Gestational Trophoblastic Diseases (GTD)

Gestational Trophoblastic Diseases (GTD)

Definition

GTDs involve abnormal proliferation of the trophoblast of the placenta, which can be benign but have malignant potential. GTDs are relatively rare but important due to their potential for malignant transformation and the need for careful monitoring and management.

Classification of GTDs

WHO Classification

This classification divides GTDs into:

1. Molar Pregnancy

   • Hydatidiform Mole

     • Partial Mole: Has a lower risk of developing into malignant GTN compared to a complete mole.

     • Complete Mole: Carries a higher risk of developing into malignant GTN.

   • Invasive Mole: Although primarily discussed under molar pregnancies, it has malignant potential. It is characterized by the invasion of the myometrium by molar tissue.

2. Trophoblastic Tumors

   • Choriocarcinoma: A fast-growing, aggressive cancer that can spread to distant organs.

   • Placental Site Trophoblastic Tumor (PSTT): Arises from the intermediate trophoblast and tends to be less sensitive to chemotherapy.

   • Epithelioid Trophoblastic Tumor (ETT): A rare and slow-growing tumor that also originates from intermediate trophoblast.

Benign vs. Malignant Classification

• Benign: Molar pregnancies (partial and complete).

• Malignant: Invasive mole, choriocarcinoma, PSTT, and ETT. These require aggressive management to prevent metastasis.

Diagnosis of Gestational Trophoblastic Neoplasias

• Histopathological examination or biopsy is rarely performed due to clinical diagnosis based on clinical examination findings and hCG levels. Clinical examination may reveal an enlarged uterus, vaginal bleeding, and, in some cases, the expulsion of grape-like vesicles.

• Treatment is typically initiated with chemotherapy, as most common tumors are chemo-sensitive. Early diagnosis and prompt treatment are crucial for improving outcomes.

Risk Factors for GTD

1. Previous History of Molar Pregnancy: The most significant risk factor. The risk increases with each subsequent molar pregnancy.

2. Age of Patient: Females over 40 years and adolescent females are at higher risk due to susceptibility to abnormal fertilization. Advanced maternal age is a well-established risk factor.

3. Geographic Location: More common in Southeast Asian countries. This suggests a potential genetic or environmental influence.

Hydatidiform Mole (Molar Pregnancy)

Abnormal Trophoblast Proliferation

Leads to the uterus size being larger than expected for the gestational period in about 50% of females. In some cases, the size may be equal to or less than expected due to hydropic degeneration, especially in partial moles. Discrepancies in uterine size compared to gestational age should raise suspicion.

Fetal Tissue

• Partial Mole: Trophoblast allows some growth of the inner cell mass, resulting in the presence of some fetal tissue. Fetal parts may be present but are usually abnormal.

• Complete Mole: Trophoblast proliferation does not allow inner cell mass growth, resulting in no fetal parts. The absence of fetal parts is a key diagnostic feature.

Common Complaint

Vaginal bleeding, which can vary from spotting to heavy bleeding.

Prevention of Pregnancy-Induced Hypertension (PIH)

Normally, cytotrophoblast leads to trophoblastic invasion, converting high-resistance spiral arteries into low-resistance vessels. However, abnormal proliferation impairs this, leading to PIH. PIH occurring before 20 weeks of gestation should raise suspicion for molar pregnancy. Early-onset PIH is a red flag for molar pregnancy.

Increased hCG Levels

Due to abnormal trophoblast proliferation, leading to hyperemesis gravidarum. Markedly elevated hCG levels are a hallmark of molar pregnancies.

• Hyperthyroidism: Because the alpha subunit of hCG is similar to TSH. High hCG levels can stimulate the thyroid gland.

• Theca Luteal Cysts: Bilateral cysts due to hCG's functional similarity to LH and FSH. These cysts usually regress after the evacuation of the mole.

Types of Trophoblast

1. Syncytiotrophoblast: Highly differentiated, hormone factory of the placenta, secretes hCG. It is responsible for producing large amounts of hCG in molar pregnancies.

2. Cytotrophoblast: Primitive trophoblast, forms the fetal side of the placenta, helps form chorion membranes, and prevents PIH. It plays a crucial role in placental development and function.

3. Intermediate Trophoblast: Invades the decidua, myometrium, and blood vessels; secretes hCG to a lesser extent than syncytiotrophoblast.

   • Molar pregnancies, choriocarcinoma, and invasive moles primarily involve syncytiotrophoblast, leading to high hCG levels. The degree of hCG elevation can help differentiate between different types of GTDs.

   • PSTT and ETT arise from intermediate trophoblast, resulting in high but not extremely elevated hCG levels. Therefore, hCG is not a reliable marker for these tumors. Alternative markers and imaging techniques are often needed for diagnosis.

pathogenesis of a molar pregnancy

Partial Mole

An ovum is fertilized by two sperms (dispermic), resulting in a triploid zygote. The most common karyotype is $69, XXY$. This genetic abnormality leads to abnormal placental development.

• Extra genetic material comes from the father, disrupting normal embryonic development.

Complete Mole

An ovum loses its genetic material (maternal chromosomal inactivation) and is fertilized by a single sperm. The sperm's genetic material duplicates, resulting in a diploid zygote $46, XX$ but with the entire genetic material from the father (androgenesis). This results in no fetal development.

• In 20% of cases dispermic fertilization leads to the same outcome. Both sperm contribute genetic material after maternal chromosomal inactivation.

Twin Pregnancy Scenario

If one twin is a molar pregnancy and the other is a normal intrauterine pregnancy, the molar pregnancy should be removed. Complications for the surviving twin include abortion, preeclampsia, hemorrhage, and thyrotoxicosis. Careful monitoring of the remaining twin is essential.

Complete Mole vs. Partial Mole

p57 KIP2 is a maternally imprinted gene product and is useful in differentiating complete from partial moles on histopathology.

Investigations

Ultrasound is the investigation of choice. Transvaginal ultrasound provides better visualization and diagnostic accuracy.

Complete Mole

A complex echogenic intrauterine content with cystic and anechoic spaces, known as snowstorm appearance. Absence of fetal parts, amniotic fluid, and presence of theca lutein cysts. The "snowstorm" appearance is a classic ultrasound finding.

Partial Mole

Cystic spaces in the placenta, decreased amniotic fluid, and increased transverse diameter of the gestational sac. It closely resembles a missed abortion. Differentiation can be challenging, requiring histopathological examination.

Management

Suction Evacuation

For both partial and complete moles at any gestational age and uterine size. Increased risk of hemorrhage, so packed cells should be available. Start oxytocin drip after initiating suction evacuation to reduce the risk of trophoblastic embolization. Follow with sharp curettage, sending tissue for histopathological examination. Close monitoring for complications is essential.

• Histopathological examination is the gold standard for diagnosis. It confirms the diagnosis and helps differentiate between complete and partial moles.

Hysterectomy

Considered if the patient is over 40 years, has completed her family, and it is a complete mole. This eliminates the risk of GTN but is only suitable for women who do not desire future fertility.

Theca Lutein Cysts

Resolve spontaneously after evacuation and do not require specific management. Regular monitoring is advisable until complete resolution.

Histopathological Findings

Complete Mole

• Absent fetal or embryonic tissue. This is a key diagnostic criterion.

• Diffuse hydropic swelling of the villi and trophoblastic proliferation. The villi appear enlarged and edematous, with excessive trophoblastic growth.

Partial Mole

• Present fetal or embryonic tissue. Fetal parts may be present but are often abnormal.

• Focal hydropic swelling of the villi and trophoblastic proliferation. The swelling and proliferation are less extensive compared to complete moles.

• Scalloping of the villi and trophoblastic inclusion bodies. These are characteristic histopathological features.

Follow-Up

hCG Levels

Investigation of choice for follow-up. Draw initial levels 48 hours post-suction evacuation, then weekly until undetectable. Consistent and accurate monitoring is critical.

• Complete Mole: hCG levels become undetectable by 7 weeks. Close monitoring is continued even after hCG normalization.

• Partial Mole: hCG levels become undetectable by 6 weeks. Regular follow-up is essential to detect any signs of malignant transformation.

• After hCG becomes undetectable, repeat monthly for six months. This surveillance period helps detect any recurrence or development of GTN.

Contraception

Pregnancy should be avoided for six months to avoid confusion between new pregnancy and potential GTN. Effective contraception is essential during the follow-up period.
Oral combined pills are the contraceptive of choice. They are safe and effective in preventing pregnancy.

If pregnancy occurs despite contraception, the rates of live birth and congenital anomalies mirror the general population. However, close monitoring is necessary to rule out GTN.

Rate of Subsequent GTN

• Complete Mole: 15-20% risk of subsequent GTN. This necessitates vigilant follow-up and monitoring.

• Partial Mole: 1-5% risk of subsequent GTN.

  • Of GTN cases, 15% are locally invasive, and 5% are metastatic. Early detection and management are crucial to prevent serious complications.

GTN After Nonmolar Pregnancy

Metastatic disease is more common than locally invasive disease. This highlights the aggressive nature of GTN following nonmolar pregnancies.

Common Metastasis Sites

1. Lungs (80%): This is the most common site of metastasis.

2. Vagina

3. Pelvis

4. Liver and Brain (10% each): These are less common but carry a poor prognosis.

Anti-D Administration

Administer anti-D to Rh-negative females undergoing suction evacuation for partial mole due to the presence of fetal tissue. Consider in complete mole as well until histopathology confirms the absence of fetal tissue. This prevents Rh sensitization.

Risk Factors for GTN (HOTS)

• H: hCG levels $≥ 100,000$ international units/liter. Markedly elevated hCG levels indicate a higher risk.

• O: Older age group (over 40 years). Advanced maternal age is associated with increased risk.

• T: Theca lutein cysts ($≥ 6 cm$). Large cysts are indicative of significant trophoblastic activity.

• S: Size of the uterus increased more than expected for gestational age. Discrepancies in uterine size suggest abnormal proliferation.

Prophylactic chemotherapy is not routinely given even if these factors are present. Close monitoring and follow-up are preferred.

Quiescent Gestational Trophoblastic Disease

Low levels of hCG (< 200 international units) persist for several months post-evacuation. Follow-up without chemotherapy is indicated, as 20% of cases may develop into active disease. Regular hCG monitoring is crucial.

Hyperglycosylated hCG (hCGH) may differentiate between quiescent and active GTN. Elevated levels of hCGH may suggest active disease.

Gestational Trophoblastic Neoplasia (GTN)

May follow molar pregnancy (most common), abortion, ectopic pregnancy, or normal pregnancy. GTN can arise from any gestational event.

Common Types of GTN

• Invasive mole is the most common GTN after H-mole evacuation, always develops after a hydatidiform mole. It is characterized by local invasion of the myometrium.

• Choriocarcinoma most commonly occurs after molar pregnancy and is especially common after non-molar pregnancy or full-term pregnancy. It is an aggressive and rapidly metastasizing tumor.

• PSTT most commonly develops after a full-term pregnancy. It is a rare tumor that arises from the placental site.

Signs and Symptoms of GTN

• Persistent bleeding after molar evacuation. This is a common sign of GTN.

• Persistent theca lutein cysts. Failure of theca lutein cysts to regress may indicate GTN.

• Subinvolution of the uterus. The uterus fails to return to its normal size.

• Shock. This can occur due to hemorrhage or metastasis.

• Signs of metastasis (e.g., lungs, vagina). Symptoms depend on the site of metastasis.

Lab Criteria for GTN

• Plateau of hCG levels within 10% of the previous value for four weeks. This indicates persistent trophoblastic activity.

• Increasing values of hCG by $≥ 10$. Rising hCG levels are suggestive of GTN.

• hCG detectable even after six months of suction evacuation. Persistent hCG elevation is a key diagnostic criterion.

• Histopathological examination showing GTN. Biopsy confirms the presence of malignant tissue.

Invasive Mole

Often locally invasive, metastasizes in 5% of cases, and always develops after H-mole. Histopathology shows the presence of villi and trophoblast extending to the myometrium, potentially perforating the uterus. Uterine perforation can lead to serious complications.

Choriocarcinoma

Can develop after molar or non-molar pregnancy and commonly metastasizes. Appears as a highly vascular, dark red or black mass. Histopathology shows sheets of trophoblast without villi, and trophoblast can extend to the myometrium. The absence of villi is a key diagnostic feature.

FIGO Staging for GTN

• Stage I: Disease confined to the uterus. Treatment is typically highly effective.

• Stage II: GTN spread outside the uterus but confined to pelvic structures, with the vagina being the most common site of metastasis. Vaginal metastases are often easily accessible for diagnosis and treatment.

• Stage III: GTN extends to the lungs, presenting with cough and hemoptysis. Chest x-ray may show cannonball or snowstorm appearances. These appearances refer to the characteristic patterns of lung metastases.

• Stage IV: Distant metastasis to sites other than lungs (e.g., liver or brain). This stage has a poorer prognosis.

WHO Scoring System for GTN

Divides GTN into low-risk and high-risk categories, primarily used for FIGO stages II and III. This scoring system helps guide treatment decisions.

• Stage I is always low risk.

• Stage IV is always high risk.

Factors in WHO Scoring

• Age of the patient

• Antecedent pregnancy

• Interval between antecedent pregnancy and GTN onset

• Pretreatment hCG levels

• Largest tumor size

• Site of metastasis

• Number of metastases

• Prior failed chemotherapy

A total score of 0-6 indicates low risk, while a score of $≥ 7$ indicates high risk. These scores guide the selection of appropriate chemotherapy regimens.

Management Based on Risk

Low-Risk GTN

Single-agent chemotherapy, typically methotrexate, given in multiple doses (e.g., day 1, 3, 5, 7) with folinic acid on alternate days for two weeks. Actinomycin D is an alternative. Folinic acid helps mitigate the side effects of methotrexate.

High-Risk GTN

Multi-agent chemotherapy, such as EMACO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine). This combination is more effective in treating aggressive and metastatic disease.

Management of Stage I GTN

Hysterectomy plus single-agent chemotherapy if the patient does not desire fertility. If fertility is desired, consider one more curettage and single-agent chemotherapy or just single-agent chemotherapy. The choice of treatment depends on the patient's desire for future fertility.

Follow-Up After Treatment

Follow-up for one year, with pregnancy contraindicated during this time. Regular hCG monitoring is essential during this period.

Indications for Hysterectomy in GTD

• Complete mole in a patient over 40 with a completed family.

• Excessive uncontrollable bleeding during suction evacuation.

• Invasive mole with excessive uncontrollable bleeding.

• Stage I GTN (hysterectomy plus single-agent chemotherapy).

• PSTT and ETT (hysterectomy plus multi-dose chemotherapy). Hysterectomy is often necessary for these tumors due to their resistance to chemotherapy.

Indications for Radiotherapy in GTD

Brain metastasis. Radiotherapy can help control brain metastases and improve neurological symptoms.

Management of Subsequent Pregnancy After GTD

• The risk of repeat molar pregnancy is 1-2%. Patients should be counseled about this risk.

• No increased risk of congenital anomalies or abortion but a higher risk of stillbirth. Close monitoring during pregnancy is essential.

• Perform an early ultrasound. This helps confirm the viability of the pregnancy and rule out molar pregnancy.

• Send the placenta or products of conception for histopathological examination. This helps detect any abnormalities.

• Measure beta hCG levels six weeks postpartum. This ensures that there is no residual trophoblastic disease.