Gestational Trophoblastic Disease

Diagnosis

Hydatidiform Mole

Indications for Testing

  • Excessive uterine enlargement and vaginal bleeding

Laboratory Testing

  • Serum βhCG
    • Mild elevation – determine whether result represents false-positive interference from antibodies (refer to hCG Testing topic)
      • Perform urine hCG – negative result expected if interfering antibodies are causing the elevation (interfering substances not excreted in urine)
      • Request serial dilution – no parallel decrease is seen in false-positive result
      • Order hCG test with different assay – testing with reagent using different species of animal antibody may help determine if result is due to interfering antibody
    • Elevated above expected level for gestational age (usually <100,000 mIU/mL) – partial hydatidiform mole (PHM)
    • Marked elevation (>100,000 mIU/mL) – complete hydatidiform mole (CHM)
      • 40-50% of cases
    • Persistent elevation after evacuation – suggestive of invasive or persistent mole

Histology

  • DNA content/cell cycle analysis – useful for distinguishing PHM from CHM
    • PHM – usually triploid
    • CHM – usually diploid or (rarely) tetraploid
  • DNA markers – useful for distinguishing PHM from CHM
    • PHM – shows maternal DNA contribution and usually a double paternal DNA contribution
    • CHM – shows exclusively paternal DNA contribution
    • Biparental CHM (rare) – not detected by this method
  • Immunohistochemistry
    • p57 – used to distinguish CHM from PHM and nonmolar pregnancies
      • p57 is expressed from maternal CDKN1C allele on 11p15 chromosome – paternally imprinted, maternally expressed gene
      • CHM shows absence of staining in villous cytotrophoblast; PHM and nonmolar pregnancies show positive stain
    • Other useful immunohistochemical markers
      • PHLDA2 
        • Gene is located within a 1Mb region on chromosome 11p15.5, which also contains CDKN1C/p57 – paternally imprinted, maternally expressed
      • Human placental lactogen
      • Placental alkaline phosphatase

Imaging Studies

  • Pelvic ultrasound – absence of fetal heartbeat; abnormal echogenic pattern in placenta
    • CHM – marked swelling of chorionic villi; vesicular pattern
    • PHM – focal cystic changes of placenta; ratio of transverse to anterior/posterior dimensions of gestational sac >1.5

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 (Kohorn 2001)
    • hCG increase of  ≥10% of 3 values over at least 2 weeks (eg, days 1, 7, 14)
    • hCG plateau of 4 values over 3 weeks (eg, days 1, 7, 14, 21)
    • hCG persistence for ≥6 months after evacuation of mole
    • Histologic diagnosis of choriocarcinoma

Laboratory Testing

  • Serum βhCG – markedly elevated or continued rise postpregnancy
    • Epithelioid trophoblastic tumor (ETT), placental site trophoblastic tumor (PSTT) – mild elevation common

Imaging Studies

  • Chest x-ray
  • MRI/CT to rule out disseminated metastatic disease

Prognosis

  • Prognostic factors based on WHO scoring system
    • Adapted by FIGO
    • Prognostic factors in modified WHO scoring system include age, previous pregnancy state, tumor size, pretreatment βhCG, metastatic disease, and interval since last pregnancy
    • Prognostic score is combined with the FIGO Anatomic Score
    • Higher numbers indicate a worse prognosis (≥7)
    • Distinction between high- and low-risk disease is probably most important for stages II and III
    • Treatment regimens may be modified based on risk assessment

Differential Diagnosis

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

Monitoring

  • Serum βhCG – monitor in a sequential fashion (Soper 2004)
    • Hydatidiform mole
      • Monitor for return to normal values for up to one 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
        • Two-week intervals until return to normal values and then monthly thereafter for one year; βhCG yearly thereafter
      • Small number of patients have persistent low-level hCG 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

Clinical Background

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 hydatidiform mole (complete or partial), invasive mole, gestational choriocarcinoma, and placental site trophoblastic tumor. GTD can be either benign or malignant.

Epidemiology

  • Incidence
    • Hydatidiform mole
      • 1/600 spontaneous abortions
      • 1/1,000 pregnancies; regional differences observed
    • Gestational trophoblastic neoplasm (GTN)
      • 1/20,000-40,000 pregnancies
        • 50% post-term pregnancies
        • 25% post-molar pregnancies
        • 25% post-other gestational events
      • Choriocarcinoma risk – 1/50,000 pregnancies
      • Persistent, invasive, or metastatic mole
      • Placental site trophoblastic tumor (PSTT)/epithelioid trophoblastic tumor (ETT)
  • Age – childbearing years
  • Sex – exclusively female
  • Ethnicity – increased incidence in Latin America, Middle East, and Southeast Asia
    • In the U.S., African Americans have the highest incidence of choriocarcinoma and the lowest survival rate

Risk Factors

  • Previous molar pregnancy (risk in next pregnancy is 1-2%)
    • 2,000-fold increased risk for GTN following partial or complete hydatidiform molar pregnancies
  • Asian ancestry (7-10 times higher risk)
  • Older maternal age
    • Women >40 years have a five- to tenfold higher risk of complete molar pregnancy
  • Familial disease – rare
    • NLRP7 and (rarely) KHDC3L gene mutations implicated

Pathophysiology

  • All GTD is derived from trophoblastic cells that form the placenta
  • Hydatidiform mole – considered benign
    • Placental villi become edematous and form small grape-like structures
    • Classification
      • Partial hydatidiform mole (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
      • Complete hydatidiform mole (CHM)
        • Hydropic degeneration of all villi
        • Absent embryo, cord, or amniotic structures
        • Diploid genome
        • Absence of maternally expressed gene products
    • Risk for persistent GTD
      • CHM – 15% risk
      • PHM – 0.5% 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
      • Rare
    • Epithelioid trophoblastic tumor (ETT)
      • Chorionic-type extravillous trophoblastic cells in the chorion laeve
      • 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
      • Pregnancy-induced hypertension
      • Cystic enlargement of the ovaries
      • Hyperthyroidism (CHM)
  • 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
    • Most ETTs present many years after full-term delivery

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Beta-hCG, Quantitative (Tumor Marker) 0070029
Method: Quantitative Electrochemiluminescent Immunoassay

Aid in diagnosis and monitoring of GTN

Result is not interpretable as a tumor marker in pregnant females

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

 
Products of Conception, Ploidy by Flow Cytometry 2006178
Method: Quantitative Flow Cytometry

Distinguish between PHM and CHM

Parent of origin not determined for triploidy

 
Molar Pregnancy, 16 DNA Markers 0051755
Method: Polymerase Chain Reaction/Fragment Analysis

Distinguish between PHM and CHM

Clinical sensitivity - 99%; clinical specificity - >99%

Rare biparental CHM not detected by this method  
P57 by Immunohistochemistry 2005542
Method: Immunohistochemistry

Distinguish CHM from PHM and nonmolar pregnancies

Cannot distinguish between PHM and nonmolar pregnancies

 
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Beta-hCG, Urine Qualitative 0020229
Method: Immunoassay

Aid in diagnosis and monitoring of GTN

Beta-hCG, Quantitative (Tumor Marker), CSF 0020730
Method: Quantitative Electrochemiluminescent Immunoassay

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

Placental Alkaline Phosphatase (PLAP) by Immunohistochemistry 2004097
Method: Immunohistochemistry
Human Placental Lactogen (HPL) by Immunohistochemistry 2003938
Method: Immunohistochemistry