Gestational Trophoblastic Disease (GTD)

Gestational Trophoblastic Disease (GTD)

• GTD is a spectrum of disorders resulting from abnormal placental (trophoblast) growth and invasion.
• It ranges from benign conditions like hydatidiform mole to malignant gestational trophoblastic neoplasia (GTN).

Clinical Classification

• Benign GTD makes up 80% of cases and includes partial and complete hydatidiform moles (HM).
• Malignant GTD constitutes 20% of cases and includes persistent or invasive moles (12-15%), choriocarcinoma (5-8%), and rare placental site trophoblastic tumors.

Hydatidiform Mole

• It is an abnormal placental condition with degenerative and proliferative changes in chronic villi, forming clusters of small cysts.
• Hydatidiform moles, also known as H.mole, are a benign neoplasia of the chorion with malignant potential.

Epidemiology of HM

• Globally, hydatidiform moles occur in less than 1 in 1000 pregnancies, while in Asia, the rate is 2 in 1000 pregnancies.
• The risk of recurrence is 1% after one previous mole and 25% after two previous moles.

Risk Factors for HM

• Race and ethnicity, with Asian populations being more affected.
• Maternal age extremes: younger than 15 years or older than 40 years.
• Previous history of molar pregnancy.
• Faulty diet, specifically deficiencies in animal fat, folic acid, and carotene.
• Higher incidence in maternal blood group AB and lower in group O.
• Genetic predisposition.

Pathology of HM

• Absent central blood vessels in the villi leads to fetal demise.
• Hydropic degeneration of villi occurs.
• Hyperplasia of trophoblasts leads to increased human chorionic gonadotropin (HCG) and theca lutein cysts in the ovary.

Complete Mole

• Karyotype is 90% 46 XX or 10% 46XY, with all chromosomes paternally derived.
• No fetus is present.
• hCG levels are often greater than 100,000 mIU/mL.
• Primary symptom is bleeding.
• Secondary symptoms include large uterine size for gestational age, hyperemesis, theca lutein cysts, preeclampsia, and hyperthyroidism.
• The risk of persistence (GTN) is 20%.

Partial Mole

• Karyotype is 69XXX or 69XXY (70%) or 69xyy, with one chromosome set maternal and two chromosome sets paternal.
• A fetus may be present.
• hCG levels are rarely elevated above normal levels for pregnancy.
• Primary symptom is bleeding.
• Uncommon secondary symptoms.
• The risk of persistence (GTN) is 4%.

Clinical Presentation of HM

• Symptoms of early pregnancy are present.
• Can cause amenorrhea and excessive vomiting due to elevated B-hCG.
• Irregular vaginal bleeding, which may contain vesicles that are diagnostic.
• Pain may present as colicky (uterine contraction), stabbing (perforation), or dull aching (uterine distension).
• Undue enlargement of the abdomen occurs, with absent fetal movements even when the uterus reaches above the umbilicus.
• Dyspnea and palpitation are felt with a much enlarged uterus.

Signs of HM

• Anemia due to blood loss can occur.
• Early onset of pre-eclampsia (PET) is possible in 20% of patients.
• Thyrotoxicosis due to high HCG levels.
• Dehydration (Hyperemesis Gravidarum).
• Breast signs of pregnancy may be present.
• Rapid pulse is often seen.
• Blood pressure is usually elevated but might be lowered in rare cases with HEG, potentially causing dehydration.
• Abdominal examination reveals that the uterus may be large for date (50%), same as date (25%), or small for date (25%).
• A Doughy sensation of the uterus is often detected.
• Fetal parts are impalpable and the fetal heart is inaudible.
• Vaginal examination indicates signs of pregnancy, vesicles (pathognomonic), and ovarian cysts.

Diagnosis of HM

• Clinical presentation
• B.HCG levels in blood greater than 100,000 IU/ml, requiring follow-up.
• Ultrasound detects a "snow storm" appearance with no fetal part in complete moles, a fetus inpartial moles, and ovarian cysts.
• Chest X-ray shows a "canon ball" appearance.
• MRI of the pelvis is performed.

Complications of HM

• Anemia, infection, bleeding, shock, hyperthyroidism, pre-eclampsia, DIC, trophoblastic embolization to the lung, theca lutein cysts of the ovary, recurrence (2%), and malignant change (choriocarcinoma).
• Risk factors include patient age greater than 40 years, high parity greater than 3, uterine size greater than 20 weeks, theca cyst greater than 6cm, and serum HCG greater than 100,000 IU/ml.

Differential Diagnosis of Early Pregnancy Bleeding

• Abortion
• Ectopic pregnancy
• V.M
• Local causes
• Drugs
• Blood diseases

Management of HM

• Active trophoblastic appearance indicates greater risk of malignancy.
• Cross-match blood.
• Prepare 6 units of blood.
• Molar tissue should be removed after diagnosis.
• Evacuation via suction curettage under general anesthesia is curative in over 80% of patients with hydatidiform mole.
• Send curettage and myometrial biopsy specimens to histopathology to exclude myometrial invasion.
• Ensure empty uterus using intraoperative ultrasound.
• Control bleeding with oxytocin infusion.
• Ovarian cysts usually resolve spontaneously after evacuation, and do not need removal unless complicated.
• Hysterotomy is indicated when the uterus is higher than the umbilicus (>24 weeks), suspicion of perforating vesicular mole, severe uterine hemorrhage, or cervical stenosis.
• Hysterectomy is indicated if the patient is over 40 years old, there's increased malignancy risk, the patient has completed her family, there is severe uncontrollable bleeding after hysterotomy, or there is a perforating mole.

Post-Molar Evacuation Follow-Up

• Crucial for the early recognition of persistent trophoblastic tissue and development of GTN.
• Monitor uterine involution, ovarian cyst regression, and cessation of bleeding clinically.
• Measure serum hCG levels quantitatively 48 hours post-evacuation, then weekly until normal for three consecutive readings, followed by monthly for a year.
• Pregnancy is discouraged to prevent overlap with rising hCG levels. Use mechanical or oral contraceptives until hCG levels normalize post-evacuation.

Indications for Chemotherapy After Hydatidiform Mole Evacuation

• Serum hCG greater than 20,000 i.u/L at any time.
• Raised hCG at 4 to 6 weeks post-evacuation.
• Evidence of metastasis (hepatic, brain, or pulmonary).
• Persistent uterine hemorrhage with raised hCG levels.

Gestational Trophoblastic Neoplasia (GTN)

• Heterogeneous lesions from aberrant fertilization.
• Unique pathogenesis: maternal tumor comes from fetal tissue.
• Most curable gynecologic malignancy.
• Can be invasive mole (non-metastatic), choriocarcinoma (metastatic, treated with chemotherapy and serum BHCG follow-up), or placental site trophoblastic tumor (PSTT).

Invasive Mole

• Invasive moles, or chorioadenoma destruens, are characterized by their invasive nature.
• They perforate the myometrium and even the peritoneum of the uterus.
• They are a type of complete vesicular mole.
• They do not give rise to metastasis.

Clinical Manifestation of Invasive Mole

• Irregular vaginal bleeding.
• Uterine subinvolution.
• Theca lutein cysts that persist after emptying the uterus.
• Abdominal pain.
• Metastatic focus manifestation.

Diagnosis of Invasive Mole

• History and clinical manifestation.
• Successive measurement of HCG.
• Ultrasound examination.
• X-ray and CT scans.
• Histologic diagnosis after hysterectomy.

Choriocarcinoma (Metastatic GTN)

• Choriocarcinomas are subdivided into good-prognosis (low risk) and poor-prognosis (high risk).
• Incidence in the West is 1:10,000 to 1:70,000 pregnancies; in Asia, it is 1:6,000 pregnancies.
• Patients with blood type A+ve are more predisposed than B+ve.
• It is a malignant tumor of trophoblast that invades the myometrium, causing marked destruction and bleeding.
• Often follows a hydatidiform mole in about 50% of cases.
• Normal pregnancy can still occur in about 25% of cases.
• Abortion and ectopic pregnancy account for about 25% of cases.
• Choriocarcinoma is more likely to occur after a complete mole.

Pathological Features of Choriocarcinoma

• In the uterus 90% of cases; 10% of cases in the, vagina, lung, liver, and brain
• Malignant hyperplasia of both cytotrophoblasts, and syncytiotrophoblasts.
• Extensive hemorrhage.
• Absence of villi (present in V.M).
• Destruction of the surrounding myometrium.

Spread of Choriocarcinoma

• Direct: Through the myometrium, leading to uterine perforation, internal hemorrhage, and peritonitis.
• Blood: Transports cancer to the vagina (30%), lung (80%, the commonest site), liver, brain (10%), skull, and spine (10%).

Causes of Death in Choriocarcinoma

• Vaginal bleeding
• Haemoptysis
• Intraperitoneal hemorrhage
• Peritonitis
• Metastasis to the vital organs e.g., brain.
• Pulmonary complications

Clinical Features of Choriocarcinoma

• Recent history of vesicular mole expulsion, abortion, or full-term pregnancy.
• Persistent vaginal bleeding is the most common presentation.
• Other symptoms include haemoptysis and abdominal pain.
• Palpable abdominal mass may present if there is an enlarged uterus or parauterine metastasis,
• Neurological symptoms may occure.

Signs of Choriocarcinoma:

• Marked deterioration of the general condition, as manifested in anemia and cachexia.
• Abdominal swelling
• Symmetrically enlarged uterus.

Investigations for Choriocarcinoma:

• Serum hCG
• CBC
• L.F.T.
• U/S for abdomen and pelvis
• Chest X-ray for pulmonary metastasis
• Liver scan
• CT scan for the secondaries
• EEG

Clinical Classification of GTN

• FIGO system scores patients; those scoring 6 or below receive low-risk treatment, while those scoring 7 or more receive high-risk treatment (chemotherapy).
• Classified according to the presence of metastasis.
• Non-metastatic GTN is limited to the uterus.
• Metastatic GTN can have good or poor prognosis.

Anatomy staging (FIGO, 2000)

• Stage I: Uterus
• Stage II: vagina, vulva
• Stage III: lung metastasis
• Stage IV: distant metastasis

GTN Treatment

• Options are Chemotherapy (single or multi-agent), surgery and Radiotherapy.
• Single-agent chemotherapy is used in Non-metastatic and good prognosis GTN.
• Multi-agent chemotherapy is used Poor Prognosis metastatic trophoblastic neoplasia and drug-resistant tumors.
• EMA-CO (Etoposide, Methotrexate, Actinomycin D, Cyclophosphamide, Vincristin) is a regimen used in high-risk patients.
• Total abdominal hysterectomy may be performed if reproduction is not desired and for old age women.
• Surgical excision of isolated metastases (e.g., pulmonary) if resistant to chemotherapy.
• Surgery is also important in controlling bleeding, infection, and complications.
• Used for removing remained or drug-resistant foci.
• Whole brain irradiation for cerebral metastases and whole-organ irradiation for hepatic metastases.

Follow-Up

• After successful therapy, physical examination, chest x-ray, and hCG levels are monitored for serial interval measurement.
• Repeat evaluation, staging, and chemotherapy are done if hCG levels rise.
• Women who undergo chemotherapy are advised against conceiving for one year after treatment.

Placental Site Trophoblastic Tumor

• Rare tumors, accounting for 0.23% of GTD cases.
• They have normal HCG levels but high human placental lactogen levels, making this a useful tumor marker.
• Chemoresistant and radioresistant.