Gestational Trophoblastic Disease (GTD)

Gestational trophoblastic disease (GTD) encompasses a large group of neoplastic diseases arising from trophoblastic tissue. The most common diseases are the following:

Hydatidiform mole-Complete and Incomplete mole
Invasive mole (Chorioadenoma destruens)
Choriocarcinoma
Epithelioid trophoblastic tumor
Placental site trophoblastic tumor

In addition, there are some proliferations of trophoblastic tissue which are benign but may histologically mimic disease.

Miscellaneous trophoblastic lesions
Exaggerated placental site
Placental site nodule or plaque

Patients with molar pregnancy, the most common form of GTD, may present with vaginal bleeding and excessive uterine enlargement for gestational age, usually between 11-25 weeks of pregnancy. Pregnancy induced hypertension may occur in 1/4 of patients. Other presenting signs include hyperthyroidism and hyperemesis gravidarum. Characteristically, the serum HCG is elevated. An ultrasound of the uterus reveals a characteristic snowstorm pattern, representing the hydropic chorionic villi which characterizes the disease. After evacuation of the uterus, careful clinical follow up with serial measurements of the serum HCG is necessary to ensure there is no recurrence and all of the disease has been removed.

Incidence

Complete Mole

1/1000 pregnancies
Most frequent form of molar pregnancy and GTD

Incomplete mole

25-74% of all molar pregnancies

Choriocarcinoma

1/20,000 pregnancies
The more abnormal the pregnancy, the more likely this will occur
1/160,000 normal gestations
1/15386 abortions
1/5333 ectopic pregnancies
1/40 molar pregnancies

Epithelioid trophoblastic tumor

Very rare

Placental site trophoblastic tumor

Rarest form of GTD

Age Range

Usually disorders of reproductive age
Increased risk of moles at the extremes of reproductive age
Complete mole : 11-25 weeks of pregnancy
Incomplete mole : 9-34th weeks of pregnancy
Invasive mole : May occur simultaneously with intracavitary molar pregnancy

Risk Factors

Low socioeconomic conditions
Diet : Possible dietary deficiency of carotene
Blood groups : Choriocarcinoma more frequent in Blood Group A

Stronger for women of type A and husbands of type O and conversely for group O women and type A husbands

History of prior spontaneous abortions : More common in hydatidiform mole and choriocarcinoma
Term pregnancy and live births : Protective effect and increases with an increased number of live births

Pathogenesis

Complete Mole

46XX with both X chromosomes androgenic or paternal origin-Results from duplication of the haploid sperm in an empty ovum. 3-13% have normal 46XY but both XY chromosomes are paternal-Results from dispermy, fertilization of an empty ovum by two sperm. Hydatidiform moles are pregnancies characterized by abnormal development of both embryonic and extraembryonic tissues and are associated with the misexpression of imprinted genes. The vast majority of complete hydatidiform moles are diploid and androgenetic, whereas partial hydatidiform moles are triploid, with an extra set of chromosomes of paternal origin.

Incomplete Mole

Triploidy (69 chromosomes) with maternal chromosome complement. Most are 69XXY, 69XXX, and rarely 69XYY. Results from fertilization of an egg with a haploid set of chromosomes by either two sperms, each with a haploid set of chromosomes or by a single sperm with a diploid genome of 46 XY (diandric-paternally derived triploidy).

Placental site trophoblastic tumor (PSTT)

Placental site trophoblastic tumor (PSTT) is a neoplastic proliferation of the implantation intermediate trophoblast.

Laboratory Investigations

FISH: Determination of DNA ploidy by fluorescence in situ hybridization (FISH) in hydatidiform moles: Evaluation of FISH on isolated nuclei.
β- hCG
In the past 20 years, the diagnosis of hydatidiform moles has become more difficult because of the widespread use of early uterine evacuation. Differentiating hydropic degeneration, partial, and complete moles is important because of their different prognosis. However, clinical diagnosis is less obvious, and the pathologist has to separate the different entities on the basis of very subtle morphologic criteria.In difficult cases, ploidy may be determined by various methods, including fluorescence in situ hybridization (FISH) on routine histological sections from paraffin-embedded specimens. However, FISH analysis is often difficult because of the presence of numerous truncated nuclei. In this context, we have tested the advantages of FISH on isolated nuclei, a well-known variant of the technique that might be more sensitive.

Gross Appearance

Complete mole

Hydropic chorionic villi
Large for dates uterus

Incomplete mole

Often small for dates uterus, resembling a missed abortion
Volume of tissue usually <200 ml
Villi are grossly enlarged but smaller than seen in a complete mole
Fragments of normal placenta and a fetus may be found

Invasive mole

Requires demonstration of molar villi invading into the myometrium or deported to extrauterine sites.

Choriocarcinoma

Usually presents with abnormal uterine bleeding but symptoms of metastases may be the first symptom.
Dark red hemorrhagic mass with a shaggy irregular surface.

Epithelioid trophoblastic tumor

Similar presentation as choriocarcinoma and invades the myometrium in an expansile rather than permeative growth
Not associated with central necrosis or hemorrhage
Elevated serum β-HCG

Placental site trophoblastic tumor

Variable in size but may present with diffuse nodular enlargement of the myometrium-occasionally polypoid projecting into the uterine cavity
Invasive tumor frequently extends into the uterine serosa and adnexal structures

Histological Types

1. Complete mole

Enlarged edematous chorionic villi with central cisterns
Usually avascular villi
Haphazard circumferential trophoblastic proliferation around the villus

2. Incomplete mole

Molar change is focal with a mixture of edematous villi and small relatively normal sized villi
Central cisterns are less conspicuous
Smaller villi with stromal fibrosis
Invaginations of trophoblast into the villous stroma giving a scalloped appearance, appearing as inclusions within the stroma

3. Invasive mole

Molar villi with trophoblast within the myometrium or at an extrauterine stie
Villi are usually 4-5 mm in diameter but hydropic changes are not as marked as in complete moles

4. Choriocarcinoma

Masses and sheets of trophoblastic cells without villi invading the surrounding tissue and permeating vascular spaces
Central hemorrhage and necrosis with a rim of viable tumor

5. Epithelioid trophoblastic tumor

Admixture of intermediate, cyto- and syncytio-trophoblastic cells with considerable nuclear atypia

6. Placental site trophoblastic tumor

Abundant extracellular eosinophilic fibrinoid is present within the tumor
Blood vessel walls are extensively replaced by trophoblastic cells and fibrinoid material
Extensive necrosis may be present

Metastasis

Lungs, brain, liver

5-Years Survival Rate

In diseases treated with surgery and combination chemotherapy:
Disease confined to uterus-100%
Metastatic disease-83%

Treatment

Combination of surgery with chemotherapy
MAC-methotrexate, actinomycin D, and chlorambucil

Prognosis & Recurrence