Gestational Trophoblastic Disease

  • Diagnosis
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Topics
  • Videos

Hydatidiform Mole

Indications for Testing

  • Excessive uterine enlargement and vaginal bleeding

Laboratory Testing

  • Serum beta-hCG
    • 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 suggests invasive or persistent mole of invasive or persistent mole


  • 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 [from ACOG guideline, 2004])
    • 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


  • 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
    • Hyperthyroidism
  • GTN – metastatic cancer from another site (ovarian, colorectal)
  • 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

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.


  • 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
  • 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 partial or complete hydatidiform molar pregnancies
  • Asian, American Indian, African (GTN only) ancestry
  • Older maternal age – women >40
  • Familial disease – rare
    • NLRP7 and (rarely) KHDC3L gene mutations implicated (Wang, 2009)


  • 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
          • PHM – 0.5% risk
      • Complete hydatidiform mole (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 hCG
      • 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, CNS, hepatic
    • Most ETTs present many years after full-term delivery; similar pattern for PSTT
      • Most common sign and symptom is amenorrhea or abnormal vaginal bleeding
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


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


Parent of origin not determined for triploidy

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


Rare biparental CHM not detected by this method

P57 by Immunohistochemistry 2005542
Method: Immunohistochemistry


Cannot distinguish between PHM and nonmolar pregnancies


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

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]

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

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 2014; 93(3): 575-85. PubMed

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

References 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

Medical Reviewers

Last Update: September 2016