1. Gestational Trophoblastic Disease GTD
By Dr. Dalya Muthefer

2. Gestational Trophoblastic Disease GTD
Is defined as a spectrum of disorder resulting from an abnormal placental ( trophoblast ) growth and invasion, it is ranged from the benign condition ( hydatiform mole ) to the malignant ( gestational trophoblastic neoplasia GTN ).
These disease retain certain characteristic of the normal placenta such as invasive tendencies and the ability to make hCG hormone.

3. Clinical classification :
Benign = 80% (HM)
Partial HM .
Complete HM .
Malignant=20% (GTN) include
Persistant or invasive mole =12-15% of cases.
Choriocarcenoma=5-8% of cases .
Placental site trophoblastic tumor (rare).

4. Epidemiology
Less than 1 in pregnancies in most of the world, 2 in 1000 in Asia . 
Risk of recurrence is % (previous one mole).
25% (previous two moles).

5. Risk factors
Extremes of maternal age < 15 years or > 40 years of age.
Patients with previous history of molar pregnancy.
Possible other factors: deficiency of animal fat and carotene , history of prior spontaneous abortion .
The incidence is in excess in maternal blood group A, and deficit in group O.
Low socioeconomic state .
Using of oral contraceptive pills

6. Hydatidiform mole (HM)
Complete mole
Partial mole

7. Comparison of Complete and partial moles
Feature
Complete Mole
Partial Mole
Age
Greater risk (5-103)
Not age related
Karyotype
90% XX, 10% XY
All chromosomes paternally derived
XXX or XXY
1 Chromosome set maternal:
2 chromosome sets paternal
Fetus
Absent
Present
hCG
Often > mIU/mL
Rarely elevated above normal levels for pregnancy
Primary Symptom
Bleeding
Secondary Symptoms
Large uterine size for gestational age
Hyperemesis
Theca Lutein cysts
Preeclampsia
Hyperthyroidism
Un common
Risk of persistence (GTN)
20% 4%

8. Partial mole
Complete mole

9. Management of HM :
In general , the more active trophoblastic appearance the greater the risk of malignancy.
Patients with hydatidiform mole are curative over 80% by treatment of evacuation. (suction curettage)
About 90% of cases ,the trophoblastic tissue die out completely.
About 10% of cases the trophoblastic tissue does not die out completely and may persist or recur as invasive mole or choriocarcinoma.

10. The follow-up after moler evacuation :
The follow - up after evacuation is key necessary to ensure early recognition of persistent trophoblastic tissue and the development of GTN, this includes :
Clinically ( uterine involution , ovarian cyst regression and cessation of bleeding )
Serial quantitative measurement of serum hCG level 48 hours after evacuation of the mole then at weekly intervals till the hCG become normal for three consecutive reading .Then monthly for 6 months then yearly .
To achieve effective follow - up , the pregnancy should be avoided to avoid the overlap of raising HCG level due to recent pregnancy , the use of mechanical or oral contraceptive pills until the hCG levels returns to normal after the evacuation of the mole.

11. Indication of chemotherapy after the evacuation of the hydatidiform mole :
Serum hCG >20000 i.u/L , at any time after evacuation of mole.
Raised hCG at 4 to 6 weeks after evacuation of mole.
Evidence of metastases ,hepatic ,brain and pulmonary.
Persistent uterine hemorrhage after evacuation of mole with raised hCG levels.

12. Early diagnosis of persistent trophoblastic disease ensures a good prognosis and an effective system of follow-up.
A rising or persistently elevated serum hCG concentration is diagnostic of GTN after a new pregnancy is ruled out.
Approximately percent of these cases represent invasive mole , and 25 percent are choriocarcinomas ; placental site trophoblast tumors are rare.

13. High-risk postmolar trophoblastic tumor:
Pre - evacuation uterine size larger than expected for gestational duration.
Bilateral ovarian enlargement (> 9 cm theca lutein cysts)
Age greater than 40 years.
Very high hCG levels(>100,000 m IU/ml).
Medical complications of molar pregnancy such as toxemia , hyperthyrodism and trophoblastic embolization (villi come out of placenta ).
Repeated hydatidiform mole .

14. Gestational trophoblastic neoplasia (GTN)
Invasive mole
Choriocarcinoma
Placental site trophoblastic tumor

15. Gestational trophoblastic neoplasia (GTN)
GTN defines a heterogeneous group of lesions that represent an aberrant fertilization event.
The pathogenesis is unique because the maternal tumor arises from fetal tissue.
It is the most curable gynecologic malignancy.
Malignant trophoblastic disease can exist in:
Invasive mole ( = non – metastatic form).
Choriocarcinoma = metastatic form
(Both are treated with chemotherapy and follow up by serum BHCG). 
Placental site trophoblastic tumor (PSTT).

16. Invasive mole
The diagnosis of invasive moles or “chorioadenoma destruens” is applied to the moles characterized by :
Abnormal peneterativeness
Extensive local invasion
Excessive trophoblastic proliferation
With preserved villous pattern.
The proliferative villi may invade the myomatrum , paramatrum ,broad ligament , or the vaginal wall , although there is rarely evidence of metastasis.
The morbidity and mortality (10%) of this disease results from the penetration of the tumor through the myomatrum and to the pelvic vessels with the resultant hemorrhage

17. Clinical Manifestation
irregular vaginal bleeding.
uterine subinvolution.
theca lutein cyst does not disappear after emptying uterus.
abdominal pain.
metastatic focus manifestation.
Diagnosis
history and clinical manifestation.
successive measurement of HCG.
ultrasound examination.
X-ray and CT.
histologic diagnosis obtained after hysterectomy .

18. Invasive hydatidiform mole infiltrating the myometrium

19. Choriocarcinoma(metastatic GTN)
Choriocarcinoma subdivide into:
good-prognosis (low risk).
Poor- Prognosis (High risk).
Epidemiology
The incidence of choriocarcinoma in the West: 1 :10000 and 1 : pregnancies; and ,in Asia 1:6000 pregnancies. 
The antecedent pregnancy is :
Hydatidiform mole in about 5o% of cases.
Normal pregnancy in about 25% of cases.
Abortion and ectopic pregnancy in about 25 % of cases.
Choriocarcinoma is more likely to occur after complete mole .

20. Pathological features
Site :
In the uterus 90 % of cases; 10 % of cases in the , vagina, lung, liver, and brain.
Macroscopically:
Uterus : It may be localized in the form of hemorrhagic polyp or multiple hemorrhagic ,necrotic masses in the cavity.
Some times it is present in the uterine wall ( intramural ) and the cavity is empty.
Microscopically:
Malignant hyperplasia of both cytotrophoblasts , and syncytiotrophoblasts.
Extensive hemorrhage.
Absence of villi.
Destruction of the surrounding myomatrum.

21. Spread
Direct : Through the myomatrum and may end in uterine perforation , internal hemorrhage, and peritonitis .
Blood : The main method of spread ,and occurs to;
Genital : Vagina ( 30% ).
Extra genital : Lung ( 80% ) , ( the commonest site liver , brain (10%) and bones especially skull and spine.(10%).

22. Causes of death in choriocarcinoma :
Vaginal bleeding.
Haemoptysis.
Intraperitoneal hemorrhage.
Peritonitis.
Metastasis to the vaital organs e.g ,brain.
Pulmonary complications.

23. Clinical feathers Symptoms : Signs:
Recent history of expulsion of vesicular mole , or abortion , or full term pregnancy.
Persistent vaginal bleeding is the commonest presentation.
Haemoptysis.
Abdominal pain.
Palpable abdominal mass ( enlarge uterus or parauterine metastasis ).
neurological symptoms.
Signs:
Marked deterioration of the general condition.
An abdominal swelling may be felt.
The uterus symmetrically enlarged.
Hemorrhagic secondaries may be seen in the vagina.

24. Investigations: Serum hCG. CBC L.F.T . U/S for abdomen and pelvis.
Chest X-ray for pulmonary metastasis.
Liver scan
CT scan for the secondaries.
EEG .

25. Choriocarcinoma: Ultrasound reveals a hyperechoic mass showing hypervascularity on color Doppler.

26. Clinical classification of GTN
According to the FIGO system , patients who score 6 and below receive low-risk treatment while patients scoring 7 are given high-risk treatment (chemotherapy )
According to the presence of metastasis
Non metastatic trophblastic disease(Disease is limited to the uterus)
Metastatic either :
Good Prognosis Metastatic Trophoblastic neoplasia
Poor Prognosis Metastatic Trophoblastic neoplasia
Drug-resistant disease

27. The international federation of gynaecology and obstetrics(FIGO) prognostic scoring system employed for assessing the intensity of the initial chemotherapy treatment.
Score 1 2 4
Age ( years )
< 40
≥ 40 -
Antecedent pregnancy
Mole
Abortion
Term
Months from index pregnancy
< 4
4-6
7-13
≥13
Pre-treatment hCG (IU/L)
< 1000
>100000
Largest tumour size
< 3cm
3 - 5cm
≥ 5cm
Site of metastases
Lung
Spleen, kidny
gastrointestinal
Brain , liver
Number of metastases
1 - 4
5 - 8
> 8
Previous chemotherapy
Single agent
Two or more drugs

28. Treatment of GTN : Chemotherapy (single agent ,multi agent). Surgery.
Radiotherapy .

29. Medical (chemotherapy)
I. Non metastatic and good prognosis GTN we use the
Single agent chemotherapy .
Methotrexate ( antimetabolite ) + folinic acid . Is the treatment of choice given on alternate days followed by six rest days . The cytotoxic therapy is controlled by doing CB , platelet count and LFT.
After the hCG level gets normal ; stop the therapy and follow - up by weekly estimation of hCG levels . Physical examination, chest x-ray, and LFT.
Actinomycin D ,if there is resistance .
Treatment is 100 % successful.

30. II. Poor Prognosis metastatic trophoblastic neoplasia and drug resistant tumor we use
Multiple agent chemotherapy is recommended in this disease.
EMA - CO is considered the regimen of choice in most high–risk patients (Etoposide , Methotrexate, Actinomycin D , Cyclophosphamide, Vincristin ).
The overall survival rate for these patients is 80 – 85 %.
Patients with cerebral or hepatic metastases are treated concurrently with radiotherapy for the whole brain or liver (for hemostasis).

31. Surgery:
Total abdominal hysterectomy may be done in patients not desirous of further reproduction , and in old age woman.
Surgical excision of isolated metastases e.g. pulmonary if resistant to chemotherapy.
operation is also important in controlling bleeding , infection, complication.
in removing remained or drug-resistant foci.
Irradiation
Whole brain irradiation for cerebral metastases , and the whole organ irradiation for hepatic metastases

32. Follow-up
After successful therapy , physical examination , and chest x-ray follow - up together with the hCG levels are obtained for serial interval measurement .
If at any time hCG levels rises , repeat the evaluation , staging ,and chemotherapy.
Women who undergo chemotherapy are advised not to conceive for one year after completion of treatment.

33. Placental Site Trophoblastic Tumor .
Rare tumors (account for 0.23% cases of GTD).
It has a variety of clinical features and its course is unpredictable.
Can appear shortly after termination of pregnancy or years later.
Hysterectomy is considered optimal therapy and is usually adequate in most situations.
It has normal HCG level but high human placental lactogen level so used as a tumor marker.
It is chemoresistant and radioresistant.

34. Future Childbearing
After treatment of GTN, molar pregnancies occur in only about 1-2 % of subsequent pregnancies.
These patients should be evaluated with a first trimester ultrasonography.
Fertility rates and pregnancy outcomes are similar in patients treated for GTD compared with the general population .
Standard chemotherapy protocols have minimal impact on the subsequent ability to reproduce.
Patients treated with EMA/CO regimens have an increased rate of second malignancies, particularly hematologic.