Gestational trophoblastic disease (GTD) refers to a group of diseases caused by abnormal proliferation of trophoblastic cells following pregnancy. It includes complete and partial moles, as well as invasive moles, gestational choriocarcinomas, and placental site trophoblastic tumors. Gestational trophoblastic neoplasia (GTN) specifically refers to invasive moles, choriocarcinomas, and placental site trophoblastic tumors that are malignant in nature. Treatment depends on the risk classification of the GTN as either low or high risk based on factors like metastasis, HCG levels, and tumor size.

1. Gestational trophoblastic disease (GTD)

2. Gestational trophoblastic disease (GTD) Group of diseases Abnormal proliferation of trophoblastic cells Following an antecedent pregnancy

3. Gestational trophoblastic disease (GTD) Molar pregnancies Invasive moles Gestational choriocarcinomas Placental-site trophoblastic tumors

4. Molar pregnancies Complete mole Partial mole

5. Comparison of partial & complete mole Abortion like, others rare USG Dx, large uterus, thecalutein cysts, pre-eclamsia, etc Clinical < 5% 20% Malignant sequelae Focal hydropic villi and trophoblastic proliferation fetal or fetal RBC present Diffuse hydropic villi and trophoblastic proliferation fetal absent pathology 69,xxx triploid (2 parternal) 46,xx (parternal) Cytogenetics Partial mole Complete mole Characteristics

6. Incidence Rare disease between 0.2-9.9 : 1000 pregnancies. Asia is 10 times higher than Europe and North America. about 1.87:1000 pregnancies in Vajira Hospital.

7. Risk factors Age Socioeconomic status Reproductive history (abortion, infertile) Race/ethnic Diet (carotene, fat) Previous molar pregnancy

8. Signs & Symptoms Pregnancy 1 st  Vaginal bleeding (97%) Passage of hydropic villi. Anemia Excessive uterine size. Medical condition: Pre-eclampsia, Hyper-emesis hyperthyroidism, Resp. insufficiency. Present of theca lutein cyst.

9. Diagnosis USG vesicular sonographic pattern, (snow storm). Focal cystic change in placenta. A ratio of transverse and A-P dimension >1.5. hCG Markedly elevated (>100,000 mIU/ml in 40%).

10. Differential Diagnosis Abortion with hydropic degeneration Missed abortion Incomplete abortion Pregnancy with other complication: twins, wrong date, other ovarian tumor, etc. Choriocarcinoma

11. Management Evaluation & Stabilization Evacuation Follow up and Close monitoring of hCG

12. Evaluation & Stabilization Complete history and physical examination. Investigation: hCG, CBC, BUN, Cr, LFT, thyroid function tests pelvic USG, CXR Stabilized hemodynamic and complication.

13. Evacuation Suction curettage Dilatation & curettage (D/C) Hysterotomy Hysterectomy

14. Complication Theca lutein cysts: pain, torsion, rupture, bleeding. Respiratory distress syndrome. Hyperthyroidism. Uterine perforation.

15. Follow up Clinical-physical examination. Serum hCG 24-48 hr. after evacuation q 1 wk. until normal for 3 times. q 1 mo. until 6-12 mo. Other investigations as indicated. Contraception 6-12 mos. (OC, condom).

16. Risk factors for GTT Age > 40 yrs. Pre-evacuation hCG > 100,000 mIU/ml. Uterine size greater than GA. Theca lutein cysts > 6 cm. or bilateral cysts. Medical complication. RDS post evacuation.

17. Subsequence pregnancy Recurrent rate 1-2% (15-30% after 2 nd mole) Not increase in adverse pregnancy outcome. Recommend early ANC and 1 st  USG. Send placenta or conceptive products for histology. hCG 6 week post-partum.

18. Gestational trophoblastic neoplasia (GTN) Synonyms: gestational trophoblastic tumor (GTT), malignant GTD, persistent GTD, etc. Include invasive mole, choriocarcinoma, placental site trophoblastic tumor. Histologic present is invasive trophoblastic proliferation with or without villi. Histologic Diagnosis is not necessary before Rx. 45% present with metastatic disease.

19. Hormonal criteria Four values or more of plateaued hCG ( ± 10%) over at least 3 wks. Rising of hCG > 10% for 3 Values or more over at least 2 wks. The histologic diagnosis of choriocarcinoma. Persistence of hCG beyond 6 mos. or more.

20. Pre-therapy evaluation Assessment of clinical risk factors. Physical examination include PV Laboratory evaluation: hematologic test, basic chemistry test, hCG Radiographic survey: CXR or CT chest, USG or CT Abdomen, CT or MRI brain.

21. Clinical risk fartors Age Type of antecedent pregnancy Interval from antecedent pregnancy Previous treatment

22. Common metastatic sites Lung 80% Vagina 30% Liver 10% Brain 10% Other : GI, kidney, lymph node, etc. * Liver and brain metastasis are rarely if no lung or vaginal metastasis.*

23. FIGO stage (2000) Anatomical stage All other metastatic sites. IV Disease extend to lung with or without genital tract involvement. III Disease extend outside uterus, but limited to genital structures. II Disease confined to the uterus. I

24. FIGO stage (2000) Risk score (modified WHO) Two or more Single - - Previous failed chemotherapy >8 5-8 1-4 - Number of metastasis Liver, brain Gastro-intestinal Spleen, kidney Lung Site of metastasis - ≥ 5 3-<5 <3 Largest tumor size (cm) ≥ 10 5 10 4 -<10 5 10 3 -<10 4 <10 3 Pre-treatment hCG (IU/l) ≥ 13 7-<13 4-<7 <4 Interval from index preg. (mos) Term Abortion Mole Antecedent pregnancy - - ≥ 40 <40 Age (yrs) 4 2 1 0 score

25. FIGO stage (2000) Write stage:score such as stage II:4, stage IV:9 Minimum score = 0, maximum score = 25 Low risk group score < 7 High risk group score ≥ 7

26. Clinical classification for GTN Non-metastatic GTN Metastatic GTN Good prognosis Poor prognosis

27. Prognosis for metastatic GTN Good prognosis Duration < 4 mos. hCG < 40,000 mIU/ml No antecedent term preg. No brain or liver metastasis. No prior chemotherapy. Poor prognosis Duration ≥ 4 mos. hCG ≥ 40,000 mIU/ml. Antecedent term preg. Brain or liver metastasis. Prior chemotherapy.

28. Management of GTN

29. Low risk GTN Single agent chemotherapy most common MTX, actinomycin D. Hysterectomy if complete family. One additional dose after negative hCG. Resistant to one drug can shift to another single agent. 2.5-4% recurrence, mostly in 18 mos.

30. Single drug regimen 14 200 mg/m 2 oral x 5 days Etoposide - 30 mg/kg/d continuous 10 day infusion 5 FU 14 -10 µg/kg IV x 5 days -1.25 mg/m 2 IV Actinomycin D 14 7-14 - 1 mg/kg day 1,3,5,7 with folinic acid 0.1 mg/kg day 2,4,6,8 - 20-25 mg (0.4 mg/kg) IM x 5 days MTX Duration (days) Dose Drug

31. Criteria for drug resistance hCG plateaus with three weekly measurements. hCG rising ≥ 10% in two consecutive measurements. Evidence of new metastasis.

32. High risk GTN 5 yrs. survival nearly 90%. Initial treatment is multi-drug regimen: EMA-CO, MAC, MAC III, CHAMOCA Treatment continued 2-3 cycle after negative hCG for 3 wks. Radiotherapy for brain or liver metastasis.

33. High risk GTN Surgical resection if indicated (single lesion, resistant nodule). Salvage therapy: EMA-EP, ICE, BEP. Common causes of death are hemorrhage and pulmonary insufficiency.

34. Follow up for GTN Clinical evaluation. hCG measurement weekly until normal x 3 wks. Monthly until normal x 12-24 mos. Investigation as indicated. Contraception if remain fertility.