Gestational Trophoblastic Disease

Gestational trophoblastic disease (GTD) comprises a group of rare tumors originating from cells that would normally develop into the placenta during pregnancy. The spectrum of disease includes benign disease (complete hydatidiform mole [CHM] or partial hydatidiform mole [PHM]) and malignant tumors termed gestational trophoblastic neoplasms (GTNs), which encompass invasive mole, gestational choriocarcinoma, epithelioid trophoblastic tumor, and placental site trophoblastic tumor.

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)
    • 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

ARUP Lab Tests

Aid in diagnosis and monitoring of gestational trophoblastic neoplasm (GTN)

Result is not interpretable as a tumor marker in pregnant females

Results obtained with different test methods or kits cannot be used interchangeably

Distinguish between partial hydatidiform mole (PHM) and complete hydatidiform mole (CHM)

Distinguish between partial hydatidiform mole (PHM) and complete hydatidiform mole (CHM)

Distinguish CHM from PHM and hydropic abortion

Stained and returned to client pathologist for interpretation; consultation available if needed

Related Tests

Aid in diagnosis and monitoring of gestational trophoblastic neoplasm (GTN)

Aid in management of patients with trophoblastic tumors when used in conjunction with clinical evaluation and other diagnostic procedures

Results obtained with different test methods or kits cannot be used interchangeably

Stained and returned to client pathologist for interpretation; consultation available if needed

Identifies placental-site trophoblastic tumors and exaggerated placental sites

Stained and returned to client pathologist for interpretation; consultation available if needed

Medical Experts

Contributor

Genzen

Jonathan R. Genzen, MD, PhD
Associate Professor of Clinical Pathology, University of Utah
Chief Operations Officer, Medical Director of Automated Core Laboratory, ARUP Laboratories
Contributor
Contributor

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®