Understanding Gestational Trophoblast Disease

Introduction
The abnormal proliferation of gestational trophoblast tissue forms a spectrum of diseases from the usually benign partial hydatidiform mole through to the highly malignant choriocarcinoma and placental site trophoblast tumours.
The biology, diagnosis and therapy of these diseases, combined with their psychological impact, makes trophoblast disease an extremely important and interesting area of gynecological and oncology care.

Classification
The World Health Organization classification divides trophoblast disease into the pre malignant partial and complete hydatidiform moles and the malignant disorders of invasive mole, choriocarcinoma and placental site tumors.

Pre-malignant pathology and presentation

1. Partial mole: Partial moles are triploid with two sets of paternal and one set of maternal chromosomes.
Macroscopically Partial moles often resembles the normal products of conception with an embryo initially present which usually dies by week 8–9.
The histology shows less swelling of the chorionic villi than in complete moleand there are usually only focal changes. As a result the diagnosis of Partial mole can often be missed after a miscarriage or termination.
The clinical presentation of Partial mole is most frequently via irregular bleeding or by detection on routine ultrasound.
The obstetric management is by suction evacuation and these patients should all be followed up by serial hCG measurement.
It is fortunate that Partial moles rarely moves onto malignant disease


2. Complete mole : In the majority of Complete moles all of the genetic material is male in origin and results from the fertilization of an ‘empty’ oocyte lacking maternal DNA. The chromosome count is most commonly 46XX, which results from one sperm that duplicates its DNA, or less frequently 46XX or 46XY from the presence of two different sperms. On rare occasions
Complete mole can be biparental in origin and this type is associated with a high risk of further molar pregnancies.
The clinical diagnosis of Complete mole is most often as a result of bleeding, a large for date uterus or an abnormal ultrasound.
Macroscopically there is no visible fetal material although microscopically some embryonic cells can be present.
The histology shows the characteristic oedematous villous stroma; however, the textbook ‘bunch of
grapes’ appearance is only seen in the second trimester and as most cases are diagnosed earlier, this is now rarely seen.
The obstetric management is by suction evacuation followed by serial hCG measurement.
In contrast to Partial mole, complete mole more frequently proceeds to invasive disease with 8–20% of patients requiring chemotherapy.

Indications for chemotherapy after a Molar pregnancy 

• Raised hCG level 6 months after evacuation (even if falling)
• hCG plateau in three consecutive serum samples
• hCG >20,000 IU/l more than 4 weeks after evacuation
• Rising hCG in two consecutive serum samples
• Pulmonary, vulval or vaginal mets unless the hCG level is falling
• Heavy PV bleeding or GI/intraperitoneal bleeding
• Histological evidence of choriocarcinoma
• Brain, liver, GI metastases or lung metastases >2 cm on Chest x ray

Malignant pathology and presentation: 

1. Invasive mole (chorioadenoma destruens): Invasive mole nearly always arises from a Complete mole and is characterized by invasion of the myometrium, which can lead to perforation of the uterus. Microscopically invasive mole has a similarly benign histological appearance as Complete mole but is characterized by the ability to invade in to the myometrium and local structures if untreated.

Fortunately the incidence of invasive mole has fallen substantially with the introduction of routine ultrasound, the early evacuation of Complete moles and effective hCG surveillance.

2. Choriocarcinoma:  Choriocarcinoma is histologically and clinically overtly malignant and presents the most frequent emergency medical problems in the management of trophoblast disease.

The diagnosis most frequently follows a complete mole, but can also arise in unsupervised patients after a non-molar abortion or term pregnancy. 

The clinical presentation of choriocarcinoma can be from the disease locally in the uterus leading to bleeding, or from distant metastases that can cause a wide variety of symptoms with the lungs, central nervous system and liver the most frequent sites of distant disease.

3. Placental site trophoblast tumor: It is the least common type of gestational trophoblast disease forming less than 2% of all cases. Placental site trophoblast tumor most commonly follows a normal pregnancy but can also occur after a non-molar abortion or a complete molar pregnancy, and very rarely following a partial mole.

In contrast to the more common types of trophoblast disease which characteristically present fairly soon after the index pregnancy, in placental site trophoblast tumor the average interval between the

prior pregnancy and presentation is 3.4 years. The most frequent presentation is bleeding following amenorrhea and the hCG level, while elevated, is characteristically lower for the volume of disease than in the other types of gestational trophoblastic tumors.

The tumor is diploid and arises from the non-villous trophoblast and the pathology is characterized by intermediate trophoblastic cells with vacuolated cytoplasm, the expression of placental alkaline phosphotase(PLAP) rather than hCG and the absence of cytotrophoblast and villi.

The clinical presentation of PSTT can range from slow growing disease limited to the uterus to more rapidly growing metastatic disease that is similar in behavior to choriocarcinoma.