Gestational Trophoblastic Disease

Gestational trophoblastic disease (GTD) includes benign, premalignant, and malignant tumors that are associated with pregnancy and often result from abnormal fertilization events.   Benign GTD includes molar pregnancies, both partial hydatidiform moles (PHMs) and complete hydatidiform moles (CHMs). Gestational trophoblastic neoplasia (GTN) is a malignant disorder that includes invasive moles, choriocarcinomas, placental site trophoblastic tumors, and epithelioid trophoblastic tumors.  GTN is most common after a molar pregnancy but may also arise after an ectopic pregnancy, a spontaneous abortion, or a full-term pregnancy.   Human chorionic gonadotropin (hCG) is produced at high levels in nearly all forms of GTD; thus, hCG is an excellent marker for the diagnosis, monitoring, and evaluation of treatment response in GTN. 

Quick Answers for Clinicians

Who is most at risk of having a molar pregnancy?

Complete hydatidiform moles (CHMs), or molar pregnancies, are more common in individuals younger than 21 years and older than 35 years.  The risk is even greater for individuals older than 40 years. 

The risk of a subsequent CHM increases after one molar pregnancy, although it is still low.  The risk is increased significantly after two molar pregnancies, and familial recurrent hydatidiform mole syndrome (caused by NLRP7 or KHDC3L gene variants) should be suspected.  

Are false-positive or false-negative human chorionic gonadotropin results possible?

False-negative human chorionic gonadotropin (hCG) results are primarily caused by two situations. First, a tumor may secrete a form of hCG that some assays are unable to detect, which can be mitigated by using an assay that detects all forms of hCG.  Second, some assays are susceptible to a “hook effect,” which occurs when the assay cannot detect hCG despite the presence of extremely high levels of the hormone.  Diluting the sample before analysis allows an accurate measurement to be obtained. 

False-positive results may occur in the presence of hCG from other sources (eg, the pituitary gland) or of phantom hCG, which is caused by antibodies that interfere with the assay.  The production of pituitary hCG may be suppressed by a higher dose of an oral contraceptive.  Phantom hCG should be suspected if hCG elevation is only present in serum and not in urine, if two different commercial assays produce vastly different results, or if elevated hCG concentrations persist despite dilution of the sample. 

What additional testing is appropriate when assessing gestational trophoblastic disease?

When gestational trophoblastic disease (GTD) leads to a diagnosis of gestational trophoblastic neoplasia (GTN), some routine laboratory testing should be performed. In addition to CBC and blood chemistry assessment, standard evaluations for thyroid disease, renal function, and hepatic function should be performed.  

Indications for Testing

Testing for a hydatidiform mole should be performed on evacuated tissue when hCG levels and/or ultrasound findings suggest a molar pregnancy.  

Testing for GTN should be performed by assessing hCG levels at regular intervals following a molar pregnancy. Testing may be considered after a nonmolar pregnancy in individuals who present with abnormal vaginal bleeding, bleeding from other sites (eg, liver, intestines, lungs), pulmonary symptoms, or neurologic abnormalities. 

Laboratory Testing

Hydatidiform Mole

Due to more frequent ultrasounds in the early stages of pregnancy and more accurate hCG testing methods, molar pregnancies (or hydatidiform moles) are typically detected before the presentation of classic symptoms (eg, anemia, preeclampsia, excessive uterine size, hyperthyroidism).  

hCG Concentrations

Hydatidiform moles result in greatly increased production of hCG, and hCG testing should be performed when a molar pregnancy is suspected and may help differentiate between a PHM and a CHM.    Concentrations <100,000 IU/L are common in CHMs but are rare in PHMs. 

If hCG is elevated but imaging does not suggest a molar pregnancy, consider the possibility of a false-positive hCG test. 

Ploidy Status and Parental Contribution

When a suspected molar pregnancy has been evacuated, flow cytometry or microsatellite short tandem repeat (STR) genotyping may be performed on the tissue to determine ploidy status and parental contribution to differentiate among CHMs, PHMs, and nonmolar pregnancies.  

Evaluation of Postevacuation Tissue
Gestation Type Ploidy Status Parental Genetic Contribution

CHM

Typically diploid

Exclusively paternal

PHM

Typically triploid

Maternal and paternal

Nonmolar pregnancy

Diploid

Maternal and paternal

Source: Ngan, 2021 

p57 by Immunohistochemistry

Kinase inhibitor p57 is a gene that is paternally coded and maternally expressed and is thus absent in tissue from a CHM.  Staining for p57 can detect a CHM but cannot differentiate between a PHM and a nonmolar pregnancy.  

Gestational Trophoblastic Neoplasia

hCG is the primary marker used during surveillance for, diagnosis of, and treatment monitoring in GTN.    When measuring hCG to assess GTN, the assay used should be able to detect all forms of hCG (eg, beta-hCG [β-hCG], core hCG, C-terminal hCG, nicked-free β, β core, hyperglycosylated forms).  Because different assays can vary considerably, the same assay should be used throughout a patient’s entire course of care. 

Surveillance

Surveillance for GTN should occur following a molar pregnancy.  hCG concentrations should be measured regularly until normalization or diagnosis of GTN. 

hCG Surveillance After a Molar Pregnancy
Society hCG Testing Guidance

ACOG/SGO

Monthly for 6 months

NCCN

Every 1-2 weeks until 3 consecutive normal hCG test results, followed by 2 hCG tests at 3-month intervals

FIGO

PHM: Every 1-2 weeks until normal, followed by 1 normal result in a month

CHM: Every 1-2 weeks until normal, then monthly for 6 additional months

ACOG, American College of Obstetricians and Gynecologists; FIGO, Fédération Internationale de Gynécologie et d'Obstétrique (International Federation of Gynaecology and Obstetrics); NCCN, National Comprehensive Cancer Network; SGO, Society of Gynecologic Oncology

Source: Horowitz, 2021 ; Ngan, 2021 ; NCCN, 2022 

Patients in remission for GTN should also be under surveillance.  To monitor for recurrence, these patients should have hCG levels assessed every month for 12 months following the completion of treatment.  After surveillance ends, hCG testing may be considered in the presence of suspicious symptoms such as vaginal bleeding. 

Diagnosis

Although histology or radiology may lead to a diagnosis of GTN, it is more often diagnosed solely based on hCG levels; histologic confirmation is not required.   hCG levels can be used to diagnose GTN in the following situations :

  • hCG levels plateau (ie, do not increase or decrease by >10%) for four consecutive tests during a period of 3 weeks
  • hCG levels rise ≥10% for three consecutive tests during a period of 2 weeks

Monitoring

Treatment response for GTN should be monitored by performing hCG testing either weekly or on day 1 of each chemotherapy cycle. After three consecutive normal hCG measurements, the patient is considered to be in remission.  

ARUP Laboratory Tests

References

Medical Experts

Contributor

Jackson

Brian R. Jackson, MD, MS
Associate Professor of Pathology (Clinical); Adjunct Associate Professor, Biomedical Informatics, University of Utah
Medical Director, Support Services, IT, and Business Development, ARUP Laboratories