Gestational Trophoblastic Disease (GTD) / Trophoblastic Tumors

• Robbins & Kumar Basic Pathology, p. 703

Classification

1. Hydatidiform Mole

Epidemiology

• Incidence: ~1 in 1,000-2,000 pregnancies in the US; twice as common in Southeast Asia
• Risk higher at extremes of reproductive life (teenagers; age 40-50)

Complete vs. Partial Mole

Fig. Origin of complete (A: monospermic 46XX; B: dispermic 46XX/XY) and partial moles (C: dispermic triploid 69XXX/XXY/XYY) - Robbins Pathologic Basis of Disease

Genetics

• Complete mole: entirely paternal in origin - the ovum has lost its maternal DNA. Ninety percent arise from androgenesis (one sperm duplicates) → 46,XX; 10% from dispermy → 46,XX or 46,XY. No embryo forms.
• Partial mole: normal ovum fertilized by 2 sperm → triploid (e.g., 69,XXY). Fetal parts may be present but growth-restricted with CNS and skeletal anomalies (e.g., syndactyly).

Morphology

Clinical Features

• Presents as spontaneous miscarriage or is found on ultrasound
• hCG levels exceed those of a normal pregnancy of the same gestational age
• Treatment: suction curettage
• Post-evacuation surveillance: serial hCG for 6-12 months
• Persistent elevation of hCG → invasive mole or choriocarcinoma (requires chemotherapy)

2. Invasive Mole

• An infiltrative lesion that penetrates, and sometimes perforates, the uterine wall
• Defined diagnostically by a plateau of β-hCG over 4 measurements across 3 weeks, or a rise over 3 consecutive weekly measurements, or hCG elevated for ≥6 months
• Hydropic villi lined by proliferating cyto- and syncytiotrophoblast invade the myometrium
• Emboli to distant sites (lungs, brain) can occur in ~5% of complete moles
• Small lung metastases (<2 cm) often regress spontaneously; larger ones require chemotherapy
• Treatment: curettage, or hysterectomy; chemotherapy if indicated
• Robbins & Kumar Basic Pathology, p. 703; Schwartz's Surgery

3. Gestational Choriocarcinoma

Fig. Choriocarcinoma: (A) Bulky hemorrhagic mass invading the uterine wall; (B) Malignant cytotrophoblast and syncytiotrophoblast without chorionic villi - Robbins Pathologic Basis of Disease

Epidemiology

• 50% follow complete hydatidiform mole
• 25% follow spontaneous abortions
• ~22% follow normal pregnancies
• Remainder: ectopic pregnancies or arise within the placenta

Morphology

• Soft, fleshy, yellow-white hemorrhagic, necrotic uterine mass
• Histology: proliferating syncytiotrophoblasts and cytotrophoblasts - no chorionic villi (key distinguishing feature)
• Abundant, sometimes abnormal mitoses
• Invades myometrium; penetrates blood vessels

Clinical Features

• Irregular vaginal spotting (bloody, brown discharge)
• Very high hCG levels (higher than hydatidiform mole)
• Early and widespread hematogenous spread (lymphatic invasion is uncommon)

1. Lungs - 50%
2. Vagina - 30-40%
3. Brain
4. Liver
5. Kidney/bone

Treatment & Prognosis

• Nearly 100% remission rate with chemotherapy - one of the most chemosensitive solid tumors known
• Evacuation + chemotherapy; surgery reserved for bleeding emergencies
• Many cured patients go on to have normal subsequent pregnancies
• Non-gestational choriocarcinoma (from gonads/mediastinum) is morphologically identical but carries a worse prognosis and lacks paternally derived DNA

4. Placental Site Trophoblastic Tumor (PSTT)

Fig. PSTT: Markedly atypical trophoblasts seen splaying apart smooth muscle fibers as they invade the myometrium - Robbins Pathologic Basis of Disease

• <2% of gestational trophoblastic neoplasms
• Origin: neoplastic proliferation of extravillous (intermediate) trophoblasts
• Cell marker: produce human placental lactogen (hPL) rather than hCG; serum hCG is characteristically low
• Karyotype: diploid, often 46,XX
• Usually arises months after pregnancy (normal pregnancy in ~50%; also after abortion or hydatidiform mole)
• Presents as uterine mass with abnormal uterine bleeding or amenorrhea
• Invasion without local destruction or hemorrhage (unlike choriocarcinoma)
• Relatively insensitive to chemotherapy - primary treatment is hysterectomy
• Good prognosis if confined to uterus; 10-15% die of disseminated disease
• A 2026 systematic review (PMID 40628611) has examined fertility-sparing options for PSTT

5. Epithelioid Trophoblastic Tumor (ETT)

Fig. ETT: Sheets of mononuclear trophoblasts with clear cytoplasm, associated with characteristic pink hyaline material - Robbins Pathologic Basis of Disease

• Rarest form of GTN
• Origin: mononuclear trophoblast cells (intermediate trophoblast), often with abundant clear cytoplasm and associated with pink hyaline material
• Location: usually intrauterine or cervical; extrauterine tumors also occur
• Presents following pregnancy with amenorrhea or palpable mass
• hCG production: low (like PSTT)
• Lacks the overt invasive features of PSTT yet is capable of metastasis (lungs, bone most common)
• ~10-15% with metastatic disease succumb to the tumor
• Less chemotherapy-sensitive; surgery is preferred for localized disease

Staging & Risk Scoring (FIGO/WHO)

• Score ≤6 = Low risk → single-agent chemotherapy (methotrexate or actinomycin-D)
• Score >6 = High risk → multi-agent chemotherapy (e.g., EMA-CO)
• 5-year survival in high-risk patients: ~90%
• Schwartz's Principles of Surgery, Table 41-15

Key Diagnostic Tumor Markers

Recent Evidence