Gestational trophoblastic disease

Gestational trophoblastic diseases (GTD) include hydatidiform moles (both complete and partial), invasive moles, and choriocarcinoma. They typically arise from the abnormal fertilization of the ovum. Hydatidiform moles are benign, whereas invasive moles and choriocarcinoma are malignant lesions with a tendency to metastasize to other organs, especially the lungs. Patients with GTD frequently present with vaginal bleeding and pelvic tenderness. Complete hydatidiform moles are associated with several additional clinical features (e.g., enlarged uterus, hyperemesis gravidarum, preeclampsia). Diagnosis is established based on a significantly elevated serum β-HCG and ultrasound findings (e.g., a mass that resembles a bunch of grapes in complete hydatidiform moles). If malignancy is suspected, workup must include an x-ray of the chest to screen for lung metastases. Hydatidiform moles are normally treated via dilation and curettage, whereas choriocarcinoma typically requires chemotherapy.

Definition

• Classified as complete or partial moles (see “Etiology” below)
• Benign trophoblastic disease
• Proliferates within the uterus without myometrial infiltration or hematogenic dissemination
• May develop malignant traits and become an invasive mole
  • No histologic signs of malignancy in the primary tumor
  • Trophoblasts infiltrate the myometrium and gain access to the vascular system.
  • Hematogenic dissemination leads to metastatic growth in different organs (brain, lungs, liver).

Etiology

• Risk factors
  • Prior molar pregnancy
  • History of miscarriage
  • Patients ≤ 15 and ≥ 35 years
• Complete mole
  • Does not contain any fetal or embryonic parts
  • Caused by fertilization of an empty egg that does not carry any chromosomes. The (physiological) haploid chromosome set contributed by the sperm is subsequently duplicated.
  • In rare cases, the formation of a complete mole may also result from simultaneous fertilization of an empty egg by two sperms.
  • Fetal karyotypes
    • 46XX: more common (∼ 90% of cases)
    • 46XY: less common (∼ 10% of cases)
    • 46YY: has never been observed because it is nonviable.
• Partial mole
  • Contains fetal or embryonic parts in addition to trophoblastic tissue
  • Caused by fertilization of an egg containing a haploid set of chromosomes with two sperms (each of them containing a haploid set of chromosomes as well)
  • Fetal karyotypes: 69XXX, 69XXY, 69XYY

Complete mole is the result of paternal disomy. Partial mole is the result of triploidy.

Pathophysiology

• Hydropic degeneration of chorionic villi with concomitant proliferation of cytotrophoblasts and syncytiotrophoblasts → death of the embryo
• Invasive mole: trophoblasts invade the myometrium → increased risk of bleeding and hematogenous spread

Clinical features

• Complete mole
  • Vaginal bleeding during the first trimester
  • Uterus size greater than normal for gestational age
  • Pelvic pressure or pain
  • Passage of vesicles that may resemble a bunch of grapes
  • Endocrine symptoms (due to ↑ β-hCG level)
    • Preeclampsia (before the 20^th week of gestation)
    • Hyperemesis gravidarum
    • Ovarian theca lutein cysts: bilateral, large, cystic, adnexal masses that are tender to the touch
    • Hyperthyroidism ^[1]
• Partial mole
  • Less severe symptoms than in complete mole
  • Vaginal bleeding
  • Pelvic tenderness

Diagnostics

• Laboratory tests: β-hCG level measurement (initial test of choice) ; ^[2]
  • Markedly elevated (higher than expected for the gestational age)
  • Higher in complete mole compared to partial mole.
• Transvaginal ultrasound
  • Complete hydatidiform mole
    • Theca lutein cysts
    • Echogenic mass interspersed with many hypoechogenic cystic spaces that represent hydropic villi (referred to as “swiss cheese”, “honeycomb”, “bunch of grapes”, or “snowstorm”)
    • No amniotic fluid
    • No fetal parts
    • Lack of fetal heart tones
  • Partial hydatidiform mole
    • Fetal parts may be visualized.
    • Fetal heart tones may be detectable.
    • Amniotic fluid is present.
    • Increased placental thickness
• Uterine evacuation (for definite diagnosis and treatment): histopathological examination of evacuated uterine specimen (also see “Treatment” below)
  • Complete mole
    • Microscopy: diffuse hydropic villi, marked circumferential trophoblastic proliferation ^[3]
    • Immunohistochemical staining: p57 negative
  • Partial mole
    • Microscopy: partial occurrence of hydropic villi, minimal trophoblastic proliferation
    • Immunohistochemical staining: p57 positive
• Chest x-ray: in case of dyspnea or chest pain ^[4]

Fetal parts may be present in partial moles.

Some moles may not produce HCG at all.

Treatment

• Uterine evacuation by dilation and suction curettage: Complete moles have a 20% risk of becoming invasive and a 2% risk of developing into choriocarcinoma. Therefore, complete evacuation of the uterine cavity is the mainstay of treatment.
• Monitor β-HCG levels until in reference range (usually 8–12 weeks)
• Chemotherapy (usually methotrexate; ) if unresolved, as indicated by any of the following:
  • β-HCG values do not decrease.
  • Histological features of malignant GTD are present.
  • Metastases are present on chest x-ray.

Prognosis

• Most patients achieve normal reproductive function after recovery. ^[5]
• Risk of gestational trophoblastic neoplasia (includes choriocarcinoma and invasive moles)^[4][6]
  • Complete mole (15–20%): invasive disease occurs more commonly than choriocarcinoma
  • Incomplete mole (< 5%): risk of choriocarcinoma is negligible

Definition

• Highly aggressive, malignant tumor consisting of trophoblastic tissue
• Exhibits histological signs of malignancy and a tendency to metastasize early

Etiology ^[7]

• Choriocarcinoma only develops after fertilization and implantation of the egg.
• Most cases of choriocarcinoma are preceded by
  • Hydatidiform mole (50%)
  • Miscarriages or ectopic pregnancy (25%)
  • Normal pregnancy (25%)

Pathophysiology

• Malignant transformation of cytotrophoblastic and syncytiotrophoblastic tissue
• Destructive growth into myometrium without chorionic villi → risk of hemorrhage and early metastasis (lung, vagina, brain, liver)

Clinical features

• Postpartum vaginal bleeding and inadequate uterine regression after delivery
• Multiple theca lutein cysts
• Additional symptoms depend on the site of metastasis (e.g., seizures from metastases in the brain, dyspnea or hemoptysis from metastases in the lungs)

Diagnostics ^[8]

• Laboratory tests: : very high β-HCG (initial test of choice)
• Pelvic ultrasound ^[9]
  • Mass of varying appearance (suggestive of hemorrhage and necrosis)
  • Hypervascular on color Doppler
• Uterine dilation and curettage (D&C)
  • Histopathologic examination shows cytotrophoblasts and syncytiotrophoblasts without chorionic villi
  • Both diagnostic and therapeutic (but only limited diagnostic value)
• Staging
  • If malignancy is suspected
  • Chest x-ray: cannonball metastases (hematogenous spread → multiple nodules in the lung)

Treatment ^[10]

• Treatment of choice: methotrexate or dactinomycin ^[11]
  • Low-risk : monotherapy with methotrexate or actinomycin D
  • High-risk : multiagent chemotherapy consisting of methotrexate, actinomycin D, etoposide, cyclophosphamide, or vincristine
• Surgical treatment (e.g., hysterectomy); : may be indicated to stop bleeding; from cancerous lesions or to excise distant metastases
• Monitor β-HCG levels for at least 12 months.

Prognosis

• Cure rate of 95–100%
• Worse prognosis in the case of advanced-stage disease