Gestational trophoblastic neoplasia

Pathophysiology, Classification,Gestational trophoblastic neoplasia, presentation, management, WHO scoring , FIGO staging

1. GESTATIONAL TROPHOBLASTIC NEOPLASIA

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

3. World Health Organisation (WHO) classification of trophoblastic disease Benign Hydatidiform mole Complete Partial Malignant gestational trophoblastic neoplasia Invasive hydatidiform mole Choriocarcinoma Placental site trophoblastic tumour Trophoblastic tumour , miscellaneous Exaggerated placental site Placental site nodule or plaque Unclassified trophoblastic lesions

4. Complete Hyatidiform mole Mole without fetus or embryo Most often develops when either 1 or 2 sperm cells fertilize an egg cell that contains no nucleus or DNA All the genetic material are paternal. Therefore, there is no fetal tissue. Usually diploid, with a 46,XX karyotype, and all molar chromosomes are paternal in origin. About 10% have a 46,XY karyotype, which arises from fertilization by two spermatozoa.

5. Benign Hyatidiform mole(vesicular) The most common form of GTD It is made up of villi that are enlarged, edematous and vesicular The swollen villi grow in clusters that look like bunches of grapes Partial and complete differ in morphology, clinico -pathology and cytogenic features

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

7. Complete Mole, Pathogenesis 46XX Empty ovum 23X Dispermic diploidy Paternal chromosomes only 23X 23X 23X

8. features Edematous chorionic villi in clusters “grape like” Different sizes Average size of 1.5cm in diameter Microscopic features some enlarged villi show fluid filled space “Central cistern pattern” High hCG production

9. COMPLETE MOLAR PREGNANCY

10. Partial Hydatidiform mole Develops when 2 sperm fertilize a normal egg. Dispermy, fertilization of an intact ovum by two spermatozoa 69XXX, 69XXY Fetus growth restricted and has multiple congenital malformations often mixed in with the trophoblastic tissue. Often associated with severe hypertension Few enlarged villi and fewer masses of grape like villi.

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

12. Partial Hydatidiform mole

13. Differences between complete and partial

14. 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%

15. 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

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

17. Invasive mole ( chorioadenoma destruens ) A Hyatidiform mole that has grown into the muscle layer of the uterus. Invasive moles can either be complete or partial Complete moles become invasive much more often than partial moles. Invasive moles develop in a little less than 1 out of 5 women who have had a complete mole removed .

18. INVASIVE MOLE

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

20. Placental-site trophoblastic tumor Very rare form of GTD Develops where the placenta attaches to the lining of the uterus. This tumor most often develops after a normal pregnancy or abortion, It may also develop after a complete or partial mole is removed. They do not spread to other sites in the body. But these tumors have a tendency to invade the myometrium They are treated with surgery, not sensitive to drugs.

21. PLACENTAL SITE TROPHOBLASTIC TUMOR

22. Epithelioid trophoblastic tumor (ETT) Extremely rare type of GTD Can be hard to diagnose. It can be found growing in the cervix, to be confused with cervical cancer. ETT does not respond very well to chemotherapy the main treatment is surgery. It might have already metastasized when it is diagnosed which carries a poorer prognosis.

23. Because they are frequently found in the cervix, they may be confused with hyalinizing squamous cell carcinomas . Epithelioid trophoblastic tumours are focally immunoreactive for placental-like alkaline phosphatase (PLAP) and hPL but strongly and diffusely immunoreactive for E-cadherin and epidermal growth factor receptor

24. Because they are frequently found in the cervix, they may be confused with hyalinizing squamous cell carcinomas . Epithelioid trophoblastic tumours are focally immunoreactive for placental-like alkaline phosphatase (PLAP) and hPL but strongly and diffusely immunoreactive for E-cadherin and epidermal growth factor receptor

25. Epitheloid tumor

26. Choriocarcinoma Invades myometrium and local vasculature to disseminate haematogenously to the lung (57-80%), vagina (30%), pelvis (20%), brain (17%), and liver (10%) Half of all choriocarcinomas start off as molar pregnancies. About one-quarter develop in women who have a miscarriage , intentional abortion, or tubal pregnancy . Another quarter (25%) develop after normal pregnancy and delivery.

27. Symptoms & signs Bleeding Infection Abdominal swelling Vaginal mass Lung symptoms Symptoms from other metastases

28. Diagnosis of GTN If following are met after initial evacuation - Plateau of hCG lasting for four measurements over a period of 3 weeks E.g. days 1,7,14,21 Rise in Hcg for 3 weekly consecutive measurements Hcg remains elevated for 6months or more Histological diagnosis of choriocarcinoma

29. Early features suggesting persistent GTD or post molar syndrome Recurrent Or Persistent Vaginal Bleeding Subinvoluation Amenorrhea Persistence of ovarian enlargement. No malignancy in endometrial biopsy

30. Investigations Blood related Serum b - hCG level is highly elevated ( > 100.000 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)

31. Doppler scans choriocarcinoma Invasive mole “snow storm”

32. Cannon ball appearance on x-ray

33. GTN Vaginal Metastasis

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

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

36. Prognosis

37. 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

38. SIGNIFICANCE OF WHO SCORING WHO score 4 or less Commence treatment as soon as possible. A low risk of GTD can be managed with single-agent chemotherapy using methotrexate with folinic acid. Other drugs include etoposide. If single-agent chemotherapy is used and is not working, a more aggressive treatment is warranted to prevent the emergence of drug resistance.

39. SIGNIFICANCE OF WHO SCORING Intermediate risk GTD (WHO score 5–7) Commence on regimen that includes combination chemotherapy methotrexate and actinomycin D. If a complete response is not achieved on this regimen the patient should be commenced on etoposide, methotrexate and actinomycin D, alternating with cyclophosphamide and vincristine (EMA-CO).

40. SIGNIFICANCE OF WHO SCORING High risk GTD (WHO score 8 or more) These patients require significant chemotherapy because they include those with brain metastases, liver and gastrointestinal tract metastases and they are at significant risk from massive bleeding. A combination of chemotherapy, either EMA-CO or methotrexate and folinic acid chemotherapy is indicated.

41. FIGO staging of GTN

42. TREATMENT It is important to begin treatment as soon as possible after GTN has been detected. The main methods of treatment are: Chemotherapy Surgery Radiation therapy (which is used less often)

43. STAGE 1 Initial Single agent chemo/hysterectomy with adjunctive chemo Resistant Combination chemo Hysterectomy with chemo Local resection Pelvic infusion STAGE 2 & 3 Low risk initial Single agent chemo resistant Combination chemo High risk initial Combination chemo resistant Second line combination chemo

44. STAGE 4 Initial Combination chemotherapy Brain Whole head rediation Craniotomy to manage complication Liver Resection or embolisation to manage complication Resistant Second line combination chemo Hepatic arterial infusion

45. chemotherapy Depends on the FIGO scoring

46. SINGLE AGENT TREATMENT

47. TECHNIQUE OF SINGLE AGENT

48. COMBINATION CHEMOThERAPY

49. CHEMOTHERAPY REGIMEN FOR LOW RISK PT METHOTREXATE/FOLINIC ACID METHOTREXATE 50 MG IM REPEATED EVERY 48 HR FOR TOTAL 4 DOSES CALCIUM FOLINATE 15 MG ORALLY DAILY AFTER EACH INJ OF METHOTREXATE COURSE REPEATED EVERY 2 WK 1-15-29

50. Chemotherapy regimen for high risk patient EMA DAY1 ETOPOSIDE ACTINOMYCIN D METHOTERATE DAY 2 ETOPOSIDE ACTINOMYCIN D FOLINIC ACID CO DAY 8 VINCRISTINE CYCLOPHOSPHAMIDE

51. MANAGEMENT OF DRUG RESISTANT DISEASES LOW RISK Persistent S B hCG level is <300- actinomycin D >300IU/L –-> EMA - CO HIGH RISK Combination of surgical removal of drug resistant site- uterus,lung brain) together with chemotherapy—EMA-EP High dose comb chemo with autologous stem cell support is still investigational

52. MANAGEMENT OF ACUTE DIS INDUCED COMPLICATION Haemorrhage Usually settels with rest & chemotherapy Uterine packing Embolisation Laprotomy – rare hysterectomy Respiratory failure Oxygen Positive airway Mechanical ventilation avoided

53. DURATION OF CHEMO

54. FOLLOW - UP

55. Secondary tumors Etoposide based chemotherapy has been associated with lukemia colon cancer melanoma breast cancer 25 yr aftyer chemotherapy.

56. PERSISTENT LOW LEVEL REAL HCG

57. PREGNANCY AFTER GTD

58. Role of surgery Secondary role Chemotherapy is effective in vast majority Indications Hysterectomy disease confined to uterus Placental site trophoblastic tumours epithelioid trophoblastic tumors. Resection of Isolated chemotherapy-resistant nodules e.g. thoracotomy, craniotomy Laparotomy for bowel or urinary tract obstruction Oophorectomy for torsion of ovarian cyst

59. radiotherapy For extensive metastases Brain and liver metastases In combination with chemotherapy