GTD 2

Malignant GTN:
The malignant GTN can be classified into the non-metastatic invasive mole and the metastatic: choriocarcinoma and the PSTT.
Malignant disease can be suspected when :
1- Plateauing or rising B-hCG value over a period of 3 consecutive weeks.
2- A rise of B-hCG over a period of 2 weeks.
3- Persistence of a detectable B-hCG after 6 months of evacuation..
The frankly malignant disease is further subdivided into:
Good prognosis group (low risk group)
And the poor prognosis group (high risk group).

Choriocarcinoma:
The incidence of Choriocarcinoma is varying between 1:10 000 to 1:70 000 in the west. And between 1:250 to 1:6000 in Asia.
It is purely epithelial tumour composed of syncytiotrophoblast and cytotrophoblast.
The antecedent pregnancy is H. mole in 50%, normal pregnancy in 25% and abortion or ectopic pregnancy in 25%.
The risk of Choriocarcinoma is 2-4% after H. Mole i.e. 1000 times greater than after normal pregnancy.
Histopathological features:
Sheets or foci of trophoblast on a back ground of haemorrhage and necrosis but there are no villi, it invade the myometrium and metastasizes to the lungs, brain, liver, and other organs.
Confirmation of the diagnosis is made by dilatation and curettage but it carry high risk of uterine perforation and dissemination of the disease, so it can be diagnosed basically depending on the clinical suspicion and B-hCG levels measurement.

Clinical Presentation:
1- Vaginal bleeding is the most common symptom.
2- Lower abdominal pain because of invasion of the surrounding structures.
3- Abdominal AND/OR vaginal swelling.
4- Amenorrhea may precede bleeding caused by the high B-hCG produced by the tumor mass.
5- Pulmonary metastasis may cause dyspnoea and haemoptysis it may be misdiagnosed as pulmonary T.B and it can be diagnosed by CXR.
6- Neurological abnormality may indicate brain invasion.
7- High index of suspicion is required to diagnose it especially if it follows normal pregnancy or abortion.

On examination:
Most of the patients have enlarged uterus as well as ovarian enlargement by theca lutein cysts.
Sites of metastasis should be looked for especially in the vagina cervix and the adnexia.


Investigations:
1- B-hCG level in the serum or the urine.
2- U/S for the pelvis, liver, kidneys…
3- CXR.
4- CT for the brain, liver, and pelvic organs metastasis.
5- MRI for the brain.
6- Lumber puncture: CSF to measure the B-hCG level in the CSF it should be greater than 1:60 (the ratio of the level in the CSF to that in the serum)
7- CBP, LFT, RFT, and the coagulation study.

Classification of the disease according to the prognostic factors:
1- Good prognosis metastatic disease:
a- short duration (<4 months) between the antecedent pregnancy and chemotherapy.
b- Serum B- hCG <40 000 mIU /ml
c- No metastasis to the brain and the liver.
d- No prior chemotherapy.
2- Poor prognosis metastatic disease:
a- long duration from the antecedent pregnancy (>4 months) to chemotherapy.
b- Serum B- hCG >40 000 mIU /ml.
c- Metastasis to the brain.
d- Unsuccessful prior chemotherapy.
e- If the disease is following term pregnancy.

We have the WHO scoring system which is based on an individual risk factors including:
Age, type of antecedent pregnancy, interval from the pregnancy to initiation of chemotherapy, pretreatment B-hCG levels, size of largest tumour, site of metastasis, and failure of chemotherapy.
We have low risk and high risk categories based on total score. If 0-6 ? low risk, and if score of 7 or more ? high risk.


Staging of the disease:
FIGO anatomic staging:
Stage I: disease is confined to the uterus.
Stage II: disease extends outside the uterus but limited to the genital tract.
Stage III: disease extends to the lungs with or without genital tract invasion.
Stage IV: all other metastasis.

Treatment:

For the non metastatic GTD:
When the disease is confined to the uterus in which the diagnosis is usually made during the follow up period after evacuation of a molar pregnancy.
Therapy includes:
1- Single agent chemotherapy: either methotrexate (MTX) or actinomycin –D (dactinomycin).
2- Combined chemotherapy and hysterectomy in female who not wish to preserve reproductive function and her disease is confined to the uterus.
MTX is given in one of the following regimens:
a- MTX 30-60 mg/m2 i.m once/week this is for non metastatic disease only.
b- MTX 0.4 mg/kg/day i.v or i.m for 5 days every 14 days.
c- MTX 1 mg/kg on days 1,3,5,7 and folinic acid 0.1 mg/kg i.m on days 2,4,6,8 and repeated every 15-18 days. (This regimen is followed in our practice and associated with least side effects of MTX and least toxic).

Actinomycin –D 1.25 mg/m2 i.v every 14 days or 10-12 microgram /kg/day for 5 days every 14 days.
During the treatment cycle or once per week we have to check the RFT, LFT, CBC and platelet count
Treatment should be stopped when:
WBC<3000 PLAT <100 000, elevated liver enzymes or severe side effects: severe stomatitis, GIT ulceration or febrile course.
Switching to alternative chemotherapy when:
B-hCG rising with the treatment, titer plateauing at an elevated level, new metastasis appear while the patient on treatment and lastly if the hormone is detectable after 5 courses of chemotherapy.
*Contraception should be continued for 1 year following remission.
* Chemotherapy is continued for 1 cycle following negative titer.
* An average of 3-4 treatment cycles is required.
* The number of treatment cycle is proportionate to the initial hormone titer.
* The advantage of single agent chemotherapy is less toxic but treatment failure is about 6-10%
* follow up program: B-hCG weekly until 3 consecutive normal titer, then monthly for a year, then 2 monthly for another year, then 6 monthly for life,
Pelvic examination and CXR weekly until remission is induced then 3 monthly for 1 year then 6 monthly for life.

Treatment for the low risk metastatic disease:
In whom the metastases are confined to the lungs or pelvis and s. B- hCG <40 000 at the onset of the therapy which is started within 4 months of apparent onset of the disease. Those patients are expected to respond satisfactorily to single agent chemotherapy.
So we use either single agent chemotherapy or multiple agent chemotherapy if resistance is anticipated to single agent chemotherapy.

For poor prognosis patients:
Patients based on clinical classification of malignant disease those who respond poorly (<40% response rate to single agent chemotherapy.
Prior unsuccessful chemotherapy is one of the worst prognostic factors because of considerable toxicity and depleting bone marrow reserves.
Generally those patients require prolonged hospitalization and multiple courses of chemotherapy, specialized care, and life support measures: (antibiotics, and transfusions).
Patients with brain and liver metastases are at great risk of sudden death from hemorrhage for that reason it is standard practice in USA when treating them to include immediate institution of whole brain or whole liver irradiation concomitantly with combination chemotherapy.
For acute bleeding episodes either treated by surgical intervention or by angiographic Embolization.

Combined chemotherapy:
MAC (MTX, actinomycin-D, chlorambucil or cyclophosphamide)
Modified BAGSHAWE protocol {CHAMOCA: cycloph., hydroxyurea, MTX, vincristine(oncobin), cycloph., actinomycin-D}.
CURRENTLY: EMA-CO: (etoposide, MTX, actinomycin-D, cycloph., and vincristine).
This protocol gives the best response rate (80%), the treatment cycle should be repeated every 2 weeks and the same investigations are done (RFT, LFT, CBC …)

IF RESISTANCE OCCURS:
EMA-EP: (etoposide, MTX, actinomycin-D, etoposide and cis-platin)
Adjuvant surgery: hysterectomy, thoracotomy or craniotomy for chemotherapy resistant cases.
If failure is encountered with EMA-EP then use BEP Protocol(bleomycin, etoposide, and cisplatinum).
And there are many other new protocols of chemotherapeutic treatment.
* Triple agent chemotherapy should be continued for at least 3 cycles after negative B-hCG level is achieved.
*effective contraception should be continued.
*complete remission is said to be achieved after 3 consecutive weeks with negative titers.
*follow up the same as with the low risk group.

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.
It is treated by hysterectomy because of resistance to chemotherapy if there is metastasis it is an indication for chemotherapy with EMA-EP.
The worst prognosis is when there are more than 2 years between the antecedent pregnancy and the diagnosis of PSTT.





Prognosis:
1. For H.Mole the prognosis is excellent,
2. and for the non metastatic disease the prognosis is very good.
3. For the good prognostic group the cure rate is 75-85%,
4. and for the poor prognosis group if there is liver metastases the survival from (0-60%).
5. The survival is <20% if previous failed chemotherapy or when metastases to the CNS occur in the 1st few months following termination of chemotherapy.

Secondary tumor:
Induction by the chemotherapy is another concern; they found that those patients with multiple agent chemotherapy especially (Etoposide) have increased risk to develop myeloid leukemia and colonic cancer.

Subsequent pregnancy:
There are no extra complication during pregnancy but require good follow up by U/S and B-hCG levels because of the 2% risk of recurrence after 1 mole and 25% after 2 moles.
After delivery placenta should be sent for histopathological study and B-hCG level measurement after 6 weeks from the delivery.