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
- Serum beta-human chorionic gonadotrophin (βhCG)
- 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)
- Elevated above expected level for gestational age (usually <100,000 mIU/mL) suggests partial hydatidiform mole (PHM)
Histology
DNA Content/Cell Cycle Analysis | DNA Markers | Immunohistochemistry | |
---|---|---|---|
PHM |
Usually triploid |
Shows maternal DNA contribution Usually a double paternal DNA contribution |
Shows positive p57b stain in villous cytotrophoblast |
CHM |
Usually diploid or (rarely) tetraploid |
Shows exclusively paternal DNA contributiona |
Shows absence of p57 staining in villous cytotrophoblast |
Nonmolar |
n/a |
n/a |
Shows positive p57 stain in villous cytotrophoblast |
aBiparental CHM (rare) is not detected with DNA markers bp57 is expressed from maternal CDKN1C allele on 11p15 chromosome – paternally imprinted, maternally expressed gene n/a, not available |
- 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)
- Prognostic factors in modified WHO scoring system include
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
- βhCG during chemotherapy to determine remission
- Hydatidiform mole
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
- 1/20,000-40,000 pregnancies
- Hydatidiform mole
- 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
- PHM
- 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
- Invasive, persistent, or metastatic mole – mole with invasion into the myometrium; rare "metastasis" to extrauterine sites (lung, vagina)
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 Laboratory 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
Quantitative Electrochemiluminescent Immunoassay
Distinguish between partial hydatidiform mole (PHM) and complete hydatidiform mole (CHM)
Quantitative Flow Cytometry
Distinguish CHM from PHM and hydropic abortion
Stained and returned to client pathologist for interpretation; consultation available if needed
Immunohistochemistry
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
Quantitative Electrochemiluminescent Immunoassay
Stained and returned to client pathologist for interpretation; consultation available if needed
Immunohistochemistry
Medical Experts
References
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