Gestational Trophoblastic Diseases PDF

GESTATİONAL TROPHOBLASTİC DİSEASES ZIYA KALEM,MD ISTINYE UNIVERSITY FACULTY OF MEDICINE 1- Hydatidiform moles (complete and partial) 2- Gestational trophoblastic neoplasia Invasive moles Choriocarcinomas Placental-site trophoblastic tumors (PSTTs) ...

GESTATİONAL TROPHOBLASTİC DİSEASES ZIYA KALEM,MD ISTINYE UNIVERSITY FACULTY OF MEDICINE 1- Hydatidiform moles (complete and partial) 2- Gestational trophoblastic neoplasia Invasive moles Choriocarcinomas Placental-site trophoblastic tumors (PSTTs)  DIAGNOSIS Uterine bleeding in first trimester Vaginal expulsion of vesicles Absence of fetal heart tones and Hyperemesis gravidarum fetal structures Thecalutein cysts Rapid enlargement of the uterus or uterine size greater than anticipated Onset of preeclampsia in the by dates first trimester Human chorionic gonadotropin titers greater than expected for gestational age Hydatidiform moles and Gestational trophoblastic neoplasia (Invasive moles, Choriocarcinomas) are derived from syncytiotrophoblastic and cytotrophoblastic cells Placental-site trophoblastic tumors (PSTTs) is derived from intermediate trophoblastic cells. Women with a single previous molar pregnancy have more than 10 times the risk of having another molar pregnancy compared with those who have never had one.  Hydatidiform Mole Hydatidiform mole is the most common form of gestational trophoblastic disease and is benign in nature. Its incidence varies from 1/125 to 1/1500 It is bening in nature Risk Faktors Women younger than 20 and older than 40 years of age Nulliparous women Low socio- economic status Women whose diets are deficient in protein, folic acid, and beta-carotene Blood group A women impregnated by group 0 men have an almost10-fold greater risk of subsequently developing gestational trophoblastic neoplasia Two distinct forms of hydatidiform mole exist: Complete moles , Partial moles. Complete moles are usually euploid, paternal in origin, and sex chromatin positive-- -46,XX or 46,XY. They arise when an empty ovum (with an absent or inactivated nucleus) is fertilized by a haploid sperm that duplicates its chromosomes or by 2 haploid sperm. A partial mole, on the other hand, is triploid 69,XXY (70%), 69,XXX (27%), or 69, XYY (3%),arising when an ovum with an active nucleus is fertilized by a duplicated sperm or 2 haploid sperm. Grossly, a hydatidiform mole is characterized by multiple grapelike vesicles filling and distending the uterus, usually in the absence of an intact fetus. Despite the cytogenetic, pathologic, and clinical differences ,the clinical management of patients with CMs and PMs is similar.  Microscopically, moles may be identified by 3 classic findings: Edema of the villous stroma Avascular villi Nests of proliferating trophoblastic elements surrounding villi  Invasive Mole Invazive mole is reported in 10-15% of patients who have had a hydatidiform mole. Although considered a benign neoplasm, it is locally invasive and invades the myometrium and adjacent structures. It has the potential to completely penetrate the myometrium and cause subsequent uterine rupture and hemoperitoneum. It also has the ability to spontaneously regress.  Choriocarcinoma It is reported in 2-5% of all cases of gestational trophoblastic neoplasia The incidence in the United States is 1 in 40,000 pregnancies It may accompany or follow any type of pregnancy In half of choriocarcinoma cases, the antecedent gestational event is a hydatidiform m Another 25% follow a term pregnancy, and the remaining 25% occur after an abortion. Choriocarcinoma is a pure epithelial tumor composed of syncytiotrophoblastic and cytotrophoblastic cells. It usually presents as late vaginal bleeding in the postpartum period. An enlarged uterus, enlarged ovaries, and vaginal lesions may be noted during the physical examination. Histologic evaluation of the tumor discloses sheets or foci of trophoblasts on a background of hemorrhage and necrosis, but no villi  Histologic evaluation of the tumor discloses sheets or foci of trophoblasts on a background of hemorrhage and necrosis, but no villi  Placental-Site Trophoblastic Tumor PSTT may arise months to years after a hydatidiform mole or, less commonly, following a normal term pregnancy. The tumor is generally confined to the uterus. but local invasion may occur into the myometrium, lymphatica, or vasculature. PSTT is derived from the intermediate trophoblasts of the placental bed, with minimal or absent syncytiotrophoblastic tissue. As syncytiotrophoblastic cells are generally absent from this tumor, minimal amounts of hCG are released in relation to the tumor burden. Human placental lactogen is secreted, and its levels can be monitored to follow response to therapy  Symptoms Abnormal uterine bleeding is the most common presenting symptom (occurring in > 90% of patients with molar pregnancies ) Ten percent of these patients may have nausea and vomiting severe enough to require hospitalization About half of patients will have a uterine size that is greater than expected for their gestational age Multiple theca lutein cysts causing enlargement of 1 or both ovaries are seen in 15 -30% of women with molar pregnancies Preeclampsia in the first trimester or early second has been said to be pathognomonic for a molar pregnancy. Hyperthyroidism from stimulation of thyrotropin receptors by hCG can also occur in 10% of patients Laboratory Findings The principal characteristic of gestational trophoblastic neoplasms is their capacity to produce hCG Monitoring of hCG levels is a necessary tool for the diagnosis, treatment and surveillance of the disease process. In most instances, the hCG values exhibit a progressive decline to nondetectable levels within 14 weeks after evacuation of a molar pregnancy. (If the hCG titer rises or plateaus, it must be concluded that viable tumor continues to persist).  Ultrasonographic Findings The characteristic ultrasound pattern consists of multiple hypoechoic areas corresponding to hydropic villi (described as a "snowstorm" pattern ) A normal gestational sac or fetus is not present. Theca lutein cysts may be visualized. In a partial mole, focal areas of trophoblastic changes and fetal tissue may be noted. An ultrasonogram of a choriocarcinoma may reveal an enlarged uterus with a necrotic and hemorrhagic pattern. PSTT may show an intrauterine mass  Differential Diagnosis Normal pregnancy Abortion Ectopic pregnancy Ultrasonograpby is a useful tool, Quantitative hCG level improve the accuracy of the diagnosis. Analysis of tissue obtained from a dilatation and evacuation for histology and DNA content will prove invaluable. Complications Deportation of traphoblastic tissue to the lung can give rise to pulmonary insufficiency Symptoms of dyspnea and cyanosis, due to massive deportation of trophoblasts to the pulmonary vasculature and subsequent formation of pulmonary emboli can present within 4-6 hours after evacuation of a molar pregnancy. Spontaneous regression of these ectopic trophoblastic tissues can occur.  Treatment A.Hydatidiform Mole Evacuation: Blood type,hematocrit, and thyroid liver and renal function tests should be obtained. A chest radiograph can rule out metastasis to the lungs Suction curettage under general anesthesia is the method of choice , Intravenous oxytocin should be administered after dilation of the cervix After the completion of the evacuation, all Rh-negative patients should receive Rh immune globulin. Hysterectomy continues to remain an option for good surgical candidates not desirous of future pregnancy and for older women (who are more likely to develop malignant sequelae) Prophylactic chemoterapy Controversy surrounds the use of prophylactic chemotherapy (with methotraxate or dactinomycin) after a complete molar pregnancy. Surveillance Three-fourths of patients with malignant nonmetastatic trophoblastic disease and half of patients with malignant metastatic disease develop these tumors following a hydatidiform mole. In the remainder, disease arises subsequent to a term pregnancy, abortion, or ectopic pregnancy. The larger the uterus and the higher the hCG titer, the greater the risk for malignant gestational trophoblastic disease. Regardless of the method of termination (suction curettage or hysterectomy) or presence of high-risk features, close monitoring with serial hCG titers is essential for every patient, as the incidence of malignant sequelae approaches 20-30%. After evacuation of the molar pregnancy, the patient should undergo serial hCG determinations, beginning within 48 hours after evacuation and then at weekly intervals until hCG values decline to undetectable levels (< 5 m.IU/mL) on 3 successive assays. Then hCG measurement should be repeated monthly for at least 6 months to 1 year before the patient is released from close medical supervision. 80.7% of patients may have spontaneous regression of hCG values to normal 19% of patients need to be treated with chemotherapy because of rising or plateauing hCG levels. Therapy for persistent gestational trophoblastic neoplasia after evacuation of a hydatidiform mole is usually instituted because of an abnormal hCG regression curve. Although the hCG titer usually returns to normal by 1-2 weeks after evacuation of a hydatidiform mole, it should normalize in most women by the eighth week. Approximately 70% of patients achieve a normal hCG level within 8 weeks of evacuation. If hCG levels plateau or increase after 8 weeks of evacuation, chemoterapy should be considered.  Abnormal Human Chorionic Gonadotropin Assays “Phantom” Human Chorionic Gonadotropin “Phantom” hCG may also present after evacuation of a hydatidiform mole or following a clearly defined pregnancy event, such as an ectopic pregnancy. It should be suspected if hCG values plateau at low levels and do not respond to therapeutic maneuvers such as methotrexate. Most patients with “phantom” hCG present with low-level hCG elevations, but occasionally values as high as 200 to 300 mIU/mL have been recorded. The false-positive hCG values result from nonspecific heterophile antibodies that interfere with the hCG immunometric sandwich assays Heterophile antibodies are not excreted in the urine. Therefore, if they are the cause of serum hCG level elevation, urinary hCG values will not be detectable. The “Hook Effect” Instead of being a false-positive test such as a phantom hCG due to heterophile antibodies, the “hook effect” causes a false- negative or low hCG value in the presence of extremely elevated hCG levels. The “hook effect” can be overcome by serial dilution of the serum prior to using an hCG immunoassay B.Malignant Gestational Trophoblastic Neoplasia Malignant GTN occurs in 2.5% to 5% of patients with PM compared with ap- proximately 6.8% to more than 20% after evacuation of a CM mole Malignant gestational trophoblastic neoplasia may be diagnosed in the setting of (1) A rise in hCG levels of 10% or greater for > 3 values over 2 weeks (2) A plateau (< 10% reduction in >4 hCG values) over 3 successive weeks (3) hCG levels elevated at 6 months postevacuation (4) A tissue diagnosis of choriocarcinoma. Chest radiograph Chest computed tomography Ultrasonography (for pelvic or liver metastases) Brain metastases are best evaluated with a CT scan or magnetic resonance For women with gestational trophoblastic neoplasia who have no evidence of metastatic disease on imaging but have elevated hCG, a second uterine curettage may be of benefit, if not remaining women require single-agent chemotherapy. 1.Nonmetastatic malignant gestational trophoblastic disease Trophoblastlc disease confined to the uterus is the most common malignant lesion seen in gestational trophoblastic neoplasla. The diagnosis is usually made during the postmolar surveillance period. Therapy for patients with nonmetastatic malignant trophoblastic disease includes (1) Single-agent chemotherapy (2) Combination chemotherapy and hysterectomy, with surgery performed on the third day of drug therapy for patient who do not wish to preserve reproductive function. 2. Metastatic gestational trophoblastic disease Treatment in metastatic disease uses either single-agent chemotherapy or multiagent chemotherapy in cases in which resistance to a single agent is anticipated. W H O scoring system, in which patients are categorized into low- or high-risk groups based on risk factors , is used in determining low and high risk group Age Type of antecedent pregnancy, Interval from antecedent pregnancy to initiation of chemotherapy, Pretreatment hCG level Size of tumor Site of metastases Number of metastases Prior chemotherapy A total score of 0-6 is considered low risk and a total score > 7 is categorized as high risk. LOW-RISK PATIENT Patients can be expected to respond satisfactorily to single-agent chemotherapy if; (1) Metastases are confined to the lungs or pelvis, (2) Serum hCG levels are below 40,000 mIU/mL at the onset of treatment, (3) Therapy is started within 4 months of apparent onset of disease. The most common site of metastasis in gestational trophoblastic disease is the lungs In low-risk patients, single-agent chemotherapy with methotrexate or dactinomycin is considered the therapy of choice Failure of drug therapy does occur in 10% of cases HIGH-RISK (1) Serum hCG titers > 40,000 mIU/mL at the onset of treatment (2) Diagnosis of disease >4 months after molar pregnancy (3) Brain or liver metastases (4) Prior unsuccessful chemotherapy (5) Onset after term gestation. These patients respond poorly (< 40% response rate) to single-agent therapy. Central nervous system involvement, particularly brain metastases with focal neurologic signs, commonly occurs with choriocarcinoma. Because patients with brain or liver metastases are at high risk of sudden death from hemorrhagic lesions, it is standard practice to institute whole-brain or whole- liver irradiation concomitantly with combination chemotherapy Currently, etoposide, methotrexate, dactinomycin, cyclophosphamide, and vincristine (EMACO) chemotherapy repeated every 2 weeks provides the best response rate (approximately 80%) with the lowest side effect profile Treatment of malignant trophoblastic disease must be continued with repeated courses of combination chemotherapy until hCG titers return to undetectable levels (< 5 mIU/mL). 3. Placental-site trophoblastic tumor Because treatment of PSTT is generally resistant to chemotherapy, hysterectomy is the recommended route of treatment Partial uterine resection involving the tumor is possible if the patient desires future fertility. Chemotherapy is indicated in cases of metastatic disease. EMA-EP is the preferred regimen over EMACO  Surgery The emergence of effective chemotherapy has lessened the importance of surgical procedures for primary management of malignant GTN. However, many procedures remain useful adjuncts when integrated into the management of these patients. Primary or delayed hysterectomy can be integrated into management to remove central disease, and surgical extirpation of metastases may cure highly selected patients with drug-resistant disease. The most frequently used surgical procedure for removal of extrauterine metastases is thoracotomy with pulmonary wedge resection.