Gestational Trophoblastic Disease (GTD)

1. Gestational Trophoblastic Disease (GTD) ByAhmed Refaat Abd ELzaherAssistant Lecturer of Medical OncologySouth Egypt Cancer Institute2015

2. GTD Overview • Heterogeneous group of related lesions • Arise from abnormal proliferation of trophoblast of the placenta • Can follow any gestational event – abortion, miscarriage, ectopic, normal pregnancy • Unique because the maternal lesions arise from fetal (not maternal) tissue • Most GTD lesions produce (B-hCG) • Can be cured even in the presence of widespread metastases

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

4. Relationship of HM. IM. CH hydatidiform therapeutic or molespontaneous abortion term pregnancy ectopic invasion mole choriocarcinoma.

5. Hydatidiform mole

6. 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)

7. 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 • Blood type: • A or AB are at slightly higher risk than those with type B or O

8. Hydatidiform mole • Complete mole 23X 23X 23X sperm empty egg 46,XX 23Y 23X 23X 23Y sperm sperm empty egg 46,XY

9. Hydatidiform mole • Partial mole 23X 23Y 23X 23X 23X 23Y sperm sperm normal egg 69,XXY 23X 23X 23X 23X 23X 23X sperm sperm Normal egg 69,XXX

10. Hydatidiform Mole Clinical Manifestations: • Vaginal bleeding(97%) /anemia • Enlarged uterus (size > dates) • Pelvic pain • Theca lutein cysts • Hyperemesisgravidarum • Hyperthyroidism • Preeclampsia <20 weeks gestation • Vaginal passage of hydropic vesicles • Partial mole usually presented as incomplete or missed abortion

11. Diagnosis • Complete : U/S usually very sensitive – generalized swelling (snow-storm ) • partial mole U/S may detect focal cystic spaces of varying diameter Diagnosis on histology of curettings

12. Complete vs. partial mole

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

14. Hydatidiform Mole Treatment chemotherapy HM don’t need usually chemotherapy because HM is benign disease.

15. 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 • More than half of patients will have complete regression of hCG to normal within 2 months of evacuation. • Avoid pregnancy for at least 6 months after first normal B-hCG (oral contraceptive pills is preferable) • Subsequent Pregnancies: • Send placenta for pathology • Check B- hCG 6 weeks postpartum

16. Prognosis • Complete mole has the latent risk of local invasion or telemetastasis • The high-risk factors includes • β-HCG>100000IU/L • uterine size is > 20 weeks size. • the luteinizing cyst is >6cm • If >40 years old,the risk of invasion and metastasis may be 37%, If >50 years old,the risk of invasion and metastasis may be 56%. • repeated mole: the morbidity of invasion and metastasis increase 3~4 times

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

18. 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 • Previous hydatidiform mole

19. Invasive Mole • Myometrial invasion by hydatidiform mole • Formerly known as chorioadenoma destruens • 1 in 15,000 pregnancies • 10-17% of hydatidiform moles will progress to invasive moles

20. 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

21. Choriocarcinoma • Most aggressive type of GTN • Abnormal trophoblastic hyperplasia • Absence of chorionic villi • Direct invasion of myometrium • Most often develops from a complete hydatidiform mole • Vascular spread to distant sites: • Lungs • Brain • Liver • Pelvis and vagina • Spleen, intestines, and kidney

22. 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 • Rarely, choriocarcinomas can develop in other parts of the body in both men and women. These are not related to pregnancy as ovaries and testicles • Nongestational choriocarcinoma tends to be less responsive to chemotherapy and has a less favorable prognosis than the gestational variant

23. 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

24. 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)

25. 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

26. 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

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

28. FIGO Staging

29. The World Health Organization (WHO) scoring system for GTD

30. WHO Prognostic Score Index

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

32. 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

33. 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

34. 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

35. Metastatic Gestational Trophoblastic Tumors • Surgery • It is indicated for tumor resistant to chemotherapy and single metastases persisting despite chemotherapy. • RT • RT, in combination with chemotherapy, is clearly indicated for the primary management of patients with brain metastases.

36. 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

37. 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

38. Reproductive Performance • Most women resume normal ovarian function • Women who undergo chemotherapy are advised not to conceive for one year after completion of treatment • No increase risk of stillbirths, abortions, congenital anomalies, prematurity, or major obstetric complications

39. 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

40. 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

41. Thank You For Your Time