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.

Tabs Content

Clinical Overview

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)
  - 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)

Histology

Methods for distinguishing PHM, CHM, and nonmolar pregnancies

Methods for Distinguishing PHM, CHM, and Nonmolar Pregnancies
	DNA Content/Cell Cycle Analysis	DNA Markers	Immunohistochemistry
PHM	Usually triploid	Shows maternal DNA contribution Usually a double paternal DNA contribution	Shows positive p57^b stain in villous cytotrophoblast
CHM	Usually diploid or (rarely) tetraploid	Shows exclusively paternal DNA contribution^a	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)

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

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.

Beta-hCG, Quantitative (Tumor Marker) 0070029
Method: Quantitative Electrochemiluminescent Immunoassay

Recommended Use

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

Limitations

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

Recommended Use

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

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

Recommended Use

Diagnose complete or partial molar pregnancy

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

P57 by Immunohistochemistry 2005542
Method: Immunohistochemistry

Recommended Use

Distinguish CHM from PHM and hydropic abortion

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

Medical Experts

Genzen, Jonathan R., MD, PhD, Laboratory Section Chief, Clinical Chemistry, and Medical Director, Automated Core Laboratory, at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

Samowitz, Wade S., MD, Medical Director, Anatomic Pathology, at ARUP Laboratories; Professor of Anatomic Pathology, University of Utah

Wittwer, Carl T., MD, PhD, Medical Director, Immunologic Flow Cytometry at ARUP Laboratories; Professor of Clinical Pathology, University of Utah

References

Guidelines

Protocol for the Examination of Specimens from Patients with Gestational Trophoblastic Malignancy. Based on AJCC/UICC TNM, 7th ed, and FIGO 2009 Annual Report. Protocol web posting date: Jan 2016. College of American Pathologists (CAP). Northfield, IL [Revised: Jan 2016; Accessed: Dec 2016]
Soper JT, Mutch DG, Schink JC, American College of Obstetricians and Gynecologists. Diagnosis and treatment of gestational trophoblastic disease: ACOG Practice Bulletin No. 53. Gynecol Oncol. 2004; Reaffirmed 2016; 93(3): 575-85. PubMed
Seckl MJ, Sebire NJ, Fisher RA, Golfier F, Massuger L, Sessa C, ESMO Guidelines Working Group. Gestational trophoblastic disease: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013; 24 Suppl 6: vi39-50. PubMed
Mangili G, Lorusso D, Brown J, Pfisterer J, Massuger L, Vaughan M, Ngan HY, Golfier F, Sekharan PK, Charry RC, Poveda A, Kim J, Xiang Y, Berkowtiz R, Seckl MJ. Trophoblastic disease review for diagnosis and management: a joint report from the International Society for the Study of Trophoblastic Disease, European Organisation for the Treatment of Trophoblastic Disease, and the Gynecologic Cancer InterGroup. Int J Gynecol Cancer. 2014; 24(9 Suppl 3): S109-16. PubMed
Bolze P, Attia J, Massardier J, Seckl MJ, Massuger L, van Trommel N, Niemann I, Hajri T, Schott A, Golfier F, EOTTD group. Formalised consensus of the European Organisation for Treatment of Trophoblastic Diseases on management of gestational trophoblastic diseases. Eur J Cancer. 2015; 51(13): 1725-31. PubMed
Gestational Trophoblastic Disease Treatment (PDQ)–Health Professional Version. National Cancer Institute. [Updated: Feb 2015; Accessed: Jun 2017]

General References

Berkowitz RS, Goldstein DP. Current management of gestational trophoblastic diseases. Gynecol Oncol. 2009; 112(3): 654-62. PubMed

Lurain JR. Gestational trophoblastic disease I: epidemiology, pathology, clinical presentation and diagnosis of gestational trophoblastic disease, and management of hydatidiform mole. Am J Obstet Gynecol. 2010; 203(6): 531-9. PubMed

Lurain JR. Gestational trophoblastic disease II: classification and management of gestational trophoblastic neoplasia. Am J Obstet Gynecol. 2011; 204(1): 11-8. PubMed

Murphy KM, McConnell TG, Hafez MJ, Vang R, Ronnett BM. Molecular genotyping of hydatidiform moles: analytic validation of a multiplex short tandem repeat assay. J Mol Diagn. 2009; 11(6): 598-605. PubMed

Sebire NJ, Seckl MJ. Immunohistochemical staining for diagnosis and prognostic assessment of hydatidiform moles: current evidence and future directions. J Reprod Med. 2010; 55(5-6): 236-46. PubMed

Sebire NJ. Histopathological diagnosis of hydatidiform mole: contemporary features and clinical implications. Fetal Pediatr Pathol. 2010; 29(1): 1-16. PubMed

Seckl MJ, Sebire NJ, Berkowitz RS. Gestational trophoblastic disease. Lancet. 2010; 376(9742): 717-29. PubMed

Wang CM, Dixon PH, Decordova S, Hodges MD, Sebire NJ, Ozalp S, Fallahian M, Sensi A, Ashrafi F, Repiska V, Zhao J, Xiang Y, Savage PM, Seckl MJ, Fisher RA. Identification of 13 novel NLRP7 mutations in 20 families with recurrent hydatidiform mole; missense mutations cluster in the leucine-rich region. J Med Genet. 2009; 46(8): 569-75. PubMed

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Greene DN, Petrie MS, Pyle AL, Kamer SM, Grenache DG. Performance characteristics of the Beckman Coulter total βhCG (5th IS) assay. Clin Chim Acta. 2015; 439: 61-7. PubMed

Educational Videos

Content Review:

June 2017

Last Update: June 2019

Gestational Trophoblastic Disease

Diagnosis

Hydatidiform Mole

Indications for Testing

Laboratory Testing

Histology

Imaging Studies

Gestational Trophoblastic Neoplasm

Indications for Testing

Criteria for Diagnosis

Laboratory Testing

Imaging Studies

Prognosis

Differential Diagnosis

Monitoring

Background

Epidemiology

Risk Factors

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

ARUP Laboratories

ARUP Websites

ARUP Consult


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Gestational Trophoblastic Disease

Diagnosis

Hydatidiform Mole

Indications for Testing

Laboratory Testing

Histology

Imaging Studies

Gestational Trophoblastic Neoplasm

Indications for Testing

Criteria for Diagnosis

Laboratory Testing

Imaging Studies

Prognosis

Differential Diagnosis

Monitoring

Background

Epidemiology

Risk Factors

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

ARUP Laboratories

ARUP Websites

ARUP Consult