GTD

gtn (gestational trophoblastic neoplasia)

it is a spectrum of diseases arises from aberrant fertilization event (fetal tissues within maternal host) that includes:

1- benign hydatidiform mole which further subdivided into partial and complete mole.
2- invasive mole (chorioadenoma destruens) which can metastasize.
3- choriocarcinoma (frankly malignant).
4- placental site trophoblastic tumour (pstt).
the majority of the patients follow a benign course 80-90% and their disease remitting spontaneously.
the disease is characterized by the sensitive tumour marker (?-hcg) which is secreted by the tumour cells and allows accurate follow up of the disease.
so any woman with molar pregnancy, normal pregnancy or abortion who is presented with bleeding or a tumour should have at least one (?-hcg) assay. to exclude gtn.

etiology and epidemiology:

the incidence of this disease is varying according to many factors:
1- it is higher in asian and african women 1 in 125 deliveries in comparison to 1 in 1500 to 2000 deliveries in european and american women.
2- it is higher with maternal age < 20 (1.3 folds) and > 40 years (10 folds)
3- the risk of developing 2nd molar pregnancy is 1-3% or higher , it 40 times higher than the risk of 1st molar pregnancy.
4- diet may play a role: low protein, carotene and folic acid intake predispose to gtn.
5- higher in nulliparous women.
6- low economic status.
7- blood group a woman if married to a man with blood group o (there is 10 folds higher risk of choriocarcinoma), and if the woman of bl.gp ab it carries a relatively worse prognosis.
8- low estrogen status?
9- infrequent intercourse?













pathogenesis:

the genetics in molar pregnancy is found to be as follows:




pathology:

molar pregnancy is abnormal pregnancy characterized by multiple grapelike vesicles filling and distending the uterine cavity sometimes it develop in the tubes or the ovary, the fetus is abscent in complete mole.
histologically:
1- hydropingic degeneration and swelling of villous stroma.
2- absence of blood vessels.
3- proliferation of trophoblastic epithelium.
4- absence of fetus and amnion.
while the partial mole the fetus is present and died in the 8-9 weeks, there is mild and focal trophoblastic hyperplasia with focal atypia in the trophoblast at the implantation site, the villi are present.





comparison of complete to partial mole:

parameters complete mole partial mole
karyotype diploid 46xx or 46xy paternal triploid 69xxy or 69xxx
embryo absent present die at 8-9 weeks
villi absent present
trophoblast diffuse hyperplasia mild focal hyperplasia
implantation site trophoblast diffuse atypia focal atypia
(?-hcg) high > 50000 slight elevation < 50000
frequency of classic clinical symptoms common rare
risk for persistent gtt 20-30% < 5%

invasive mole:
it occur in 20% of patients with h.mole, pathologically it is the same as hydatidiform mole but penetrates deeply into the myometrium or the adjacent structures leading to uterine rupture and haemoperitoneum. it may regress spontaneously.

choriocarcinoma:
it is purely epithelial tumour composed of syncytiotrophoblast and cytotrophoblast it may accompany or follow any type of pregnancy, 50%after h. mole, 25% after normal pregnancy and 25% after abortion.
histologically:
sheets or foci of trophoblast on a back ground of haemorrhage and necrosis but there are no villi.

pstt:
derived from intermediate trophoblast of placental bed with minimal or absent syncytiotrophoblastic tissues.
histologically:
local invasion occurs into the myometrium and lymphatics and less commonly into the vasculature, it occur with any type of pregnancy or months to yrs later.

molar pregnancy:
clinical picture:
symptoms and signs:
1- abnormal vaginal bleeding in the 1st trimester in > 90% of the patients( brownish or bloody) , spotting or large amount of bleeding.
3/4 of them presented before the end of the 1st trimester.
2- anemia: dilutional or may be due to hemorrhage.
3- hyperemesis in 14-32% of the patients.
4- 50% of the patients have large for date uterus with soft consistency, while only 1/3 have smaller uterus.
5- no fetal parts with negative fetal heart tones.
6- multiple theca leutin cysts of the ovaries in 15-30% of the patients which regress spontaneously after termination of pregnancy.it require surgery only if complications happen.
those patients appear to have greater likelihood of developing malignant sequalae of gtn.
7- pre eclampsia early in the 1st trimester or early in the 2nd trimester.
8- hyperthyroidism: it is mild or subclinical, rarely thyrotoxicosis present.

investigations:
1-(?-hcg): this hormone is produced by gtn and can be detected in the serum or urine of all patients and its level correlate closely with the number of viable tumour cells present.
2-u/s it is the diagnostic method of choice (snow storm appearance)
3-dilatation and curettage: send the evacuate for histopathological study.

differential diagnosis:
1- normal pregnancy with bleeding( threatened abortion)
2- ectopic pregnancy
3- ???

treatment:
evacuation of the uterus preceded by complete blood count, renal function test and liver function test, and chest x- ray.
the evacuation is done by {suction curettage} which is safe rapid and effective method.
after dilatation of the cervix to 10-12 mm we pass the plastic curette and when the conceptus nearly totally evacuated we start the oxytocin and continue it for 24 hours to avoid bleeding.
blood loss is moderate so we have to prepare blood.
hysterotomy is not recommended as a treatment modality.
hysterectomy may be done if the woman > 35 years completed family and have high risk of persistent gtn hysterectomy lowers this risk from 20% to 3.5% only.
medical inducion is not recommended because fear of showering emboli through the blood stream.
all rh negative women should recieve anti-d immunoglobulin.

complications:
1- perforation
2- hemorrhage
3- deportation of trophoblastic tissues to the lungs is frequent which may regress spontaneously but sometime postevacuation acute pulmonary insufficiency may result leading to dyspnoea, and cyanosis 4-6 hours after evacuation .
4- pulmonary edema from high output heart failure , pre eclampsia, anemia, and hyperthyroidism .
5- sepsis.

prophylactic chemotherapy:
it is controversial, it is given for high risk females > 35 years prior molar pregnancy with trophoblastic hyperplasia, or in those with poor cooperation for follow up is anticipated.

surveillance following molar pregnancy:
following evacuation (?-hcg) titers should be estimated serially because of the 20-30% risk of changing to malignancy. the determination should be started 48 hours after the evacuation and weekly until it becomes undetectable on 3 successive assays.
effective contraceptive measures is essential like oral contraceptive pills or medroxyprogesterone acetate injections during the course of surveillance.
if titer remission occur spontaneously within 14 weeks then the patient should be followed monthly for 12 months before the patient is released from close medical supervision.

gynecological examination 1week after evacuation for uterine size, adnexial mass, vulval and vaginal deposits (metastasis). and should be repeated 4 weekly through the period of surveillance.

1 year after negative titers pregnancy is allowed and complications are similar to those of the general population.

**risk factors for malignant or persistent disease are:
1. the larger uterus, and the higher (?-hcg) titer at diagnosis the greater the risk of subsequent malignancy.
2. the combination of theca leutin cyst and larger than date uterus is associated with 57% risk of malignancy.
3. pathological specimens with marked nuclear atypia, presence of necrosis or hemorrhage with trophoblastic proliferation associated with high risk of persistent disease.

4. when we have abnormal (?-hcg) regression curve, and the most critical period is the 1st 4-6 weeks after evacuation. although (?-hcg) will return to normal 1-2 wks after evacuation, it should be normalized by the 8th week, but if there is rising or plateau titer at the 8th week which is seen in 15% of those patients, half of them have histological evidence of invasive mole and the other half having choriocarcinoma.

***so the indications for chemotherapy are:
1) rising titer on 2 successive weeks, 2) plateau titer on 3 successive weeks, 3) high titer at the 15th week, 4) or rising after normalization, 5) presence of histological diagnosis of choriocarcinoma, 6) metastasis, 7) or delayed post evacuation hemorrhage