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2. Staging, Classification and Treatment of Gestational Trophoblastic Disease Assoc. Prof. Gazi YILDIRIM, M.D. Yeditepe University, Medical Faculty Dept of Ob&Gyn

3. To define –Mol pregnancy –Malignant gestational trophoblastic tumors To learn –Management of GTN Objectives

4. Classification Histological classification Partial mole Complete mole Invasive mole Metastatic mole Choriocarcinoma Placental-site trophoblastlc tumour Epithelioid trophoblastic tumour Clinical classification of gestational trophoblastlc neoplasla Non-metastatic Metastatlc Low risk High risk

5. Types of GTD Benign Hydatidiform mole/molar pregnancy (complete or incomplete) Malignant Invasive mole Choriocarcinoma (chorioepithelioma) Placental site trophoblastic tumor

6. Hydatidiform mole

7. HYDATIDIFORM MOLE (MOLAR PREGNANCY) Histologically chorionic villi consist of trophoblastic proliferation and Edema of villous stroma Moles usually occupy the uterine cavity The absence or presence of a fetus or embryonic elements has been used to describe them as complete and partial moles

8. COMPLETE HYDATIDIFORM MOLE Chorionic villi transform into a mass of clear vesicles Vesicles vary in size The histological structure typically shows: 1. Hydropic degeneration and swelling of the villous stroma. 2. Absence of blood vessels in the swollen villi. 3. Proliferation of the trophoblastic epithelium to a varying degree 4. Absence of fetus and amnion.

9. Chromosomal composition in 85 percent of complete molar pregnancies is 46,XX, with both chromosomes being of paternal origin This phenomenon is termed androgenesis. Typically, the ovum has been fertilized by a haploid sperm, which then duplicates its own chromosomes after meiosis. The chromosomes of the ovum are either absent or inactivated. Occasionally, the chromosomal pattern in a complete mole may be 46,XY due to dispermic fertilization

10. Empty ovum Empty ovum 46XX 46XX or 46XY 23X or Y23X Complete Mole (46XX diploid) Complete Mole (46XX or 46XY, diploid) A single sperm fertilizes an empty ovum, with duplication of the 23X haploid set of chromosomes, giving rise to a homozygous diploid complete mole. Two sperms with two independent haploid sets of chromosomes fertilize an empty ovum, producing a dyspermic complete mole with either 46XX or 46XY karyotype. COMPLETE MOLE Modified from Cheung, 1995

14. PARTIAL HYDATIDIFORM MOLE Hydatidiform changes are focal and less advanced Some element of fetal tissue is seen There is slowly progressive swelling within the stroma of characteristically avascular chorionic villi Other vascular villi with a functioning fetal-placental circulation Karyotype typically is triploid 69,XXX, 69,XXY, or 69,XYY These are each composed of one maternal and two paternal haploid sets of chromosomes Nontriploid partial moles have been reported The nonviable fetus of a triploid partial mole typically has multiple malformations Abnormal growth is common 82 percent of fetuses had symmetrical growth restriction.

15. 23X Dyspermy 23X/23Y or 23X/23X 23Y Partial Mole (69XXY, or 69XXX, or 69XYY triploid) PARTIAL MOLE 23X 23Y 69XXY Fertilization of a normal 23X haploid ovum by two sperms, producing a triploid partial mole with either 69XXY, 69XXX or 69XYY karyotype Modified from Cheung, 1995

16. A twin gestation of a complete mole and a normal fetus and placenta is sometimes misdiagnosed as a diploid partial mole Twin pregnancies consisting of a normal fetus and a complete mole have a substantively increased risk of developing gestational trophoblastic neoplasia Generally, gestational trophoblastic neoplasia follows 20 percent of complete moles, whereas it develops in only 0.5 percent of women after a partial mole The risk of choriocarcinoma arising from a partial mole is also low

19. Fetal or embryonic tissueabsentpresent Hydatiform swelling of chorionic villiextensive focal Trophoblastic hyperplasiaextensive focal Scalloping of chorionic villiabsentpresent Trophoblastic stromal inclusionsabsentpresent Karyotype 46XX (90%);Triploid (69 XXY) 46XY (10%) Complete mole Partial mole Cohn DE, Herzog TJ. Curr Opin Oncol 2000 Sep; 12(5):492-6 FEATURES OF PARTIAL AND COMPLETE MOLE

20. INCIDENCE AND RISK FACTORS Hydatidiform mole develops in approximately 1 in 1000 pregnancies in the United States and Europe. Although it has been reported to be more frequent in other countries, especially in parts of Asia The role of gravidity, estrogen status, oral contraceptives, and dietary factors in the risk of gestational trophoblastic disease is unclear

21. Age. incidence of molar pregnancy highest in women aged 15 years or younger, and those aged 45years or older. In the latter group, the relative frequency of the lesion is at least 10 times greater than that at ages 20 to 40 years

22. Previous Mole. Women with molar pregnancies are at increased risk of developing either a complete or a partial mole in a future pregnancy Recurrent moles 1.3 percent Oocyte problem leads to molar development

23. CLINICAL COURSE. Bleeding. Vary from spotting to profuse hemorrhage. There may be considerable hemorrhage concealed within the uterus. Iron-deficiency anemia is common

24. Uterine Size. Growing uterus often enlarges more rapidly than usual Exceeding in about half of cases that expected from the gestational age. The uterus may be difficult to identify precisely by palpation because of its soft consistency. Fetal Activity. Typically no fetal heart motion is detected. There may be incomplete molar degeneration in the placenta accompanied by a living fetus.

25. Gestational Hypertension. Because hypertension caused by pregnancy is rarely seen before 24 weeks, preeclampsia that develops before this gestational age may be from hydatidiform mole or extensive molar degeneration. Hyperemesis. Significant nausea and vomiting may develop. Thyrotoxicosis. Plasma thyroxine levels in women with molar pregnancy are often elevated, but clinically apparent hyperthyroidism is unusual Hyperthyroidism is identified in about 2 percent. Serum free thyroxine is elevated as the consequence of the thyrotropin-like effect of hCG

26. Embolization. Variable amounts of trophoblastic cells escape from the uterus into the venous outflow at the time of molar evacuation The volume may be such as to produce signs and symptoms of acute pulmonary embolism or edema. This tissue can subsequently invade the pulmonary parenchyma to establish metastases.

27. DIAGNOSTIC FEATURES To summarize, the clinical and diagnostic features of a complete hydatidiform mole are: 1. Continuous or intermittent brown or bloody discharge evident by about 12 weeks and usually not profuse. 2. Uterine enlargement out of proportion to the duration of pregnancy in about half of the cases. 3. Absence of fetal parts and fetal heart motion. 4. Characteristic ultrasonographic appearance. 5. Serum hCG level higher than expected for the stage of gestation. 6. Preeclampsia-eclampsia developing before 24 weeks. 7. Hyperemesis gravidarum.

28. PROGNOSIS Mortality from molar pregnancies has been practically reduced to zero by prompt diagnosis and appropriate therapy. Earlier evacuation has not reduced the 20 percent risk for gestational trophoblastic neoplasia

29. TREATMENT Hydatidiform mole treatment consists of two phases. The first is immediate evacuation of the mole, The second is subsequent evaluation for persistent trophoblastic proliferation or malignant change. –Computed tomography or magnetic resonance imaging to evaluate the liver or brain is not performed routinely.

30. Prophylactic Chemotherapy. Controversial Toxicity from prophylactic chemotherapy may be significant Chemoprophylaxis may be considered in women with high-risk complete moles, particularly if serum hCG testing is unavailable or follow-up is impossible

31. Vacuum Aspiration. Treatment of choice for hydatidiform mole Cervical dilating agents may be necessary The cervix may be further dilated under anesthesia to a diameter sufficient to allow insertion of a suction curet. After most of the molar tissue has been removed by aspiration, oxytocin is given. Intraoperative ultrasonographic examination may help document that the uterine cavity has been emptied.

32. Oxytocin, Prostaglandins, and Hysterotomy. Labor induction rarely is used for evacuation of hydatidiform moles. Hysterectomy. If no further pregnancies are desired, hysterectomy may be preferred to suction curettage. Hysterectomy does not eliminate recurrent disease, it appreciably reduces likelihood

33. FOLLOW-UP EVALUATION OF MOLAR PREGNANCY 1. Prevent pregnancy for a minimum of 6 months using hormonal contraception. 2. Monitor serum hCG levels every 2 weeks. Serial measurement of serum hCG is important to detect trophoblastic neoplasia, 3. Chemotherapy is not indicated as long as these serum levels continue to regress. A rise or persistent plateau in the level demands evaluation for gestational trophoblastic neoplasia An increase signifies trophoblastic proliferation that is most likely malignant unless the woman is again pregnant. 4. Once the hCG level falls to a normal level, test the patient monthly for 6 months; then follow-up is discontinued and pregnancy allowed. Estrogen-progestin contraceptives or depot-medroxyprogesterone usually are used to prevent a subsequent pregnancy during the period of surveillance.

34. GESTATIONAL TROPHOBLASTIC NEOPLASIA Also called malignant gestational trophoblastic disease, Refers to –invasive mole, –choriocarcinoma, –placental site trophoblastic tumor. Any of these may follow molar pregnancy or normal pregnancy, or develop after abortive outcomes, including ectopic pregnancy.

35. ETIOLOGY Gestational trophoblastic neoplasia almost always develops with or follows some form of pregnancy. Approximately –50% of cases follow a hydatidiform mole, –25% follow an abortion, –25% percent develop after an apparently normal pregnancy.

36. PATHOLOGY The diagnosis of gestational trophoblastic neoplasia is made primarily by persistently elevated serum hCG levels.

37. Choriocarcinoma

38. Definition A malignant form of GTD which can develop from a hydatidiform mole or from placental trophoblast cells associated with a healthy fetus,an abortion or an ectopic pregnancy.

39. Characterized by abnormal trophoblastic hyperplasia and anaplasia, absence of chorionic villi Definition

40. Gross specimen of choriocarcinoma

41. Microscopic image of choriocarcinoma absence of chorionic villi

42. Common Sites for Metastatic Gestational Trophoblastic Tumors Site Per cent Lung60-95 Vagina40-50 Vulva/cervix10-15 Brain5-15 Liver5-15 Kidney0-5 Spleen0-5 Gastrointestinal0-5

43. Invasive mole

44. Definition This term is applied to a molar pregnancy in which molar villi grow into the myometrium or its blood vessels, and may extend into the broad ligament and metastasize to the lungs, the vagina or the vulva.

45. Invasive mole: the tissue invades into the myometrial layer. No obvious borderline, with obvious bleeding.

46. Invasive hydatidiform mole infiltrating the myometrium

47. Placenta Site Trophoblastic Tumor (PSTT)

48. Placenta Site Trophoblastic Tumor is an extremely rare tumor that arised from the placental implantation site Tumor cells infiltrate the myometrium and grow between smooth-muscle cells Definition

50. Placental Site Trophoblastic Tumor. Trophoblastic neoplasia arises from the placental implantation site following a normal term pregnancy, spontaneous or induced abortion, ectopic pregnancy, or molar pregnancy Histologically predominantly cytotrophoblastic cells, and immunohistochemical staining reveals many prolactin- producing cells and few gonadotropin-producing ones Thus, serum hCG levels may be normal to elevated. Bleeding is the main presenting symptom. hPL is high (human Placental Lactogen)

51. Surum hCG levels are relatively low compared to those seen with choriocarcinoma. Several reports have noted a benign behavior of this disease. They are relatively chemotherapy- resistant, and deaths from metastasis have occurred. Surgery has been the mainstay of treatment Dignosis and treatment of GTN

52. CLINICAL COURSE The most common finding is irregular bleeding associated with uterine subinvolution. The bleeding may be continuous or intermittent, with sudden and sometimes massive hemorrhage. Uterine perforation caused by invasive trophoblastic growth may cause intraperitoneal hemorrhage Metastatic lesion of the vagina or vulva Untreated, choriocarcinoma is invariably fatal.

53. Symptoms and signs Bleeding Infection Abdominal swelling Vaginal mass Lung symptoms Symptoms from other metastases

54. WHO Prognostic Scoring System Score Prognostic factor 0124 Age(years)≤39>39—— Pregnancy history Hydatidiform mole Abortion,ectopic Term pregnancy — Interval (months) of treatment <44-67-12>12 Initial hCG(mIU/ml) <10 3 10 3 -10 4 10 4 -10 5 >10 5 Largest tumor(cm) <33-5>5— Sites of metastasis LungSpleen, kidney kidney GI tract, liver Brain No. of metastasis —1-44-88 Previous (treatment) —— Single drug 2 or more 0-4 low risk, 5-7 intermediate risk, >8 high risk for death

55. FIGO Staging System for Gestational Trophoblastic Tumors StageDescription Ⅰ Limited to uterine corpus Ⅱ Extends to the adnexae, outside the uterus, but limited to the genital structures Ⅲ Extends to the lungs with or without genital tract Ⅳ All other metastatic sites

56. Substages assigned for each stage as follows: A: No risk factors present B: One risk factor C: Both risk factors Risk factors used to assign substages: 1. Pretherapy serum hCG > 100,000 mlU/ml 2. Duration of disease >6 months FIGO Staging System for Gestational Trophoblastic Tumors

58. IIb IIa

59. IIIa<3cm or locate in half lung IIIb disease beyond IIIa

61. Diagnosis and evaluation Gestational trophoblastic tumor is diagnosed by rising hCG following evacuation of a molar pregnancy or any pregnancy event Once the diagnosis established the further examinations should be done to determine the extent of disease ( X-ray, CT, MRI)

62. Treatment Nonmetastatic GTD Low-Risk Metastatic GTD High-Risk Metastatic GTD

63. Treatment of Nonmetastatic GTD Hysterectomy is advisable as initial treatment in patients with nonmetastatic GTD who no longer wish to preserve fertility This choice can reduce the number of course and shorter duration of chemotherapy. Adjusted single-agent chemotherapy at the time of operation is indicated to eradicate any occult metastases and reduce tumor dissemination.

64. Single-agent chemotherapy is the treatment of choice for patients wishing to preserve their fertility. Methotrexate(MTX) and Actinomycin-D are generally chemotherapy agents Treatment is continued until three consecutive normal hCG levels have been obtained and two courses have been given after the first normal hCG level. Treatment of Nonmetastatic GTD To prevent relapse or metastasis

65. Single-agent chemotherapy with MTX or actinomycin- D is the treatment for patients in this category If resistance to sequential single-agent chemotherapy develops, combination chemotherapy would be taken Approximately 10-15% of patients treated with single- agent chemotherapy will require combination chemotherapy with or without surgery to achieve remission Treatment of Low-Risk Metastatic GTD

66. Multiagent chemotherapy with or without adjuvant radiotherapy or surgery should be the initial treatment for patients with high-rist metastatic GTD EMA-CO regimen formula is good choice for high-rist metastatic GTD Adjusted surgeries such as removing foci of chemotherapy-resistant disease, controlling hemorrhage may be the one of treatment regimen Treatment of High-Risk Metastatic GTD

67. EMA-CO Chemotherapy for poor Prognostic Disease Etoposide(VP-16) 100mg/M 2 IV daily×2 days (over 30-45 minutes) Methotrexate 100mg/M 2 IV losding dose, then 200mg/M2 over 12 hours day 1 Actinomycin D 0.5mg IV daily×2 days Folinic acid 15mg IM or p.o. q 12 hours×4 starting 24 hours after starting methotrexate Cyclophosphamide 600mg/M 2 IV on day8 Oncovin (vincristine) 1mg/M 2 IV on day8 (Repeat every 15 days as toxicity permits)

68. Prognosis Cure rates should approach 100% in nonmetastatic and low-risk metastatic GTD Intensive multimodality therapy has resulted in cure rates of 80-90% in patients with high-risk metastatic GTD

69. Follow-up After Successful Treatment Quantitative serum hCG levels should be obtained monthly for 6 months, every two months for remainder of the first year, every 3 months during the second year Contraception should be maintained for at least 1 year after the completion of chemotherapy. Condom is the choice.

70. Placental Site Tumors. Hysterectomy is the most efficacious treatment for confirmed placental site trophoblastic tumor It is not necessary to remove the ovaries if they appear normal Although chemotherapy is recommended for metastatic disease, it is not as effective as for other gestational trophoblastic neoplasias

71. PREGNANCY AFTER GESTATIONAL TROPHOBLASTIC DISEASE Follow-up surveillance is minimally 6 months for molar pregnancy 1 year for gestational trophoblastic neoplasia Up to 2 years for cases with metastases other than to the lung. There is no difficulty with fertility or normal pregnancy outcome following Successfully treated gestational trophoblastic disease Women who have been given chemotherapy do not have an increased risk for anomalous fetuses in subsequent pregnancies The primary concern is that women who had gestational trophoblastic disease are at increased risk for developing it again in a subsequent pregnancy.