Gestational trophoblastic disease

A brief discussion on gestational trophoblastic diseases

1. GESTATIONAL TROPHOBLASTIC NEOPLASIA dr niranjan chavan

2. Professor and Unit Chief, L.T.M.M.C & L.T.M.G.H, Sion Hospital Joint Treasurer Elect, FOGSI (2021-2024) Vice President, MOGS (2021-2022) Member Oncology Committee, SAFOG (2020-2022) Dean AGOG & Chief Content Director, HIGHGRAD & FEMAS Courses Editor-in-Chief, FEMAS & JGOG Journal 50 publications in International and National Journals with 58 citations National Coordinator, FOGSI Medical Disorders in Pregnancy Committee (2019-2021) Chair & Convener, FOGSI Cell Violence Against Doctors (2015-16) Member, Oncology Committee AOFOG (2013-2015) Coordinator of 11 batches of MUHS recognized Certificate Course of B.I.M.I.E at L.T.M.G.H (2010-16) Member, Managing Committee IAGE (2013-17), (2018-20) Editorial Board, European Journal of Gynaec . Oncology (Italy) Course Coordinator of 3 batches of Advanced Minimal Access Gynaec Surgery (AMAS) at LTMGH (2018-19) DR. NIRANJAN CHAVAN MD, FCPS, DGO, MICOG, DICOG, FICOG, DFP, DIPLOMA IN ENDOSCOPY (USA)

3. What is Gestational trophoblastic disease ?? A spectrum of diseases caused by abnormal proliferation of trophoblastic tissue

4. Classification of Gestational Trophoblastic Disease WHO Classification Malformations of the chorionic villi that are predisposed to develop trophoblastic malignancies Complete Hydatidiform moles Partial Invasive Malignant neoplasms of various types of trophoblast Choriocarcinoma Epithilioid trophoblastic tumors Placental site trophoblastic tumor

5. Complete Mole: Pathogenesis Duplication 46XX Empty ovum 23X Diandric diploidy Androgenesis Paternal chromosomes only

6. Complete Mole: Pathogenesis 46XX Empty ovum 23X Dispermic diploidy Paternal chromosomes only 23X 23X 23X

7. COMPLETE MOLAR PREGNANCY

8. Partial Mole: Pathogenesis 69XXY Normal ovum 23X Dispermic triploidy Paternal extra set 23Y 23X 23Y 23X 23X

9. Partial Hydatidiform mole Fetus growth restricted and has multiple congenital malformations often mixed in with the trophoblastic tissue. Often associated with severe hypertension

10. Differences between complete and partial

11. Differences between complete and partial

12. Feature of CM/PM FEATURE COMPLETE MOLE PARTIAL MOLE Pathology Fetal /embryonic tissue Absent Present Hydatidiform swelling of chorionic villi Diffuse Focal Trophoblastic hyperplasia Diffuse Focal Scalloping of chorionic villli Absent Present Trophoblastic stromal inclusions Absent Present P57kip2 staining Negative Positive karyotype 46 xx(90%),46 xy Triploid 69xxx,69xxy Clinical presentation Typical diagnosis Molar pregnancy Missed abortion Post molar malignant sequale 15% 0.5%

13. FEATURE COMPLETE MOLE PARTIAL MOLE Clinical feature Theca lutein cyst 25-30% 5-10% Uterine size 50% large for date Small for date Medical complication Frequent Rare Need ofchemotherapy 15% 0.5% HCG value Markedly increased Moderately increased

14. SYMPTOMS Vaginal bleeding (97%) Most common symptom. Molar tissue may separate from the decidua and disrupt maternal vessels and large volume of blood may distend the endometrial cavity. Prolonged vaginal bleeding can cause anemia. Vaginal passage of hydropic vesicles .

15. SYMPTOMS Pelvic pain Hyperemesis gravidarum (8%) May require antiemetic or iv fluid replacement. Partial mole usually presents as incomplete or missed abortion.

16. SIGNS Hyperthyroidism Clinically evident hyperthyroidism is seen in 7 percent of patients . They may present with warm skin, tremor , tachycardia . (hCG simulates TSH) Preeclampsia <20 weeks gestation It was observed in 27% patients with complete hydatiform mole. It is associated with hypertension, proteinuria and hyperreflexia. E clamptic convulsions are rarely seen.

17. SIGNS Uterine size larger than period of gestation. Theca lutein cysts Prominent theca lutein cyst (6cm in diameter) develop in about 50% of patients, after molar evacuation, they normally regress spontaneously within 2-4 months. Bilateral theca lutein cysts

18. Diagnosis ULTRASONOGRAPHY - Sensitive and reliable technique Complete : generalized swelling of chorionic villi ( snow-storm appearance) Partial mole: focal cystic spaces of varying diameter in the placental tissue. Increase in transverse diameter of the gestational sac. Diagnosis on histology of curetting.

19. MANAGEMENT Evacuation of mole - Suction curettage Cervical Dilatation : Active uterine bleeding should not deter the prompt completion of dilatation Suction curettage: 12mm cannula use is strongly advised .. Sharp Curettage: To check for residual molar tissue If Rh negative, give anti D b ecause trophoblastic cells express RhD factor. Prophylactic chemotherapy is used in Mx of high risk complete molar pregnancy especially when BHCG levels are unreliable.

20. Follow-Up Care – Molar Pregnancy Follow B- hCG levels every week until 3 consecutive tests negative Then monthly B- hCG every month for 6 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 (barrier method and oral contraceptive pills is preferable) Subsequent Pregnancies : Send placenta for pathology Check B- hCG 6 weeks postpartum

21. Preventive chemotherapy O ver 40 years old T he β -HCG is over 1lacIU/L before emptying mole T he HCG regression curve is not progressively declined U terus is obviously larger than the size of the amenorrhea L uteinizing cyst is >6cm T here is still over hyperplasia of trophoblastic cells in the second curettage N o follow up conditions

22. DIAGNOSIS OF POSTMOLAR GTN In accordance with the International Federation of Gynecology and Obstetrics (FIGO) , GTN is diagnosed after a molar gestation if any of the following is observed ( 1 ) Four values or more of hCG plateau over at least three weeks (days 1, 7, 14, and 21 ), ( 2 ) A rise in hCG of 10% or greater for three or more values over at least two weeks (days 1, 7, and 14 ), ( 3 ) The presence of histologic choriocarcinoma , ( 4 ) P ersistence of hCG six months after molar evacuation .

23. Invasive Mole An invasive mole (formerly known as chorioadenoma destruens ) is a hydatidiform mole that penetrates the muscular wall of the uterus ( myometrium ). It may extend to broad ligament, vagina , vulva or metastasize to lungs. These develop in about 20% of women who have had a complete mole removed by curettage.

24. Invasive mole It can be complete or partial. More chances of complete mole converting into invasive mole as compared to partial mole. Rate of conversion to invasive mole from complete mole is <1%.

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

26. Choriocarcinoma Choriocarcinoma is a malignant form of GTD. Characterised by abnormal trophoblastic hyperplasia, anaplasia and absence of villi. Can develop from any form of pregnancy : so, called Gestational choriocarcinoma Rarely, choriocarcinomas are not related to pregnancy, can develop in ovaries, testicles, chest, or abdomen [mixed germ cell tumor ]. These are called Nongestational choriocarcinoma , which tends to be less responsive to chemotherapy and has a less favorable prognosis than the gestational variant.

27. Choriocarcinoma Type of gestation Risk of choriocarcinoma Hydatidiform mole 50% Normal term pregnancy 20 – 30 % Spontaneous abortion 23% Ectopic pregnancy 2%

28. Choriocarcinoma : PATHOLOGY Grossly T umor size of 2-10cm,soft fleshy yellow white areas with marked tendency to form large pale areas of ischemic necrosis,foci of cystic softening and extensive haemorrhage , cancer embolus is often found in parauterine veins, luteinizing cyst may be found Bulky mass with solid and cystic tan areas with extensive hemorrhage

29. Choriocarcinoma : PATHOLOGY Microscopic examination : It does not produce chorionic villi Consists entirely of proliferating cytotrophoblastic cells and syncytiotrophoblastic cells which invade the myometrium and blood vessels. Mitotic figures are common and often atypical. Cytotrophoblast -red arrow Syncytiotrophoblast - blue arrow

30. Placental-site Trophoblastic Tumor Develops at placental implantation site Incidence <2% of GTN. M ost often develops after a normal pregnancy or abortion. Originates from mononuclear intermediate cytotrophoblasts S erum ß- Hcg is less reliable marker. hPL (human placental lactogen ) is raised. Invades myometrium, blood vessels but rarely metastasize. Insensitive to chemotherapy

31. EPITHELIOD TROPHOBLASTIC TUMOR Arises from chorionic type intermediate trophoblast cells. Distinct uterine mass , no metastasis S tains with placental specific alkaline phosphatase Geographic necrosis seen.

32. Clinical manifestation [Invasive Mole and Choriocarcinoma] There is a history of: A complete mole and less commonly after a partial mole. The tumors can also develop after a normal pregnancy, ectopic pregnancy or miscarriage. Bleeding : The most common symptom is vaginal bleeding. Rarely, the tumor penetrates the uterine wall with development of internal haemorrhage Infection : Infection producing a discharge from the vagina, pain in the pelvic region, and fever.

33. Clinical manifestation [Invasive Mole and Choriocarcinoma] Amenorrhoa : may be present due to continuous hCG production Abdominal swelling : Enlarged uterus Theca-lutein cysts Vaginal mass/Ulcer : irregular or brisk haemorrhage in vaginal metastasis

34. Clinical manifestation [Invasive Mole and Choriocarcinoma] Lung symptoms after metastasis : dyspnea , cough, hemoptysis , chest pain Symptoms of distant spread: Brain: hemiplegia, seizures, headache, visual disturbances GIT and liver: epigastric pain, jaundice, malena

35. Clinical manifestation [Placental Site Tumor] Bleeding : Vaginal Bleeding. If the disease penetrates the uterine wall, there will be bleeding into the abdominal cavity along with severe abdominal pain. Persistent abdominal swelling

36. Investigations Blood related Serum β -hCG level is highly elevated ( > 1,00,000 mIU/m1) CBC, Blood group, LFTs & TFTs Imaging Chest radiograph -metastasis cannon ball pleural effusion and consolidation Ultrasound snow storm appearance no identifiable fetus Doppler color flow of uterus CT-scan and MRI-metastasis Histopathology (if curettage done)

37. Doppler scans choriocarcinoma Invasive mole “snow storm”

38. Cannon ball appearance on x-ray

39. GTN Vaginal Metastasis

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

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

42. Prognosis and staging

43. FIGO staging of GTN

44. Modified WHO Prognostic Scoring System 1 2 4 Age <40 ≥40 – – Antecedent pregnancy mole abortion term – Interval months from index pregnancy <4 4–6 7–12 >12 Pretreatment serum hCG (IU/L) <10 3 10 3 –10 4 10 4 –10 5 >10 5 Largest tumor size (including uterus) <3 3–4 cm ≥5 cm – Site of metastases lung spleen, kidney gastrointestinal liver, brain Number of metastases – 1–4 5–8 >8 Previous failed chemotherapy – – single drug ≥2 drugs

45. Chemotherapy Low risk GTN are- Non metastatic GTN Low risk metastatic- only to lungs Duration < 4 months from index pregnancy hCG < 40,000IU/l Risk score 6 or less FIGO stage 1, 2, 3 High risk GTN FIGO stage 1, 2, 3 with risk score 7 or more FIGO stage 4.

46. Stage 1 Initial Single agent chemotherapy Resistant Combination chemotherapy Hysterectomy with adjuvant chemotherapy Stage 2 and 3 Low risk Single agent (if resistant then combination chemotherapy) High risk Combination chemotherapy Stage 4 Initial Combination chemotherapy Brain Whole brain irradiation (3000cGy) Craniotomy to manage complications Liver Arterial infusion of chemotherapy Resection to manage complication Resistant Second line combination chemotherapy

47. Single agent chemotherapy Methotrexate : Many regimes I.M. Methotrexate 1mg/Kg days 1,3,5,7 I.M./ P.O. Folinic acid 0.1mg/Kg days 2,4,6,8 I.M. Methotrexate 40mg/m ² weekly : 20 % failure rate Actinomycin D : I.V. push 1.25mg/m ² every 14 days it is used in patients with hepatic dysfunction where methotrexate is contraindicated Causes severe sloughing if extravasated

48. Single agent chemotherapy Follow-up : - hCG , CBC , LFTs and creatinine prior to each cycle Continue treatment cycle for 1-3 weeks after normal - hCG A negative - hCG means no. of malignant cells <10 7 Complete remission in 85-90% 80% require only one course Toxicity : Thrombocytopenia 2%, neutropenia 6% and hepatotoxicity 14%

49. Combination Chemotherapy Repeat cycle on days 15, 16 and 22 (every 2 weeks)

50. Combination Chemotherapy In EMA-CO resistant cases , substitute Cyclophosphamide and Vincristine by E toposide and Cisplatin . ( EMA-EP regimen ).75% achieve remission For EMA-EP resistant cases : Paclitaxel with Cisplatin alternating with E toposide or I fosfamide may be used ( ICE REGIMEN ) Intensive chemotherapy causes increased risk of leukemia .

51. Conclusion Hydatidiform mole is a benign condition, 80% cured with suction D&C Malignant GTN: Choriocarcinoma PSTT ETT WHO score > 7 represents high-risk disease which requires chemotherapy. GTN is very sensitive to chemotherapy