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Gestational Trophoblastic Disease (GTD)

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Overview and Classification

• Complete hydatidiform mole (CHM)
• Partial hydatidiform mole (PHM)

• Invasive mole
• Choriocarcinoma
• Placental-site trophoblastic tumor (PSTT)
• Epithelioid trophoblastic tumor (ETT)

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PART 1: BENIGN GTD - HYDATIDIFORM MOLES

Epidemiology

• Japan: 2:1,000 pregnancies (threefold higher than the West)
• Europe/North America: 0.6-1.1 per 1,000 pregnancies
• Taiwan: 1 in 125 pregnancies
• United States: 1 in 1,500 live births
• Complete moles: 1:1,945 pregnancies
• Partial moles: 1:695 pregnancies (Ireland data from thorough pathologic review)

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Pathology and Cytogenetics

Complete Hydatidiform Mole (CHM)

• Exhibits characteristic swelling and diffuse trophoblastic hyperplasia
• 46,XX karyotype in ~90%; 46,XY in ~10%
• Chromosomes are entirely of paternal (androgenetic) origin - molar chromosomes arise from an ovum fertilized by a haploid sperm that duplicates its chromosomes; the ovum nucleus is absent or inactivated
• Mitochondrial DNA is of maternal origin

Partial Hydatidiform Mole (PHM)

1. Chorionic villi of varying size with focal hydatidiform swelling, cavitation, and trophoblastic hyperplasia
2. Marked villous scalloping
3. Prominent stromal trophoblastic inclusions
4. Identifiable embryonic or fetal tissues

• Triploid karyotype (69 chromosomes) - the extra haploid set is paternally derived
• Associated fetus exhibits stigmata of triploidy: growth retardation, syndactyly, hydrocephaly

Advances in Pathologic Diagnosis

• Flow cytometry - determines ploidy (diploid vs. triploid)
• p57 immunostaining - p57 is a paternally imprinted, maternally expressed gene product:
  • Complete mole: diploid + p57 NEGATIVE (no maternal chromosomes)
  • Hydropic abortion: diploid (sometimes triploid) + p57 POSITIVE
  • Partial mole: triploid + p57 POSITIVE

Familial Recurrent Molar Pregnancy

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Clinical Features of Complete Hydatidiform Mole

• Vaginal bleeding - most common symptom; retained blood distends endometrial cavity; large volumes may be passed
• Excessive uterine size - endometrial cavity expanded by chorionic tissue and retained blood; associated with markedly elevated hCG
• Preeclampsia - may develop before 24 weeks (unusual in normal pregnancy); patients with very large uteri may also have hyperemesis
• Hyperthyroidism - develops almost exclusively with very high hCG levels; hCG appears to be the thyroid stimulator (positive correlations between hCG and T4/T3). Anesthesia or surgery may precipitate thyroid storm - beta-adrenergic blocking agents should be administered prophylactically
• Theca lutein ovarian cysts - develop in about half of complete mole patients from hCG-mediated ovarian hyperstimulation; cysts reach >6 cm; regress spontaneously within 2-4 months after evacuation; may be complicated by torsion or rupture
• Trophoblastic embolization - rare respiratory distress from trophoblastic emboli to lungs; usually in patients with excessive uterine size and markedly elevated hCG; manifests as chest pain, dyspnea, tachypnea, bilateral pulmonary infiltrates; resolves within 72 hours with cardiopulmonary support

Clinical Features of Partial Hydatidiform Mole

• Main sign: vaginal bleeding (72.8%)
• Excessive uterine enlargement: 3.7%
• Preeclampsia: 2.5%
• Initial clinical diagnosis: incomplete or missed abortion in 91.3%, hydatidiform mole in only 6.2%
• Pre-evacuation hCG >100,000 mIU/mL in only 6.6%
• No patient had theca lutein cysts, hyperemesis, or hyperthyroidism

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Natural History

• After evacuation, hCG levels spontaneously regress to normal in most patients
• GTN (persistent trophoblastic neoplasia) develops in approximately 20% of patients after CHM evacuation
  • Locally invasive mole: 15%
  • Metastatic GTN: 4%

• GTN develops in only about 2-4% of patients
• Metastatic GTN is very rare

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Diagnosis

• Ultrasonography is the primary diagnostic tool
  • Complete mole: characteristic vesicular pattern (diffuse hydropic swelling) detectable as early as first trimester - described as "snowstorm" appearance
  • Partial mole: focal cystic spaces in placenta + increased transverse diameter of gestational sac (positive predictive value 90% when both criteria present)

• hCG levels - markedly elevated; very high levels (>100,000 mIU/mL) associated with more complications
• Histopathology of evacuated tissue - essential for definitive diagnosis

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Treatment of Hydatidiform Mole

Suction Curettage (Preferred method)

1. Oxytocin infusion - begun before anesthesia induction
2. Cervical dilation - active uterine bleeding should not delay completion
3. Suction curettage - uterine size decreases dramatically within minutes; 12-mm cannula strongly advised; for uterus >14 weeks, manual fundal massage to stimulate contraction
4. Sharp curettage - gentle curettage to remove residual molar tissue

• Rh-negative patients should receive Rh immune globulin (trophoblast cells express RhD factor)

Hysterectomy

• Preferred if patient desires sterilization (mole in situ)
• Ovaries may be preserved even with prominent theca lutein cysts
• Does not prevent metastasis - hCG follow-up is still required

Prophylactic Chemotherapy

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Post-Molar Follow-Up

• Weekly hCG measurements until normal for 3 consecutive weeks
• Monthly hCG measurements until normal for 6 consecutive months (complete mole)
• Effective contraception throughout the entire follow-up interval

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PART 2: MALIGNANT GTD - GESTATIONAL TROPHOBLASTIC NEOPLASIA (GTN)

Overview

• GTN can follow any gestational event (molar or non-molar)
• Tendency for early vascular invasion and widespread dissemination
• Trophoblastic tumors are often perfused by fragile vessels and are frequently hemorrhagic

• Plateau of hCG for 4 measurements over 3 weeks
• Rise of hCG ≥10% over 3 weekly measurements
• Persistence of hCG for ≥6 months
• Histologic diagnosis of choriocarcinoma

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Nonmetastatic (Locally Invasive) GTN

1. Irregular vaginal bleeding
2. Theca lutein cysts
3. Uterine subinvolution or asymmetric enlargement
4. Persistently elevated serum hCG levels

• Trophoblastic tumor may perforate the myometrium (intraperitoneal bleeding) or erode into uterine vessels (vaginal hemorrhage)
• Bulky, necrotic tumor may cause uterine sepsis (purulent vaginal discharge, acute pelvic pain)
• After molar evacuation, persistent GTN may have histology of either hydatidiform mole or choriocarcinoma
• After nonmolar pregnancy, persistent GTN always has histology of choriocarcinoma

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Choriocarcinoma

• Histologic hallmark: sheets of anaplastic syncytiotrophoblast and cytotrophoblast without chorionic villi
• Highly malignant; tendency for early vascular invasion with widespread hematogenous dissemination
• May follow molar or non-molar gestations; GTN after nonmolar pregnancies always exhibits choriocarcinoma histology
• Contains both cytotrophoblast and syncytiotrophoblast but no villi

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Placental-Site Trophoblastic Tumor (PSTT) and Epithelioid Trophoblastic Tumor (ETT)

• Uncommon but important variants consisting predominantly of intermediate trophoblast
• Produce small amounts of hCG and human placental lactogen (hPL) relative to their mass
• Tend to remain confined to the uterus, metastasizing late
• Relatively insensitive to chemotherapy (in contrast to other GTN)
• Hysterectomy is the primary curative treatment for nonmetastatic disease
• Patients with metastatic PSTT may still achieve remission but tumors are less responsive to chemotherapy

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Metastatic GTN

• Lungs: 80%
• Vagina: 30%
• Pelvis: 20%
• Liver: 10%
• Brain: 10%

Pulmonary Metastases

• 80% have lung involvement visible on chest radiography at diagnosis
• Symptoms: chest pain, cough, hemoptysis, dyspnea, or asymptomatic
• Four radiographic patterns:
  1. Alveolar or "snowstorm" pattern
  2. Discrete rounded densities
  3. Pleural effusion
  4. Embolic pattern (pulmonary arterial occlusion)
• Some patients have minimal gynecologic symptoms with extensive pulmonary disease

Vaginal Metastases

• Vaginal metastases are highly vascular; biopsy is associated with significant hemorrhage
• They may appear as bluish-purple submucosal lesions

Hepatic Metastases

• Usually indicate advanced disease
• Hepatic arterial infusion or hepatic resection may be required for resistant hepatic metastasis

Cerebral Metastases

• Plasma-to-CSF hCG ratio tends to be <60 in the presence of cerebral metastases
• Managed with whole-brain radiation (3,000 cGy in 10 fractions) or stereotactic radiosurgery + combination chemotherapy

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FIGO Staging

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WHO Prognostic Scoring System

• Score ≤6 = Low risk → single-agent chemotherapy
• Score >6 = High risk → multimodal therapy with intensive combination chemotherapy ± surgery ± radiation

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Diagnostic Evaluation

1. History and physical examination
2. hCG level (serum)
3. Complete blood count, renal and liver function tests
4. Chest X-ray (plain - used for staging, not CT)
5. CT or MRI scan of head as indicated

• Liver ultrasonography and CT/MRI for hepatic metastases (in patients with abnormal liver function)
• CT/MRI head for early diagnosis of asymptomatic cerebral lesions
• Chest CT detects micrometastases not visible on plain X-ray in ~40% of presumed nonmetastatic patients, but presence of micrometastases has not been shown to substantially change outcome
• CSF hCG measurement if brain CT/MRI is negative in patients with choriocarcinoma
• Pelvic ultrasonography to detect extensive uterine trophoblastic involvement

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Management of GTN

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Low-Risk Disease (Stage I and Low-Risk Stages II-III, Score <7)

• Adjuvant chemo rationale: reduces dissemination of viable tumor cells at surgery; treats occult micrometastases
• In a series of 31 patients: 100% achieved complete remission with no additional therapy
• Mandatory for PSTT and ETT stage I (relatively chemoresistant)

• 592 patients with stage-I GTN treated with primary single-agent chemotherapy
• 82.3% (487 patients) achieved complete remission
• Remaining 105 patients achieved remission after combination chemotherapy or surgery

• 168 patients treated with single-agent chemotherapy
• 77.3% (130 patients) achieved complete remission
• Remaining 38 patients required combination chemotherapy

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Single-Agent Chemotherapy Regimens

• 5-day regimen
• 8-day regimen
• Pulsatile weekly (30 mg/m² IM)

• 5-day regimen
• Pulsatile (biweekly 1.25 mg/m² IV bolus)

• 216 patients randomized to biweekly ActD (1.25 mg/m²) vs. weekly MTX (30 mg/m² IM)
• Remission rates: MTX 58%, ActD 73%
• ActD appeared superior to this weekly MTX regimen, but all patients ultimately achieved remission
• Comparison with 5-day or 8-day MTX regimens remains needed

• 8-day MTX-FA: complete remission in 87.6% of 185 patients
• Stage-I GTN: 90.2% remission; low-risk stages II-III: 68.2% remission
• Resistance more common with: choriocarcinoma, metastasis, pre-treatment hCG >50,000 mIU/mL
• Side effects: thrombocytopenia, granulocytopenia, hepatotoxicity (generally well tolerated)

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High-Risk Metastatic GTN (Stages II-IV, Score >6)

• Etoposide alone: complete remission in 95% of 60 patients with nonmetastatic/low-risk metastatic GTN
• EMA-CO in high-risk GTN: 83% remission rate (initial studies); 90.6% complete sustained remission in 96 high-risk patients (score >6) in another series
• Remission with EMA-CO in 86% of patients with brain metastasis
• Well tolerated; treatment seldom suspended due to toxicity

• 144 patients with high-risk GTN stages II-IV
• 84% (121 patients) achieved complete remission
• Before 1975 (single-agent primary therapy): only 30% achieved remission for stage IV
• After 1975 (multimodal intensive therapy): 75.7% achieved remission for stage IV

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Management of Refractory GTN

• EMA-EP (EMA-CO with substitution of etoposide + cisplatin on day 8): remission in 76% of 21 patients resistant to EMA-CO
• PVB (cisplatin, vinblastine, bleomycin)
• Ifosfamide and paclitaxel
• TE/TP (paclitaxel, etoposide, cisplatin): 3 complete + 4 partial responses in 7 EMA-CO resistant patients
• FUDR-containing regimens: complete remission in all 21 patients with drug-resistant GTN (Wan et al.)
• 5-FU + ActD: remission in 9 of 11 (82%) patients with drug resistance
• Autologous bone marrow transplantation / stem cell rescue: complete remissions reported; role not yet fully defined

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Special Situations

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Duration of Therapy and Follow-Up

• Combination chemotherapy given as frequently as toxicity permits until 3 consecutive normal hCG levels
• After normal hCG attained: at least 3 additional courses to reduce relapse risk
• All GTN patients: weekly hCG until normal for 3 consecutive weeks, then monthly until normal for 12 consecutive months

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False-Positive hCG Tests

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Subsequent Pregnancies

• Patients can anticipate normal future reproduction
• No increased risk of spontaneous abortion, stillbirth, or congenital malformations compared to the general population
• Pregnancy should be deferred until completion of the follow-up period

• After achieving remission with chemotherapy, patients can anticipate normal future reproduction
• No increased teratogenicity or adverse obstetric outcomes demonstrated in post-chemotherapy pregnancies

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Key Points Summary (from Berek & Novak)

1. GTD is a group of interrelated tumors including complete/partial moles, invasive moles, choriocarcinoma, PSTT, and ETT.
2. Complete and partial moles differ in chromosomal origin, histopathology, clinical presentation, and risk of GTN.
3. hCG is a critical marker for diagnosing GTN, monitoring chemotherapy response, and detecting relapse.
4. Metastases can occur after any type of GTD but are more common after nonmolar pregnancies; most common sites are lung and vagina.
5. Single-agent chemotherapy achieves high remission rates in nonmetastatic and low-risk metastatic GTN.
6. High-risk GTN requires primary combination chemotherapy, surgery for complications, and occasionally radiation.
7. After achieving remission with chemotherapy, patients can anticipate normal future reproduction.

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Recent Updates (2023-2026)

• PD-L1 is highly expressed on trophoblastic tissue, providing biological rationale for checkpoint blockade
• Pembrolizumab (anti-PD-1) has shown responses in refractory GTN, with complete responses documented
• The systematic review by Wang et al. [PMID 37594534] and the 2024 review by Baas et al. [PMID 37703867] describe "Immunotherapy for GTN: A New Paradigm" - cases of chemotherapy-refractory disease responding to immune checkpoint inhibitors
• A 2026 narrative review (Barcellos et al., PMID 41627371) specifically reviews checkpoint inhibition in GTN with a focus on anti-tumor immune reawakening

• A 2026 meta-analysis by Salmeri et al. [PMID 41066778] analyzed clinical outcomes in multiple pregnancy with complete hydatidiform mole and coexisting normal fetus - this rare condition carries significant maternal and fetal risks, and the evidence base for management is now more systematically characterized.

• Systematic reviews (2025) on magnitude of GTD in Africa and East Africa confirm higher incidence in low-resource settings and highlight histopathologic patterns (PMID 41120163, 41029567).

• A 2025 meta-analysis (PMID 40555372) characterized the prevalence of depression and anxiety in GTD, highlighting the psychological burden that should be addressed alongside medical management.

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