitant hemoconcentration and alteration in vascular hemodynamics (see the section on preeclampsia in Chapter 22). Hysterectomy or induction of labor with prostaglandins is not usually recommended, because of the increased risk of blood loss and other sequelae. The bilaterally enlarged multicystic ovaries (theca lutein cysts) resulting from follicular stimulation by high levels of circulating hCG do not represent malignant changes. The theca lutein cysts invariably regress within a few months of evacuation and, therefore, do not require surgical removal.
Patients who have no interest in further childbearing or have other indications for hysterectomy may be treated by hysterectomy with ovarian preservation. Despite removal of the entire primary neoplasm, the risk of persistent GTN is 3% to 5%.
Postevacuation Management
Because of the predisposition for recurrence, patients should be monitored closely for 6 to 12 months after the evacuation of a molar pregnancy. Rh-negative patients should be given Rh immunoglobulin. Follow-up consists of periodic physical examination to check for vaginal metastasis and appropriate involution of pelvic structures. Quantitative hCG levels should be checked within 48 hours following evacuation, every 1 to 2 weeks while elevated, and at 1 to 2 months thereafter. Quantitative hCG levels that rise or reach a plateau are an indication of persistent disease and the need for further treatment after a new pregnancy has been ruled out. During the first year, the patient should be treated with a reliable contraceptive method to prevent an intercurrent pregnancy. Multiple studies have proven the safety of oral contraceptive use after a molar pregnancy. The risk of recurrence after 1 year of remission is <1%. The risk of recurrence with subsequent pregnancies is 1% to 2%. There is no increase in congenital anomalies or complications in future pregnancies.
MALIGNANT GESTATIONAL TROPHOBLASTIC NEOPLASIA
Postmolar or persistent GTN is often diagnosed when hCG levels do not fall appropriately after a molar pregnancy but can also occur after a normal pregnancy. This disease can be localized or widespread (metastatic). An invasive mole, a localized form, is histologically identical to a complete mole. It invades the myometrium without any intervening endometrial stroma seen on histological sample. Occasionally, it may be diagnosed on curettage at the time of initial molar evacuation.
Although invasive moles are histologically identical to antecedent molar pregnancies while invading the myometrium, choriocarcinomas are a malignant transformation of trophoblastic tissue. Instead of hydropic chorionic villi, the tumor has a red, granular appearance on cut section and consists of intermingled syncytiotrophoblastic and cytotrophoblastic elements with many abnormal cellular forms. Clinically, choriocarcinomas are characterized by rapid myometrial and uterine vessel invasion and systemic metastases resulting from hematogenous embolization. Lung, vagina, central nervous system, kidney, and liver are common metastatic locations. Choriocarcinoma may follow a molar pregnancy, normal-term pregnancy, abortion, or ectopic pregnancy. In the United States, choriocarcinoma is associated with approximately 1 in 150,000 pregnancies, 1 in 15,000 abortions, 1 in 5,000 ectopic pregnancies, and 1 in 40 molar pregnancies.
Treatment
Early identification and treatment are important. Abnormal bleeding for more than 6 weeks after any pregnancy should be evaluated with hCG testing to exclude a new pregnancy or GTN. Failure of quantitative hCG levels to regress after treatment of a molar pregnancy suggests that further treatment is needed. Identified metastatic sites should not be biopsied to avoid bleeding complications. Most GTN, including malignant forms, are highly sensitive to chemotherapy, which often results in a cure, allowing for future reproduction.
Nonmetastatic persistent GTN is completely treated by single-agent chemotherapy. Single-agent chemotherapy is either methotrexate or actinomycin D. The prognosis for metastatic GTN is more complex, divided into good and poor prognostic categories (Table 45.2). The World Health Organization has developed a prognostic scoring system for GTN that includes a number of epidemiologic and laboratory findings; this system was later combined into the International Federation of Gynecology and Obstetrics (FIGO) staging system (Table 45.3). A FIGO score of 7 or above classifies metastatic GTN as high risk, requiring multiagent chemotherapy. The combination chemotherapeutic regimen with the highest success rate is called EMACO, which stands for etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine (Oncovin). Adjunctive radiotherapy is sometimes performed with patients who have brain or liver metastasis. Surgery may be necessary to control hemorrhage, remove chemotherapy-resistant disease, and treat other complications to stabilize high-risk patients during intensive chemotherapy. The 5-year survival rate for nonmetastatic and good-prognosis disease approaches 100%. The 5-year survival rate for poorprognosis metastatic disease is 80%.
Placental Site Tumors
Placental site tumor is a rare form of trophoblastic disease. The tumor is composed of monomorphic populations of intermediate cytotrophoblastic cells that are locally invasive at the site of placental implantation. The tumor only secretes small amounts of hCG and can be better followed by human placental lactogen levels. This tumor is rarely metastatic and is much more resistant to standard chemotherapy. Hysterectomy as initial therapy is often curative.
Clinical Follow-Up
You diagnose her with a complete mole and plan a dilation and curettage. You have uterotonics on hand. She recovers well from this procedure and sees you regularly for quantitative beta human chorionic gonadotropin levels for a full 12 months. One year later, you clear her, and she conceives again in 18 months. She is carefully monitored throughout the pregnancy and ultimately delivers a healthy baby at term.
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