Gestational Trophoblastic Disease

Diagnosis

Hydatidiform Mole

Indications for Testing

Excessive uterine enlargement and vaginal bleeding

Laboratory Testing

• Recommended testing
  • Serum beta-human chorionic gonadotrophin (βhCG)
    • Order as quantitative tumor marker if trophoblastic disease suspected
    • βhCG tumor marker test measures additional forms of βhCG (free β subunits and intact βhCG) not measured by test used for pregnancy
    • Urine testing can be used in case of suspected false positive
• βhCG concentration results interpretation
  • Elevated above expected level for gestational age (usually <100,000 mIU/mL) suggests partial hydatidiform mole (PHM)
    • Elevated levels also found in melanoma; carcinomas of the breast, gastrointestinal tract, lung, and ovaries; and in benign conditions, including cirrhosis, duodenal ulcer, and inflammatory bowel disease (IBD)
  • Marked elevation (>100,000 mIU/mL) suggests complete hydatidiform mole (CHM)
  • Persistent elevation after evacuation suggests invasive or persistent mole
  • Mild elevation common in epithelioid trophoblastic tumor (ETT) or placental site trophoblastic tumor (PSTT) 

Histology

• Other useful immunohistochemical markers
  • PHLDA2
  • Human placental lactogen
  • ​Placental alkaline phosphatase

Imaging Studies

Pelvic ultrasound – absence of fetal heartbeat; abnormal echogenic pattern in placenta

Gestational Trophoblastic Neoplasm

Indications for Testing

Suspicion of gestational trophoblastic neoplasm (GTN) (eg, abnormal vaginal bleeding during or after pregnancy)

Criteria for Diagnosis

• International Federation of Gynecology and Obstetrics (FIGO) criteria for diagnosis of GTN (Soper, ACOG, 2004)
  • βhCG increase of  >10% in 3 values over at least 2 weeks (eg, days 1, 7, 14)
  • βhCG plateau in 4 values over 3 weeks (eg, days 1, 7, 14, 21)
  • βhCG persistence for >6 months after evacuation of mole
  • Histologic diagnosis of choriocarcinoma

Laboratory Testing

• Serum βhCG
  • Order as quantitative tumor marker if trophoblastic disease suspected
  • βhCG tumor marker test measures additional forms of βhCG (free β subunits and intact βhCG) not measured by test used for pregnancy
  • Urine testing can be used in case of suspected false positive

Imaging Studies

• Pelvic Doppler ultrasound
• Chest x-ray
• Magnetic resonance imaging (MRI) of pelvis
• CT of chest/abdomen
• MRI of brain
• Consider positron emission tomography (PET)-CT

Prognosis

• FIGO Staging System and modified WHO prognostic scoring system
  • Prognostic factors in modified WHO scoring system include
    • Age
    • Previous pregnancy state
    • Tumor size
    • Pretreatment βhCG
    • Interval since last pregnancy
    • Site and number of metastases
    • History of failed chemotherapy
  • Prognostic WHO score is combined with the FIGO Anatomic Stage (I-IV)

Differential Diagnosis

• Hydatidiform mole
  • Multiple gestation pregnancy
  • Uterine malignancy
  • Germ cell tumor
  • Pituitary hCG
  • Hyperthyroidism
• GTN – metastatic cancer from another site (ovarian, colorectal)

Monitoring

• Serum beta-human chorionic gonadotrophin (βhCG) – monitor in a sequential fashion (Soper, 2004)
  • Hydatidiform mole
    • Monitor for return to normal values for up to 1 year (every 1-2 weeks until normal, monthly once normalized)
    • Pregnancy discouraged during this period
  • Gestational trophoblastic neoplasm (GTN)
    • βhCG during chemotherapy to determine remission
      • 2-week intervals until return to normal values and then monthly thereafter for 1 year; βhCG yearly thereafter
    • Small number of patients have persistent low-level βhCG elevation called "quiescent GTN"
      • Follow these patients more carefully; 6-10% will ultimately relapse
    • Post-GTN pregnancy
      • Pelvic ultrasound recommended in first trimester of subsequent pregnancy to confirm normal gestation (1-2% risk of recurrence in next pregnancy)
      • 6-week postpartum βhCG
      • Postdelivery examination of placental products of conception

Background

Epidemiology

• Incidence
  • Hydatidiform mole
    • 1/600 spontaneous abortions
    • ~1/1,000 pregnancies; regional differences observed
  • GTN
    • 1/20,000-40,000 pregnancies
      • 50% post-term pregnancies
      • 25% postmolar pregnancies
      • 25% post-other gestational events
    • Choriocarcinoma risk – 1/50,000 pregnancies
• Age – childbearing years
• Sex – exclusively female
• Ethnicity – increased incidence in Latin America, Middle East, and Southeast Asia
  • U.S. – African Americans have the highest incidence of choriocarcinoma and the lowest survival rate

Risk Factors

• Previous molar pregnancy
  • High risk for GTN following complete hydatidiform molar pregnancy
  • Increased risk for GTN following partial hydatidiform molar pregnancy
• Asian or American Indian ancestry, or (for GTN only) African ancestry
• Older maternal age – women >40 years
• Familial disease – rare, more common in recurrent CHM
  • NLRP7 and (rarely) KHDC3L gene mutations implicated (Wang, 2009)

Pathophysiology

• All GTD is derived from trophoblastic cells that form the placenta
• Hydatidiform mole – considered benign
  • Placental villi become edematous and form small grapelike structures
  • Classification
    • PHM
      • Focal trophoblastic proliferation with mixture of normal villi and edematous villi
      • Embryo, cord, and amniotic structures are present but abnormal
      • Triploid genome (69,XXY; 69,XYY; 69,XXX) due to additional paternal haploid chromosome contribution
      • Presence of maternally expressed gene products
        • PHM – 0.5% risk
    • CHM
      • Hydropic degeneration of all villi
      • Absent embryo, cord, or amniotic structures
      • Diploid genome
      • Absence of maternally expressed gene products
        • CHM – 15% risk
• GTN – neoplastic and potentially malignant
  • Invasive, persistent, or metastatic mole – mole with invasion into the myometrium; rare "metastasis" to extrauterine sites (lung, vagina)
    • Swollen villi; hyperplastic trophoblast
    • May coexist with a normal pregnancy (rare)
  • Gestational choriocarcinoma
    • Neoplastic syncytiotrophoblast and cytotrophoblast elements without chorionic villi; hemorrhage, necrosis
    • Usually metastasizes early
  • Placental site trophoblastic tumor (PSTT)
    • Absence of villi, proliferation of intermediate trophoblast cells in the myometrium
    • Usually limited to uterus; secretes low levels of beta-human chorionic gonadotrophin (βhCG)
    • Rare
  • Epithelioid trophoblastic tumor (ETT)
    • Chorionic-type extravillous trophoblastic cells in the chorion laeve
    • Variant of PSTT – clinical behavior similar to PSTT
    • Rare

Clinical Presentation

• PHM – vaginal bleeding in the absence of other symptoms is most common presentation
• CHM
  • Most frequently diagnosed in first half of pregnancy
  • Most common symptom is abnormal vaginal bleeding – usually 6-16 weeks gestation
  • Other symptoms include the following
    • Uterine enlargement not commensurate with stage of pregnancy
    • Absent fetal heart tones
    • Hyperemesis gravidarum
    • Pregnancy-induced hypertension
    • Cystic enlargement of the ovaries
    • Hyperthyroidism
• GTN
  • Most common symptom is abnormal vaginal bleeding during or after a pregnancy
  • Commonly presents with metastatic symptoms
    • Pulmonary metastatic disease is most common – hemoptysis, shortness of breath, cough, chest pain
    • Other sites – vagina, central nervous system (CNS), liver
  • Most ETTs present many years after full-term delivery; similar pattern for PSTTs
    • Most common sign and symptom is amenorrhea or abnormal vaginal bleeding