1. Gestational trophoblastic disease (GTD) is abnormal growth of trophoblast cells that can range from benign to malignant. It includes complete and partial hydatidiform moles, as well as gestational trophoblastic neoplasia (GTN) such as invasive mole, choriocarcinoma, and placental site trophoblastic tumor. 2. A 24-year-old woman presented at 14 weeks pregnant with vaginal bleeding, nausea, vomiting, and elevated blood pressure. On examination, her uterus was enlarged beyond gestational age and no fetal heart tone was detected. 3. GTD is typically diagnosed through ultrasound, urine and blood tests. Molar pregnancies are

1. Presenter: Dr. Abdulkarim Jabra
MBChB, MD OB/GYN SPECIALIST
Topic:
Gestational Trophoblastic disease

2. Scenario
A 24-year-old Filipino nurse is 14 weeks
pregnant by dates. She complains of
vaginal bleeding as well as severe nausea
and vomiting. Her uterus extends to her
umbilicus but no fetal heart tones can be
heard. Her blood pressure is 150/95mmhg.
A dipstick urine shows 2+ proteinuria.

3. Gestational Trophoblastic Disease
Introduction
Gestational trophoblastic disease (GTD) is a spectrum of
abnormal growth and proliferation of the trophoblasts of the
placenta that continue even beyond the end of pregnancy of
the placenta.
These diseases are characterized by a reliable tumor marker,
which is the ß-subunit of human chorionic gonadotropin (ß-
hCG), and have varied tendencies for local invasion and spread.
 Benign GTD includes (a) Hydatidiform mole—complete, (b)
Hydatidiform mole—partial.
GTN encompasses: Persistent hydatidiform mole, invasive
mole, choriocarcinoma and a rare entity of placental site
trophoblastic tumor

4. Gestational trophoblastic neoplasia (GTN) refers to the subset
of GTD that develops malignant sequelae. These tumors require
formal staging and typically respond favorably to
chemotherapy.
Most commonly, GTN develops after a molar pregnancy but
may follow any gestation(such as follow abortion, ectopic, and
even normal pregnancy).
Trophoblastic disease following a normal pregnancy is either
choriocarcinoma or PSTT and not a benign or invasive mole.
The prognosis for most GTN cases is excellent, and patients
are routinely cured, even with widespread metastases.

7. EpidemiologyAndRisk Factors
The incidence of GTN is about 1 in 5000 pregnancies in
oriental countries and 1 in 50,000 in Europe and North
America.
More than 50% occur after molar pregnancy, about 25% after
abortion and/or ectopic pregnancy and a few after normal
pregnancy.
Nonmetastatic (locally invasive) lesions develop in 15% and
metastatic lesions develop in about 4% of patients after molar
evacuation.

8. Diagnosis of postmolar GTN is made when the hCG level
plateaus for 3 or more consecutive weeks or reelevates.
 This may occur in 15–20% following hydatidiform mole.
Postmolar GTN of serious nature may be either invasive mole
or choriocarcinoma but GTN after nonmolar pregnancy is
always a choriocarcinoma.

9. Risk factors: Increased prevalence geographically is most
common in Taiwan and the Philippines.
Other risk factors are maternal age extremities (age <20, age
>35) carries a higher risk of GTD and folate, Vitamin A
deficiencies.
A history of prior unsuccessful pregnancies also raises the risk
of GTD.
Combination oral contraceptive (COC) pill use has been
associated with an increased risk of GTD.

10. HydatidiformMole(MolarPregnancy)
Hydatidiform moles are abnormal pregnancies characterized
histologically by aberrant changes within the placenta.
Classically, the chorionic villi in these placenta show varying degrees
of trophoblast proliferation and edema of the stroma within villi.
Chromosomal abnormalities play an integral role in hydatidiform
mole development.
Moles usually occupy the uterine cavity, however, occasionally they
develops as ectopic pregnancy.
Hydatidiform moles are categorized as either complete hydatidiform
mole or partial hydatidiform moles.

11. Classificationof GTNis done as follows:
Benign GTN is the classic hydatiform mole (H-mole). Incidence
is 1:1200 the US; but 1:120 in the far East.
Complete mole (most common benign GTN) result from
fertilization of an empty egg with a single X sperm resulting in
paternally derived (androgenic) normal 46,XX karyotype.
No fetus, umbilical cord, or amniotic fluid is seen.
The uterus filled with a grape-like vesicles composed of
edematous avascular villi.
Progression to malignancy is 20%.

12. Incomplete mole (less common) results from fertilization of a
normal egg with 2 sperm resulting in triploid 69.XXY karyotype.
A fetus, Umbilical cord, and Amniotic fluid is seen, which
results ultimately in fetal demise.
Progression to malignancy is 10%

17. Clinical findings
The most common symptom is bleeding prior to 16 weeks
gestation and passage of vesicles from vagina. Other symptoms
of a molar pregnancy include hypertension, hyperthyroidism,
hyperemesis gravidarum, embolization and no fetal heart tones
appreciated.
The most common signs are fundus larger than dates, absence
of fetal heart tones, and bilateral cystic enlargements of the
ovary known as theca-lutein cyst.
The most common site of distant metastasis is the lung.

18. Summery clinical features
1. 1 to 2 months of amenorrhea.
2. Big significant of nausea and vomiting
3. Uterine bleeding (spots to perfuse hemorrhage).
4. Uterine growth is more rapid than the expected size.
5. Absence of fetal parts and fetal heart rate.
6. Early onset of pre-eclampsia (before 24 weeks).
7. Serum hCG level higher than expected for the stage of
gestation.

19. Diagnosis and mgment of H-mole
The diagnosis is confirmed with sonogram showing homogenous
intrauterine echoes without a gestational sac or fetal parts
(snowstorm ultrasound).
Management: baseline quantitative ß-hCG titer; chest X-ray to rule
out lung metastasis; and section D&C to evacuate the uterine
contents.
No chemotherapy; serial ß-hCG titers until (-ve); follow-up one year
on oral contraceptive pill to ensure no confusion between rising ß-
hCG titers from recurrence disease and normal pregnancy.
A single agent chemotherapy is highly effective in nonmetastatic
and low-risk metastatic GTN.

20. Definitive Management: Suction evacuation (SE) is the method
of treatment. It is safe, rapid and effective in almost all cases.
Suction evacuation can safely be done even when the uterus is
of 28 weeks gestation.
Hysterectomy. Rarely, if there is increased risk of gestational
trophoblastic neoplasia (GTN) and there's no desire for future
pregnancies, the uterus may be removed (hysterectomy).
The risk of malignant transformation of molar pregnancies
after human chorionic gonadotropin levels return to normal is
low, roughly 0.4%

22. COMPLICATIONSOFMOLARPREGNANCY
Hemorrhage and shock
Sepsis
Perforation of the uterus
 Pre-eclampsia
Acute pulmonary insufficiency.
Coagulation failure
 Choriocarcinoma late develops

23. Malignant GTN is the gestational trophoblastic tumor (GTT)
which develop in three categories.
Non-metastatic disease is localized only to the uterus.
Good prognosis metastatic disease has distant metastasis; the
most common location is the pelvic or lung. Cure rate is > 95%
Poor prognosis metastatic disease has distant metastasis
(most commonly brain or liver). Other poor prognosis factors
are serum ß-hCG level >40,000, >4months from the antecedent
pregnancy, and following a term pregnancy. Cure rate is 65%.

24. Persistent Gestational Trophoblastic
Neoplasia(GTN)
 Persistent GTN is evidenced by persistence of trophoblastic
activity following evacuation of molar pregnancy.
This is clinically diagnosed when the patient presents with (a)
Irregular vaginal bleeding. (b) Subinvolution of the uterus. (c)
Persistence of theca lutein cysts and (d) Level of hCG either
plateaus or reelevates after an initial fall.
After molar evacuation serum -hCG becomes normal in about
7–9 weeks.

25. Placental Site Trophoblastic Tumor
The tumor arises from the trophoblast of the placental bed.
Incidence is less than 1% of all patients with GTN. 15–20% of these
patients develop metastases.
Syncytiotrophoblast cells are generally absent, instead intermediate
trophoblast cells are predominant.
ß-hCG secretion is low but human placental lactogen (hPL) is
secreted and this is monitored during the follow up.
Serial serum hPL may be a reliable marker and hPL is useful for
immunohistochemical staining to confirm the diagnosis.
The entity is not responsive to chemotherapy. Hysterectomy is the
preferred treatment.

26. Epithelioidtrophoblastictumor
Epithelioid trophoblastic tumor is a distinct entity from
choriocarcinoma and PSTT.
It develops from the intermediate trophoblast and
microscopically it resembles to PSTT.
This tumor is resistant to chemotherapy and hysterectomy is
primary method of treatment.

27. INVASIVEMOLE(CHORIOADENOMA
DESTRUENS)
Invasive mole comprises about 15% of all GTN. The prominent
features of this type of mole are invasive and destructive
potentialities.
Invasive mole shows abnormal penetration through the
muscle layers of the uterus. The uterine wall may be perforated
at multiple areas showing purple, fungating growth with
massive intraperitoneal hemorrhage.
The neoplasm may invade the pelvic blood vessels and
metastasizes to vagina or distant sites as like those in
choriocarcinoma.

28. Diagnosis
1. On laparotomy: (a) Perforation of the uterus through which
purple fungating growth is visible. (b) Hemoperitoneum.
2. Histology: There is penetration of the uterine wall by the
hyperplastic trophoblastic cells which still retain villus
structures. There is no evidence of muscle necrosis.
3. Persistent high level of urinary or serum hCG.

29. CHORIOCARCINOMA
Choriocarcinoma is a highly malignant tumor arising from the
chorionic epithelium.
About 3–5% of all patients with molar pregnancies develop
choriocarcinoma.
Amongst all patients with choriocarcinoma, around 50% develop
following a hydatidiform mole, 30% occur after a miscarriage or an
ectopic pregnancy and 20% after an apparently normal pregnancy.
The primary site is usually anywhere in the uterus. Rarely, it starts in
the tube or ovary. Ovarian choriocarcinoma (nongestational) may
also be associated with malignant teratoma or dysgerminoma.
There are evidences of hemorrhage and muscle necrosis. The
villous pattern is lost.

30. SPREADOF GTN
Apart from the local spread, vascular erosion
takes place early and hence distant metastases
occur rapidly.
The common sites of metastases are lungs
(80%), anterior vaginal wall (30%), brain (10%),
liver (10%), and others.

31. CLINICALFEATURESOF GTN
The clinical features depend on the location of the primary growth
and on its secondary deposits.
Patient Profile
There is usually a history of molar pregnancy in recent past. Rarely,
its relation with a term pregnancy, abortion or ectopic pregnancy
may be established.
Symptoms
The following are the usual symptoms :
 Persistent ill health
 Irregular vaginal bleeding, at times brisk
 Continued amenorrhea.

32. Other symptoms due to metastatic lesions are:
 Lung: Cough, breathlessness, hemoptysis
 Vaginal: Irregular and at times brisk hemorrhage
 Cerebral: Headache, convulsion, paralysis or coma
 Liver: Epigastric pain, jaundice.
Signs
 Patient looks ill
 Pallor of varying degrees.
Physical signs are evident according to the organ involved.

33. Bimanual examination reveals subinvolution of the uterus.
There may be a purplish red nodule in the lower-third of the
anterior vaginal wall,
Unilateral or bilateral enlarged ovaries may be palpable through
lateral fornices.
Chest X-rayX-ray shows ‘cannon ball’ shadow or ‘snow storm’
appearance due to numerous tumor emboli. Pleural effusion may be
present.
Pelvic Sonography helps not only to localize the lesion but to
differentiate GTN from a normal pregnancy.
Diagnostic Uterine Curettage: Pretherapy D and C reduces the
intrauterine tumor bulk.

34. DIAGNOSISOF METASTASES
Vaginal nodules: Excision biopsy or biopsy should not be done.
Massive hemorrhage following resection may need packing or
selective embolization.
Cerebral: The ratio of hCG levels in spinal fluid and serum is
higher than 60. CT scan or MRI.
Liver: CT scan; ultrasonography.
Chest: X-ray (metastasis); CT may show micrometastases
which are not visible on a chest radiograph.
Metastases to other sites are uncommon when pelvic
examination and chest X-ray are normal.

35. STAGING
The anatomic staging for gestational trophoblastic tumors (GTT)
as described by FIGO is tabulated below:
The drawbacks of the anatomic staging are:
As the site of lesion cannot be located precisely, even though
hCG is elevated, it is not logical to categorize the lesion to be as
stage I.
It does not help in treatment.
The prognosis is poorly correlated.

36. MANAGEMENTOF GTN
1. Preventive
2. Curative
Preventive
Prophylactic chemotherapy ‘At risk’ women are:
 Age of patient > 35 years.
 Initial levels of serum hCG ≥100,000 IU/mL
– hCG level fails to become normal by 7–9 weeks time or there is re-
elevation.
– Histologically diagnosed as infiltrative mole.
 Evidence of metastases irrespective of the level of hCG.
 Previous history of a molar pregnancy.
 Woman who is unreliable for follow up.
Disadvantage of routine chemotherapy is unnecessary exposure of the toxic
drugs to all women who may not need it. Majority (80–90%) of women do not
develop persistent GTN.

37. Curative
- Chemotherapy
- Surgery
- Radiation
In general, patients with nonmetastatic (low risk) and good
prognosis disease are treated effectively with single agent
therapy (methotrexate or actinomycin). The patients with poor
prognosis metastatic disease should be treated with
combination drug regimen (EMA-CO regimen).
Management of GTN needs thorough assessment of the extent
of the disease.
Chemotherapy regimen is decided on the consideration of
anatomic staging

39. Whatever drugs are used, the basic formalities
are to be followed as tabulated in Table 24.22.

40. Radiation: Patients with brain metastases require whole-brain
radiation therapy (3000 cGy over 10 days).
Intrathecal high dose methotrexate may be administered to prevent
hemorrhage and for tumor shrinkage.
Liver Metastasis : Interventional radiology (hepatic artery ligation or
embolization) or whole liver radiation (2000 cGy over 10 days) along
with chemotherapy may be effective. Hepatic metastasis has a poor
prognosis.
Transplacental metastases to the fetus is rare and the prognosis is
poor.
Prognosis: The cure rate is almost 100% in low risk and about 70% in
high risk metastatic groups.
Recurrences: For nonmetastatic GTN 2–3%; ‘good prognosis’
metastatic disease 3–5% and ‘poor prognosis’ disease 21%.
Recurrence following 12 months of normal hCG level is < 1%.

41. Placeof Hysterectomy
Primary hysterectomy has got a limited place(Total hysterectomy is
to be done on day 3 of a course of chemotherapy).
 Chemotherapy alone is successful in curing 85% of patients with
nonmetastatic and good prognosis metastatic GTN.
In patients with nonmetastatic or good prognosis metastatic
disease, hysterectomy decreases the number of courses of
chemotherapy.
Types of Surgery
 Total hysterectomy is enough. The ovaries are usually not involved and if
involved, can be effectively cured with postoperative chemotherapy.
 Lung resection (thoracotomy) in pulmonary metastasis in drug resistant
cases.
 Craniotomy for control of bleeding.

42. FutureChildbirth
There is no adverse effect on the subsequent pregnancy
provided the conception occurs after 1 year of completion of
chemotherapy.
Pregnancy should be confirmed by USG early and hCG level is
to be measured 6 weeks after delivery to exclude persistent
GTN.
Incidence of placenta accreta is increased.
Follow up is mandatory for all patients at least for 2 years.
Serum hCG is measured weekly until it is negative for three
consecutive weeks. Thereafter it is measured monthly for 6
months and 6 monthly thereafter for life.

43. Increased risk for the development of secondary malignancies
like leukemia, colon cancer, and breast cancer has been
observed. This is common after treatment with multiple agent
chemotherapy. Etoposide is reserved for resistant and high-risk
cases only.

44. SURVEILLANCEDURINGANDAFTERTHERAPY
OFGTN

45. Phantom ß-hCG
In some patients mildly elevated levels of ß-hCG serum
persist. But in reality there is no true ß-hCG or no trophoblastic
desease is present.
This ‘phantom’ ß-hCG is due to heterophile antibodies in the
patient’s serum that interfere with the ß-hCG immune assay
and cause a false positive result.
 In such a situation patient does not need any active
management neither chemotherapy nor hysterectomy.
The diagnosis can be confirmed by doing the urine test that
will be negative. Heterophile antibodies are not filtered in the
urine.