Gestational Trophoblastic Disease

Hydatidiform Mole

Indications for Testing

Symptoms of molar pregnancy, including excessive uterine enlargement and vaginal bleeding

Laboratory Testing

βhCG
- PHM – elevated above expected level for gestational age (usually <100,000 mIU/mL)
- CHM – marked elevation (>100,000 mIU/mL) in 40-50% of cases
- Elevated levels (but not usually >100,000 mIU/mL) are 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
- Mild elevation may represent false-positive interference (see hCG Testing topic)
  - Perform urine βhCG – negative if false-positive serum test due to interfering antibody
  - Request serial dilution – no parallel decrease in false-positive result
  - Urine and serum βhCG – performing hCG with an assay that uses a different species of reagent animal antibodies may help to determine if result is due to an interfering antibody
- Persistent elevation of hCG after evacuation suggests invasive mole

Histology

DNA content/cell cycle analysis – used to distinguish PHM from CHM
- Partial moles are usually triploid
- Complete moles are usually diploid or (rarely) tetraploid
DNA markers – used to distinguish PHM from CHM
- Partial moles show maternal DNA contribution and usually a double paternal DNA contribution
- Complete moles show exclusively paternal DNA contribution
- Rare biparental complete mole 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 (paternally imprinted, maternally expressed gene)
  - Complete mole shows absence of staining in villous cytotrophoblast; partial moles show positive stain
- Human placental lactogen and placental alkaline phosphatase – established immunohistochemical markers in GTN
- PHLDA2 – useful immunohistochemical marker
  - Located within a 1-Mb region on 11p15.5 that also contains CDKN1C/p57 (paternal imprinted, maternally expressed)

Imaging Studies

Pelvic ultrasound – no fetal heart tones, mixed echogenic pattern replacing 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 neoplasia

Criteria for Diagnosis

International Federation of Gynecology and Obstetrics (FIGO) recommendations for diagnosis of GTN (Ngan 2007)
- hCG increase of ≥10% of 3 values recorded over 2 weeks
- hCG plateau of ±10% of 4 values over 3 weeks
- hCG persistence after evacuation of mole for ≥6 months
- Histologic diagnosis of choriocarcinoma

Laboratory Testing

βhCG – markedly elevated or continued rise post-pregnancy
- ETT, PSTT – mild elevations 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
- Accounts for age, previous pregnancy state, tumor size, pretreatment βhCG, metastatic disease and interval since last pregnancy
- Score is attached to 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)

βhCG – monitor in a sequential fashion (Soper 2004)
- Hydatidiform mole – monitored for return to normal values for up to one year (every 1-2 weeks until normal, monthly once normalized); pregnancy discouraged during this period
- 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
Pelvic ultrasound recommended in first trimester of subsequent pregnancy to confirm normal gestation (1-2% risk of recurrence in next pregnancy)
6-week post-partum βhCG
Post-delivery examination of placental products of conception

Gestational trophoblastic disease (GTD) comprises a group of rare tumors originating from cells that would normally develop into the placenta during pregnancy. The main tumor types are hydatidiform mole (complete or partial), invasive mole, choriocarcinoma, and placental site trophoblastic tumor (rare). GTD tumors can be either benign or malignant.

Epidemiology

Incidence
- Hydatidiform mole – non-neoplastic
  - 1/600 spontaneous abortions
  - 1/1,000 pregnancies with regional differences observed
  - Risk for persistent gestational trophoblastic disease
    - Complete mole – 15% risk
    - Partial mole – 0.5% risk
- Gestational trophoblastic neoplasm (GTN) – typically malignant
  - Overall risk – 1/20,000-40,000 pregnancies
    - 50% post-term pregnancies
    - 25% post-molar pregnancies
    - 25% post-other gestational events
  - Choriocarcinoma risk – 1/50,000
Age – childbearing years
Sex – exclusively female
Ethnicity – increased risk 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; NALP7 mutation implicated in some cases

Pathophysiology

All GTD is derived from placenta
Hydatidiform mole
- 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 80% of the time (usually 46,XX)
    - Absence of maternally expressed gene products
  - Invasive mole – mole with invasion into the myometrium; rare "metastasis" to extrauterine sites (lung, vagina)
    - May coexist with a normal pregnancy (rare)
    - May be a precursor to GTN
    - Swollen villi; hyperplastic trophoblast
GTN
- Gestational choriocarcinoma
  - Neoplastic syncytiotrophoblast and cytotrophoblast elements without chorionic villi; hemorrhage, necrosis
  - Usually metastasize early
- Epithelioid trophoblastic tumor (ETT)
  - Chorionic-type extravillous trophoblastic cells in the chorion laeve; rare
- Placental site trophoblastic tumor (PSTT)
  - Absence of villi, proliferation of intermediate trophoblast cells in the myometrium
  - Usually limited to uterus; rare

Clinical Presentation

Complete hydatidiform mole
- Most frequently diagnosed in the 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 dates
  - Absent fetal heart tones
  - Hyperemesis
  - Pregnancy-induced hypertension
  - Hyperthyroidism (CHM)
Partial hydatidiform mole – vaginal bleeding with no other symptoms is most common
GTN
- May have subtle symptoms
- 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

Tests generally appear in the order most useful for common clinical situations

Test name: Beta-hCG, Quantitative (Tumor Marker)

ARUP #: 0070029

Methodology: Quantitative Electrochemiluminescent Immunoassay

Use:

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

Limitations:

Result cannot be interpreted as absolute evidence of the presence or absence of malignant disease

Result is not interpretable as a tumor marker in pregnant females

Test name: Beta-hCG, Urine Qualitative

ARUP #: 0020229

Methodology: Immunoassay

Use:

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

Limitations:

Result cannot be interpreted as absolute evidence of the presence or absence of malignant disease

Result is not interpretable as a tumor marker in pregnant females

Test name: Molar Pregnancy, 16 DNA Markers

ARUP #: 0051755

Methodology: Polymerase Chain Reaction/Fragment Analysis

Use:

Diagnosis of PHM and CHM

Test name: DNA Content/Cell Cycle Analysis, Products of Conception

ARUP #: 0093386

Methodology: Quantitative Flow Cytometry

Use:

Distinguish between PHM and CHM

Limitations: Contamination of villi/decidua may occur

Test name: P57 by Immunohistochemistry

ARUP #: 2005542

Methodology: Immunohistochemistry

Use:

Distinguish CHM from PHM and nonmolar pregnancies

Additional Tests Available

Test name: Alpha Subunit of Pituitary Glycoprotein Hormones

ARUP #: 0092526

Methodology: Quantitative Immunoradiometric Assay

Comments:

Test name: Beta-hCG, Quantitative (Tumor Marker), CSF

ARUP #: 0020730

Methodology: Quantitative Electrochemiluminescent Immunoassay

Comments:

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

Test name: Placental Alkaline Phosphatase (PLAP) by Immunohistochemistry

ARUP #: 2004097

Methodology: Immunohistochemistry

Comments:

Test name: Human Placental Lactogen (HPL) by Immunohistochemistry

ARUP #: 2003938

Methodology: Immunohistochemistry

Comments:

Guidelines

General

Comprehensive Review: July 2011
Last Update: November 2011

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