1. Gestational Trophoblastic Disease (GTD) MAJOR NABILA AMIN ASSISTANT PROFESSOR CONSULTANT GYNAECOLOGIST CMH RAWALPINDI

2. GTD Overview Heterogeneous group of related lesions Arise from abnormal proliferation of trophoblast of the placenta Unique because the maternal lesions arise from fetal (not maternal) tissue Most GTD lesions produce the beta subunit of human chorionic gonadotropin (B-hCG)

3. Overview Hydatidiform Mole: Complete Partial ** Benign Gestational Trophoblastic Neoplasia (GTN): Persistent/Invasive Mole Choriocarcinoma Placental-Site Trophoblastic Tumor (PSTT) ** Malignant

4. Hydatidiform Mole North America: 0.6-1.1 per 1000 pregnancies Asia: 2-10 per 1000 (3x Western countries) Difference possibly related low dietary intake of carotene (vitamin A deficiency) and animal fat More common at reproductive extremes in age (>35y or <20y)

5. Hydatidiform Mole Risk Factors: History of previous GTD –If one previous mole, 1% chance of recurrence (vs. 0.1% in general population) –If 2 previous moles, risk of recurrence increases to 16-28% Smoking Vitamin A deficiency

6. Hydatidiform Mole Clinical Manifestations: Vaginal bleeding/anemia Enlarged uterus (size > dates) Pelvic pain Theca lutein cysts Hyperemesis gravidarum Hyperthyroidism Preeclampsia <20 weeks gestation Vaginal passage of hydropic vesicles

10. Hydatidiform Mole Treatment Evaluate for coexisting conditions: - History and physical - CBC, coagulation profile, serum chemistry - thyroid function - blood type and crossmatch - chest radiography - pelvic ultrasonography Evacuation of mole - Suction curettage - Hysterectomy if completed childbearing If Rh negative, give rhogham

12. Follow-Up Care – Molar Pregnancy 80% of patients cured by evacuation Follow B-hCG levels every two weeks until 3 consecutive tests negative Then monthly B-hCG every month for 6-12 months Avoid pregnancy for at least 6 months after first normal B-hCG Birth control during follow-up period Subsequent Pregnancies: –Send placenta for pathology –Check B- hCG 6 weeks postpartum

13. Gestational Trophoblastic Neoplasia (GTN) Persistent/Invasive Mole Choriocarcinoma Placental-Site Trophoblastic Tumor (PSTT) ** Malignant

14. Risk Factors for GTN After Mole Preevacuation uterine size greater than gestationl age or larger than 20 weeks gestation Theca-lutein cysts larger than 6 cm Age > 40 years Serum hCG levels > 100,000 mIU/mL Medical complications of molar pregnancy Previous hydatidiform mole

15. Invasive Mole Myometrial invasion by hydatidiform mole 1 in 15,000 pregnancies 10-17% of hydatidiform moles will progress to invasive moles

16. Persistent Mole Definition of persistent molar disease and need for chemotherapy (at least one of the following): –B-hCG plateau for ≥ 4 values for ≥ 3 weeks –B-hCG increase of ≥ 10% for ≥ 3 values for ≥ 2 weeks –B-hCG persistence 6 months after molar evacuation –Histopathologic diagnosis of choriocarcinoma –Presence of metastatic disease

17. Choriocarcinoma Most aggressive type of GTN Abnormal trophoblastic hyperplasia Absence of chorionic villi Direct invasion of myometrium Vascular spread to distant sites: –Lungs –Brain –Liver –Pelvis and vagina –Spleen, intestines, and kidney

18. Choriocarcinoma May come from any type of pregnancy - 25% follow abortion or tubal pregnancy - 25% with term gestation - 50% from hydatidiform moles 2-3% of moles progress to choriocarcinoma Incidence 1 in 40,000 pregnancies

19. Placental-Site Trophoblastic Tumor (PSTT) Originate from intermediate cytotrophoblast cells Secrete human placental lactogen (hPL) B-hCG often normal Less vascular invasion, necrosis and hemorrhage than choriocarcinoma Lymphatic spread Arise months to years after term pregnancy but can occur after spontaneous abortion or molar pregnancy

20. Placental-Site Trophoblastic Tumor (PSTT) Most common symptom is vaginal bleeding Tend to: - Remain in uterus - Disseminate late - Produce low levels of B-hCG compared to other GTN - Be resistant to chemotherapy (treat with surgery)

21. Signs & Symptoms GTN Continued uterine bleeding, uterine perforation, enlarged irregular uterus, persistent bilateral ovarian enlargement From metastatic lesions: abdominal pain, hemoptysis, melena, increased intracranial pressure (headaches, seizures, hemiplegia), dyspnea, cough, chest pain

22. Diagnosis of GTN Increase or plateau in B-hCG after molar pregnancy Pathologic diagnosis by D&C or biopsy of metastatic lesions WARNING: biopsy of metastatic lesions can result in massive hemorrhage Metastatic workup: CXR (or CT chest), CT abdomen/pelvis +/- CT/MR of brain

23. Classification & Staging of GTD FIGO Staging –Describes anatomic distribution of disease World Health Organization (WHO) Scoring Index –Describes prognosis

24. FIGO Staging StageDescription I Disease confined to the uterus II Disease extends outside the uterus but limited to genital structures (adnexa, vagina, and broad ligament) III Disease extends to the lungs with or without genital tract involvement IV Disease involves any other metastatic sites

25. WHO Prognostic Score Index Score Characteristic0124 Age<40≥40-- Antecedent pregMoleAbortionTerm- Interval from index pregnancy <4 months 4-6 months 7-12 months>12 months Pretreatment hCG<10 3 10 3 - 10 4 10 4 -10 5 >10 5 Largest tumor size (including uterus) < 3cm3-4 cm≥5cm- Site of metastasesLungSpleen, kidney GI tractLiver, brain Number of metastases-1-45-8>8 Previous failed chemotherapy --Single drug≥2 drugs

26. Therapy for GTN Low-risk = score ≤6 High-risk = score ≥7 Single agent therapy for nonmetastatic (stage I) or low-risk metastatic (stage II and III) with score <7  survival rates ~ 100% Combination chemotherapy +/- adjuvant radiation and/or surgery for high-risk metastatic disease or score ≥7

27. Therapy: Nonmetastatic GTN Single-agent with either methotrexate or dactinomycin Chemotherapy continued until hCG values normal and then 2-3 cycles beyond Change to alternative single-agent for hCG plateaus above normal or toxicities If significant elevation of hCG or new metastases, switch to multiagent 85-90% cured with initial regimen, <5% will require hysterectomy for cure

28. Therapy: Low-risk Metastatic GTN Low-risk metastatic disease can be treated with single-agent therapy with 5-day regimens Cure rates ~100% but 30-50% will be develop resistance to first agent If resistance to sequential single-agent chemotherapy (5-10% of patients), switch to multiagent chemotherapy

29. Therapy: High-risk Metastatic GTN Stage IV Stage II/III with score > 7 Disease refractory to single-agent chemotherapy Combination Chemotherapy: EMACO: –Day 1: Etoposide, Methotrexate and Dactinomycin –Day 8: Cyclophosphamide and Vincristine (Oncovorin) –Repeat q2 weeks until remission –Continue for at least 2-3 cycles beyond first normal hCG MAC (Methotrexate, Dactinomycin, Cyclophosphamide) EMA/EP – EMA + Etoposide and Cisplatin

30. Therapy: High-risk Metastatic GTN Cure rates 80-90% Hysterectomy and/or thoracotomy may be useful in resistant setting or symptomatic management Poorer prognosis with choriocarcinoma, metastases to places other than lung and/or vagina, number of metastases, and failure of previous chemotherapy

31. PSTT Therapy Hysterectomy Chemotherapy for metastatic disease or nonmetastatic disease with poor prognosis: - Interval from index pregnancy > 2 years - Deep myometrial invasion - Tumor necrosis - Mitotic count > 6 per 10 high-power fields Survival rates: –~100% for nonmetastatic disease –50-60% for metastatic disease

32. Follow-up Care After completion of chemotherapy, follow serial hCG every 2 weeks for three months, then monthly for one year Physical examinations every 6-12 months and imaging as indicated

33. Reproductive Performance Most women resume normal ovarian function No increase risk of stillbirths, abortions, congenital anomalies, prematurity, or major obstetric complications No evidence of reactivation At increased risk for development of second episode

34. False Positive Serum hCG Phantom hCG syndrome/ phantom choriocarcinoma 3-4% of healthy individuals have human-antimouse antibodies that can mimic hCG immunoreactivity To verify: –Urine hCG should be negative –Should not show parallel decrease with serial dilutions –Test at national B-hCG reference lab

35. Summary Hydatidiform mole is a benign condition, 80% cured with suction D&C Malignant GTN: –Persistent or invasive mole –Choriocarcinoma –PSTT WHO score > 7 represents high-risk disease GTN very sensitive to chemotherapy