Gestational Trophoblastic Disease (GTD) - Complete Overview

1. Hydatidiform Mole (Complete and Partial)
2. Invasive Mole
3. Choriocarcinoma
4. Placental Site Trophoblastic Tumor (PSTT)
5. Epithelioid Trophoblastic Tumor (ETT)

1. Hydatidiform Mole

Genetics & Pathogenesis

• Complete mole: fertilization of an "empty" egg by one sperm that duplicates (androgenesis, monospermic, 46,XX) or by two sperm (dispermic, 46,XX or 46,XY). No embryonic development occurs.
• Partial mole: normal egg fertilized by two sperm; triploid (69,XXY). Fetal development may occur but fetus is growth-restricted with lethal anomalies.
• Incidence: ~1 in 1,000-2,000 pregnancies in the USA; twice as common in Southeast Asia.

Gross Morphology

Microscopic Morphology

• Complete mole: ALL or most villi are abnormal - enlarged, smooth, oval, with central cavitation (cisterns) and myxomatous edematous stroma. Covered by diffuse circumferential trophoblastic hyperplasia involving both cytotrophoblasts AND syncytiotrophoblasts. No fetal vasculature.
• Partial mole: Only a fraction of villi is enlarged and edematous; trophoblastic hyperplasia is focal and limited to syncytiotrophoblasts; villi have irregular/scalloped outlines with prominent trophoblastic inclusions.

2. Invasive Mole

Key Features

• A complete mole that becomes locally aggressive
• Hydropic villi penetrate deeply into or perforate the myometrium, causing life-threatening hemorrhage
• Retains hydropic villi (unlike choriocarcinoma)
• Villi may embolize to lungs or brain, but these emboli do not grow and regress spontaneously
• Lung metastases occur in ~5% of complete moles

Morphology

• Microscopically: hydropic villi + proliferation of both cytotrophoblasts and syncytiotrophoblasts invading myometrium
• Distinguished from choriocarcinoma by the presence of chorionic villi

3. Choriocarcinoma

Pathogenesis

• Malignant neoplasm of trophoblastic cells arising from a previously normal or abnormal pregnancy
• Incidence: 1 in 20,000 to 30,000 pregnancies in the USA
• 50% arise after a complete hydatidiform mole
• 25% follow spontaneous abortions
• ~22% follow normal pregnancies
• Remainder after ectopic pregnancies

Gross Morphology

• Soft, fleshy, yellow-white tumor with large pale areas of necrosis and extensive hemorrhage
• Destructive, hemorrhagic invasion of the myometrium
• May appear as a grossly identifiable mass or present with widespread metastasis

Microscopic Morphology

• Composed of proliferating syncytiotrophoblasts and cytotrophoblasts (both components must be present)
• Chorionic villi are ABSENT - this is the critical distinguishing feature from moles
• Mitoses are abundant and sometimes abnormal
• Tumor invades the underlying myometrium, frequently penetrates blood vessels
• May extend to uterine serosa and adjacent structures

Clinical Features & Spread

• Hematogenous spread is characteristic: lungs (50%) > vagina (30-40%) > brain > liver > bone > kidney
• Lymphatic invasion is uncommon
• Despite being extremely aggressive, gestational choriocarcinoma is remarkably sensitive to chemotherapy - nearly 100% cure rate even with metastases
• Non-gestational choriocarcinomas (from gonads/ovary/testis) have a relatively poor response to chemotherapy

4. Placental Site Trophoblastic Tumor (PSTT)

Pathogenesis

• Neoplastic proliferation of extravillous (intermediate) trophoblasts - cells that migrate from the cytotrophoblast of the placenta and invade the maternal decidua and myometrium
• Intermediate trophoblasts have features overlapping cytotrophoblasts AND syncytiotrophoblasts
• They produce human placental lactogen (hPL) rather than large amounts of hCG - so serum hCG levels are LOW
• Diploid tumors (often 46,XX karyotype), arise months after pregnancy
• Comprise less than 2% of gestational trophoblastic neoplasms

Gross Morphology

• Well-circumscribed, firm nodule in the myometrium or endometrium
• Cut surface is tan-white

Microscopic Morphology

• Sheets and cords of mononuclear intermediate trophoblasts infiltrating between individual smooth muscle fibers of the myometrium
• Cells are large with abundant clear to eosinophilic cytoplasm
• Nuclear atypia and mitotic figures present
• No chorionic villi
• Fibrinoid material often deposited around individual cells
• Immunohistochemistry: HPL positive, hCG focally positive, cytokeratin positive

Clinical Course

• Generally indolent course with favorable outcome if confined to endometrium/myometrium
• NOT as sensitive to chemotherapy as other trophoblastic tumors
• Prognosis is poor once it spreads to extrauterine sites
• Treatment: hysterectomy is typically required

5. Epithelioid Trophoblastic Tumor (ETT)

• Rare variant arising from chorionic-type (implantation site) intermediate trophoblasts
• Presents as a nodule in the endometrium, lower uterine segment, or endocervix
• Microscopically: uniform, mononuclear epithelioid cells in nests surrounded by necrosis (giving a "geographic" necrosis pattern); cells are smaller than PSTT cells
• Low hCG; hPL negative; p63 positive (helpful for distinction from PSTT)
• Treatment: hysterectomy; less responsive to chemotherapy than choriocarcinoma

Summary Table

• Robbins, Cotran & Kumar Pathologic Basis of Disease (9780443264528), pp. 956-958
• Robbins & Kumar Basic Pathology (9780323790185), pp. 702-706