Gestational Trophoblastic Disease

1. Gestational Trophoblastic Disease YASHODHARA PRADEEP Prof., OBGYN QMH CSMMU LKO 2014

2. Classification of GTT • GTD Epidemiology, Pathogenesis, Aetiology, β hCG, • Clinical Features of Premalignant(GTD) Complete Mole(CM); Partial Mole • Management of Complete Mole, or Partial Mole • Post evacuation Follow up , Chemotherapy • Contraception • Clinical Features of Malignant (GTN) Invasive Mole, Placental site tropho blastic tumor( PSTT) Chorio CA • Investigations • GTN ChorioCA Diagnosis, Investigation, Management • Chemotherapy • Follow up

3. Introduction • Gestational Trophoblastic disease is a term used to describe the heterogeneous group of interrelated lesions that arise from abnormal proliferation of placental trophoblast. GTD Lesions are histologically different and can be Benign and malignant.

4. WHO Classification GTD Premalignant Diseases • Complete Hydatidiform Mole ( C M ) • Partial Hyadatidiform Mole ( P M ) Malignant Diseases (Gestational Trophoblastic Neoplasia) Nonmetastatic • Invasive Mole • Placental site trophoblastic tumor ( PSTT ) • Epitheloidtumour • Metastatic • Gestational Choriocarcinoma

5. Epidemiology • It is common in oriental countries- Philippines, China, Indonesia, Japan, India, Central and Latin America and Africa. • Highest incidence- Philippines- 1 in 80 pregnancies • Lowest incidence- Europe- 1 in 752 pregnancies • India- 1 in 400 pregnancies • Calculated Incidence of complete mole- 1 in 1945 pregnancies partial mole- 1 in 695 pregnancies • Age C Ms most common at the extremes of reproductive age • The incidence of CM rises fm I:1000 to 1:76; 1:6.5 in subsequent pregnancies • CM is the most common antecedent to Chorio CA. But it can occur after any type of pregnancy 3% after invasive mole; 16% after CM

6. Homozygous 85% Pathogenesis of complete H Mole

7. Heterozygous 15% Pathogenesis of complete H Mole

8. Pathogenesis of Partial H. Mole

9. Gestational Trophoblastic Disease Genetic & Pathology • C M Always contains Paternal DNA alone so androgenic Macroscopically like bunch of grapes • P M are Triploidy two paternal & one maternal sets of chromosomes hyperplasia of chorionic villi with embryo usually dies 8-9 weeks of gestation • P57 cycline dependent kinase inhibitor paternally imprinted gene which is maternally expressed • P57 kip2 immunostaining is negative in CM in contrast to PMs Hydropic abortions & normal placenta • Invasive mole can be diagnosed by USG & rising titers of hCG • Presence of chorionic villi distinguish Invasive mole from Choriocarcinoma • Chorio CA. Grossly abnormal karyotypes with diverse ploidies • PSTT are rare slow growing malignant tumor; intermediate trophoblast from cytotrophoblast produce little hCG

10. Aetiological factors • Genetic factor: Autosomal recessive Genomic Imprinting; Abnormal Methylation • In cases of Familial recurrent molar pregnancy; Defective locus at 19q 13.4 at single gene NALP7 , it is member of CATERPILLAR family involved in inflammation & Apoptosis in genetic CM • Three other genes H19, P57, IGF-2 • Chorio CA. heterozygosity at specific genes deletion 7p12-q11.2; Amplification of 7q21-q31 region ; loss of 8p12-p21 • Breast & ovarian cancer also show the abnormalities in heterozygosity in amplification at 7q21-q31 , & loss of 8p12-p21

11. Human chorionic gonadotrophin • Beta hCG is pituitary/ placental glycoprotein • Commercially available Beta hCG test based on sandwich assay principle & rely on two antibodies • Rare chance of false negative or false positive results with Rabit polyclonal antibodies RIA used in both serially diluted urine & blood samples . • Sensitivity of this test in serum is 1 IU/L, in urine 20 IU/L • Beta h CG is tumor marker • New Assayare in research Hyperglycosylated hCG (hCG-H ) specific for cases subsequently require chemotherapy (Clinical GTDs ) Cole etal 2006a

12. Beta h CG as Tumor marker • Half life is 24-36 hrs • Marker for pregnancy ,GTD, Germ cell tumors & 15% of epithelial ovarian malignancies • H CG levels are also associated with tumor volume 5 IU/l corresponds to 104-105 viable tumor size • Beta hCG used as prognostic marker & progression of disease or response to therapy, drug resistance at earlier stage. • hCG is best tumor marker known

13. Clinical features Complete Mole • Most common in first trimester or early Second trimester • Vaginal bleeding is the most common symptom (84-97%) • Uterus is larger than POG (28%) • Presents with the features of threatened abortion; Amenorrhea, pain & bleeding P/V • Associated features of Hyperemesis Gravidarum Requires Antiemetic , IV fluids etc • Toxaemia or PET 10-15% • hyperthyroidism 7%

14. Clinical features • Theca leutin cysts • Beta h CG levels > 100.000 • O/E • Passage of grapes like vesicle or spontaneous expulsion of entire mole • Pulmonary , cervical, Vaginal metastasis may occur disappears after evacuation of mole • The presence of metastasis does not necessarily imply invasive mole or chorio CA • Macroscopic features: Bunch of grapes due to villous swelling • Branching contain hyperplastic cyto & syncytio trophoblast with many vessels

15. Complete Molar Pregnancy

16. High Risk For Developing Post molar tumor • Patients presenting with any of the following signs of marked trophoblastic proliferations • hCG Levels > 100,000 mIU/L • Excessive Uterine Enlargement • Theca leutin cyst 6cm or larger

17. Clinical features PARTIALMOLE • Findings not as characteristic as in CM • Most commonly presents in late Ist or second trimester • Uterus is often not enlarged more than POA • More often presents as Missed or incomplete abortion • Pre evacuation h CG levels are not more than 100,000IU/ L • Macoscopic : villous swelling is less intense • Embryo is present • Microscopic: Trophoblastic hyperplasia, indented outlines & round inclusions • Presence of nucleated RBS of embryo in villous structure • Due to Early demise of embryo less documentation of PM

18. Management Of Molar Pregnancy There are 2 important basic lines: • Evacuation of the mole • Regular follow up to detect persistent Trophoblastic disease If both basic lines are done appropriately, mortality rates can be reduced to zero.

19. Management of Molar Pregnancy For complete mole: Suction Curettage Procedure: 1. Emergency tray should be ready and blood should be handy. 2. Oxytocin infusion: begun before induction of anaesthesia. 3.Cervical dilation

20. Management 4. Suction curettage: Suction canula up to a maximum of 12 mm is usually sufficient to evacuate all complete molar pregnancies. If the uterine size is larger than 14 weeks of gestation, one hand should be placed on top of fundus and uterus should be massaged to stimulate uterine contraction and reduce the risk of perforation. 5. Sharp curettage: gentle sharp curettage is done to remove any residual molar tissue. Cervical preparation with prostaglandins or misoprostol should be avoided to reduce the risk of embolisation.

21. Should products of conception be examined histologically? Histological examination is indicated in: • Failed pregnancies (missed or molar): all medically or surgically managed cases • Products of conception obtained after all repeat evacuations (post abortive or post partum). There is no need after therapeutic termination: provided that foetal parts are identified on USG A urine pregnancy test should be performed 3 weeks after medical management of failed pregnancy if products of conception are not sent for histological examination.

22. Anti-D Prophylaxis (RCOG) NOT required in Complete Mole: because of poor vascularisation of the chorionic villi and absence of the D-antigen. Required in: -partial mole: due to presence of RBCs -complete mole: if diagnosis is not confirmed histopathologically.

23. Second uterine evacuation • There is NO clinical indication for the routine use of second uterine evacuation. • It may be useful for symptom control in selected patients with heavy bleeding or curative if the recurrent molar tissue is confined to the uterine cavity, particularly in those with hCG levels <1500 IU/L.(Recent Advances)

24. Post Evacuation Surveillance • Done to detect persistent trophoblastic disease (GTN) • A baseline serum βhCG is obtained within 48 hours after evacuation • Levels are monitored every 2 weeks until normalisation and urine βhCG levels analysed monthly after this. • These levels should progressively fall to an undetectable level (<5 mu/ml). • The average time to achieve the first normal β-hCG level after evacuation is about 9 weeks. • If symptoms are persistent, more frequent βhCG estimation and USG examination ± second evacuation is advised.

25. Optimum follow up period following normalization of βhCG If βhCG has reverted to normal in • ≤56 days (8 weeks) of the pregnancy event: follow up is for 6 months from the date of uterine evacuation. • >56 days of the pregnancy event: follow up is for 6 months from normalisation of hCG level. All women should notify at the end of any future pregnancy, whatever the outcome of the pregnancy. β hCG levels are measured 6-8 weeks after the end of pregnancy to exclude disease occurrence.

26. Contraception • Should NOT conceive until follow up is complete. • Use Barrier method until hCG revert to normal (?OCPs may act as growth factor for trophoblastic tissue). • Once hCG has normalised, the combined oral contraceptive pill may be used. • IUCD should not be used until hCG levels are normal to reduce the risk of uterine perforation.

27. Role of hysterectomy • If the patient desires surgical sterilization, a hysterectomy may be performed with the mole in situ. • Hysterectomy does not prevent metastasis; therefore, patients will require follow up with assessment of hCG levels. • The ovaries may be preserved at the time of surgery, even in the presence of prominent theca luiten cysts.

28. Role of prophylactic chemotherapy • The long term prognosis for women with a H. Mole is not improved with prophylactic chemotherapy. Because toxicity- including death- may be significant, it is not recommended routinely (ACOG 2004). • It may be useful in the high-risk cases when follow up are unavailable or unreliable. HIGH RISK FACTORS: • hCG level >100,000 mIU/ml • Excessive uterine enlargement • Theca lutien cysts 6 cm in diameter

29. Chances of malignant transformation • Complete H.Mole 16% • Partial H.Mole 0.5%

30. Gestational trophoplastic NeoplasiaNonmetastatic Invasive Mole: Clinical features • Clinical diagnosis by persistence or rising titers of Beta h CG in the weeks after molar evacuation & USG • Persistent bleeding p/v • Lower abdominal pain due to invasion in myometrium, vulva, vagina or intra abdominal metastasis • It may spread to adjacent pervic structures bladder , rectum; hematuria, bleeding P/ R • Pulmonary metastasis • Mostly due to initial diagnosis of CM is missed & not on Beta h CG follow up

31. Clinical features Placental Site Trophoblastic Tumor (PSTT): • it is rare slow growing tumor • Women mainly presents with menstrual irregularities & lower abdominal pain, galactorrhea due to hyperprolactinemia increased h PL • Little or no h CG is produced ( Free B hCG fragment ) • Rarely presents as nephrotic syndrome, hematuria or DIC • Spread is late local Infiltration & metastasis is through lymphatic • Microscopically: In the normal placenta it is distinct from villous trophoblast & infiltrates the decidua, myometrium, & spiral arteries. • Mainly from intermediate trophoblast derived fm cytotrophoblast

32. Metastatic Gestational Trophoblastic Neoplasia • Second most common GTN • 1 in 30,000 pregnancies • Early haematogenous spread is characterstic of choriocarcinoma • 40% after molar pregnancy: Easily Diagnosed • 60% non-molar pregnancy: Difficult to Diagnose

33. Metastatic Gestational Trophoblastic Neoplasia • GTN arises when the normal regulatory mechanisms controlling the proliferation and invasiveness of trophoblastic tissue are lost. • Diagnosis of the GTN is made on • Clinical presentation • Elevated b-HCG • Evidence of metastasis • Imaging • Tissue for Histology- Seldom obtained • (Definitive Histological Diagnosis of type of GTN is not made in most cases).

34. Metastatic Gestational Trophoblastic Neoplasia CHORIOCARCINOMA: Clinical features • Occurs mainly following any form of pregnancy, mainly after CM • Difficult to differentiate from Invasive mole as H/P is not possible • Clinical features of bleeding p/v , lower abdominal pain, or in 1/3 of cases no pelvic symptoms but symptoms of distant metastasis lungs , brain ,liver, skin, cauda equina & the heart may present • Highly malignant , appears as soft purple largely hemorrhagic mass

35. Clinical features of chorio CA • Microscopic: implanting blastocyst with central cores of mononuclear cytotropho surrounded by rim of multinucleated syncytiotrophoblast & distinct absence of chorionic villi extensive areas of necrosis & haemorrage &frequent evidence of tumor in the sinuses • The hypervascularity & absence of connective tissue support are the reason for its highly malignant behaviour • DIAGNOSIS IS ALWAYS BY BETA h CG

36. investigations • Quantitative beta hCG • X Ray Chest • Pelvic Doppler USG • Abdominal doppler USG to rule out liver & renal metastasis • CT chest , abdomen • MRI brain • Beta h CG in cerebrospinal fluid • PET • FD PET • Genetic studies

37. Which women should be investigated for Persistent GTD after a non molar pregnancy? (RCOG Guideline) • Any women who develops persistent vaginal bleeding after a pregnancy event. • A urine pregnancy test should be performed in all cases of persistent or irregular vaginal bleeding after a pregnancy event. • Symptoms from metastatic disease, such as dyspnoea or abnormal neurology, can occur very rarely.

38. FIGO REQUIREMENT FOR MAKING DIAGNOSIS OF GTN Four values or more of plateaue hCG over at least 3 weeks: days 1, 7, 14 and 21. A rise of hCG of 10% or greater for 3 values or more over at least 2 weeks: days 1, 7, and 14. Histologic diagnosis of choriocarcinoma. Persistence of hCG beyond 6 months after mole evacuation.

39. Myometrial invasion Vesicles Invasive H. Mole Sometimes involving the peritoneum, parametrium, or vaginal vault. Originate almost always from H. mole

40. Metastatic disease

41. Metastatic Disease If the pelvic examination & chest X-ray are negative, it is very uncommon to have metastatic involvement of other sites.

42. Chest X ray: widespread metastatic lesions.

43. GTN Vaginal Metastasis

44. Cranial MRI scan: Large metastasis on the left (black arrows) Brain MRI of a patient with a solitary brain metastasis in remission

45. Autopsy specimen Multiple hemorrhagic hepatic metastasis CT Scan: Liver metastsis

46. Management of GTN • Prognostic score is central to the management of GTN. • A single universally accepted, anatomical staging and prognostic scoring system for GTN was developed by FIGO in 2000.

47. ANATOMIC FIGO STAGING SYSTEM FOR GTN (2000)

49. WORK UP OF GTN • History & physical examination • Serial weekly hCG measurement in serum. • Hemogram, LFT, KFT • Chest X-ray • USG whole abdomen pelvis to rule out hepatic and renal metastasis • CT or MRI brain • CSF analysis – in metastatic disease. • PET • FDG PET • Curette to be done if there is uterine bleeding. There is grave dangerous of hemorrhage at the biopsy site.

50. GTN Serial hCG levels FIGO scoring Low risk (<6) High risk (> 6) Single-agent chemotherapy Combination chemotherapy Resolution Life-long hCG follow-up Relapsed/resistant disease Second-line chemotherapy+ surgical debulking