Gestational Trophoblastic Disease


Article Author:
Shaina Bruce


Article Editor:
Joel Sorosky


Editors In Chief:
Michelle Miranda


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Frank Smeeks
Kristina Soman-Faulkner
Radia Jamil
Patrick Le
Sobhan Daneshfar
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
6/18/2019 3:23:57 AM

Introduction

Gestational trophoblastic disease (GTD) is a group of tumors defined by abnormal trophoblastic proliferation.[1] Trophoblast cells produce human chorionic gonadotropin (hCG). GTD is divided into hydatidiform moles (contain villi) and other trophoblastic neoplasms (lack villi).[1] The non-molar or malignant forms of GTD are called gestational trophoblastic neoplasia (GTN). They include the invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor.[2] These malignancies can occur weeks or years following any pregnancy but occur most commonly after a molar pregnancy.

Etiology

Hydatidiform mole (HM) is associated with abnormal gametogenesis and/or fertilization. Risk factors include extremes of age, ethnicity, and a prior history of an HM which suggests a genetic basis for its etiology.[2] Compared to women aged 21 to 35 years, the risk of the complete mole is higher for women older than 35 years and younger than 21 years, and 7.5 times higher for woman greater than 40 years.[2] The risk of repeat molar pregnancy in women with a history of molar pregnancy is approximately 1% which is ten to 20 times the risk for the general population[2]. Interestingly, a history of prior spontaneous abortion has been reported to give women a two to three-fold increase in molar pregnancy compared to a woman without a history of spontaneous abortion.[2]

Epidemiology

Epidemiological studies have reported a large variation in the incidence of HM. Southeast Asia and Japan have the highest reported incidence which has been estimated to be two in 1000 pregnancies. In the United States, HMs occur in approximately 1 in 600 therapeutic abortions and 1 in 1500 pregnancies. Twenty percent of these patients will develop malignant transformation requiring chemotherapy after the evacuation of the mole. In the United States, choriocarcinoma occurs in approximately 1 in 20,000 to 40,000 pregnancies; 50% occur after term pregnancies, 25% of molar pregnancies, and 25% after other gestational events. However, in Southeast Asia and Japan choriocarcinoma rates are higher at three to nine per 40,000 pregnancies. The incidence rates of both hydatidiform mole and choriocarcinoma have declined over the past 30 years in all populations.[2]

Pathophysiology

Hydatidiform moles are essentially very edematous immature placentas. They are broken down into complete and partial moles. A complete molar pregnancy happens when an empty ovum is fertilized by a sperm. This results in the development of only placental parts. A complete mole typically has a karyotype of 46,XX and is completely paternal in origin. A partial mole occurs when two sperm fertilizes a single ovum. This results in the development of some or all fetal parts. A partial mole normally has a triploid karyotype of 69,XXX, 69,XXY or 69,XYY; however, a diploid karyotype may also exist.[3]

Histopathology

The classic description of gestational trophoblastic tissue is a "bunch of grapes." Microscopically, diffuse villous enlargement with hydropic changes can be observed. There is almost always some degree of cytologic atypia with many cells being mitotically active. Central cisterns, as well as trophoblastic hyperplasia, will also be present. Stromal changes such as stromal mucin and apoptosis appear early and can help to make the diagnosis. In partial molar pregnancies, fetal tissue will be present. The fetal tissue will be absent in complete moles.[3]

History and Physical

Partial and complete hydatidiform moles have distinct pathological and clinical features which are outlined below.

Karyotype

  • Partial: 69,XXX or 69,XXY
  • Complete: 46,XX or 46,XY

Fetal tissues

  • Partial: present
  • Complete: absent 

Villous edema

  • Partial: variable, focal
  • Complete: diffuse

Trophoblastic proliferation

  • Partial: focal
  • Complete: Diffuse

Clinical Presentation

  • Partial: uterus small for gestational age, low presenting hCG level, rare medical complications.
  • Complete: uterus 50% larger for gestational age, high presenting hCG level, medical complications occur approximately 25% of the time and include hypertension, hyperthyroidism, anemia, hyperemesis gravidarum.

Malignant sequelae 

  • Partial: less than 5%
  • Complete: approximately 20%

Presentation

  • Partial: often as missed abortion in absence of symptoms
  • Complete: clinical or ultrasonographic diagnosis [2]

Evaluation

Hydatidiform moles are usually diagnosed during the first trimester of pregnancy. The most common presentation is abnormal bleeding. Other signs include uterine enlargement greater than expected for gestational age, absent fetal heart tones, cystic ovary enlargement, hyperemesis gravidarum, and abnormally high level of hCG for gestational age.

Ultrasound is the gold standard in non-invasive techniques. The most commonly described appearance of a molar pregnancy on ultrasound is the "snowstorm" or "bunches of grapes" pattern of the uterus. However, this is not as commonly seen today due to earlier diagnosis, often in the first trimester. The majority of first-trimester complete moles have a sonographic appearance of a complex, echogenic intrauterine mass which contains multiple small cystic spaces. These spaces correspond to the hydropic villi on gross pathology. Despite the utility of ultrasound in making this diagnosis, in patient's who are presumed to have a spontaneous abortion, a molar pregnancy is detected only after pathology evaluation of a uterine curettage sample. This most often occurs in those with a partial mole.[4]

Treatment / Management

Surgical uterine evacuation (dilation and evacuation, suction curettage) is the mainstay of management for complete or partial moles. A hysterectomy is an option for patients who have completed childbearing. Medical management is controversial and not well studied. There is some concern that inducing uterine contractions with uterotonics may increase the risk of metastatic disease.[1][5][1]

All patients with HM should be monitored with serial serum hCG testing values after evacuation to evaluate for post-molar gestational trophoblastic neoplasia (GTN).  Guidelines from the American College of Obstetricians and Gynecologists advise the following protocol:

  • Every week until non-detectable for 3 weeks, then
  • Every month for 6 months: If the hCG remains undetectable for six months, then the patient may resume trying to become pregnant.

Following the evacuation of a complete or partial molar pregnancy, if hCG levels rise or remain elevated over several weeks, the patient is classified as having GTN. The diagnosis of post-molar GTN is based upon the International Federation of Gynecology and Obstetrics (FIGO) criteria:

  • hCG levels plateau (remain within plus or minus 10% of the previous result) across four measurements over a 3-week period.
  • hCG level increases more than 10% across three values over a 2-week duration
  • Persistence of detectable serum hCG for more than 6 months after molar evacuation. [2]

Pearls and Other Issues

Among women with molar pregnancy, the risk factors for developing GTN include:

  1. Complete mole with signs of trophoblastic proliferation (uterine size greater than gestational age, serum human chorionic gonadotropin [hCG] levels more than 100,000 mIU/mL)
  2. Ovarian theca lutein cysts greater than 6 cm in diameter
  3. Age greater than 35 to 40 years.

Some institutions offer prophylactic chemotherapy for high-risk women with complete moles. Evidence shows that this may decrease the incidence of gestational trophoblastic neoplasia. All patients with GTD should have a chest x-ray to evaluate for pulmonary metastasis. [1]

Patients with molar pregnancies must be monitored for associated complications including hyperthyroidism, pre-eclampsia, and ovarian theca lutein cysts. Molar pregnancy induced hyperthyroidism should resolve with the evacuation of the uterus, but patients may require beta-adrenergic blocking agents before anesthesia to reverse effects of thyroid storm. Pre-eclampsia also resolves quickly after the evacuation of the uterus. Theca lutein cysts will regress spontaneously with falling beta-HCG levels. However, patients must be counseled on signs and symptoms of ovarian torsion and ruptured ovarian cysts. [2]


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Gestational Trophoblastic Disease - Questions

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A 32-year-old G2P0010 at 16 weeks gestational age is being followed for a dichorionic-diamniotic twin gestation. She has a questionable third sac suggestive of a molar pregnancy. She now presents with daily headaches, palpitations, nausea, and right upper quadrant pain. Her blood pressure is 171/92. Labwork shows platelets 308,000/mL, creatinine 0.6, aspartate aminotransferase 16 U/L, alanine aminotransferase 15 U/L, thyroid stimulating hormone less than 0.01 U/mL, and beta-human chorionic gonadotropin (hCG) 621,538 mIU/mL. Which of the following is true regarding this patient?



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Methotrexate is prescribed for gestational trophoblastic disease. Which of the following should be prescribed together to reduce methotrexate side effects?



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What is the first step in the treatment of a 40-year-old who is 7 weeks with a molar pregnancy?



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Which of the following is not an early symptom in a patient with gestational trophoblastic disease?



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Which of the following is not a complication of gestational trophoblastic disease?



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Which biochemical marker is used to evaluate gestational trophoblastic disease?



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The patient is a 23-year old G1P0 who had an ultrasound at 11 weeks gestation concerning for molar pregnancy. She has a dilation and evacuation procedure and pathology indicates a complete mole. Which of the following characteristics are consistent with this diagnosis?



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Which of the following tests are not typically needed when evaluating a patient with gestational trophoblastic disease?



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Which of the following patients meets criteria for gestational trophoblastic neoplasia?



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A 33-year-old G2P1001 at 7 weeks presents with vaginal bleeding. Ultimately she is diagnosed with a spontaneous abortion and is taken for a dilation and evacuation procedure. Pathology of the products of conception shows a partial mole. Her beta-human chorionic gonadotropin (hCG) values trended as follows: postoperative day (POD) zero - 2056 mIU/ml, POD 7 - 77 mIU/ml, POD 14 - 32 mIU/ml, POD 21 - less than 5 mIU/ml, POD 28 - less than 5 mIU/ml, POD - less than 5 mIU/ml, POD 85 - less than 5 mIU/ml, POD 115 - 7 mIU/ml. What is the next step in management?



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A 25-year-old G2P1011, who is day-3 post-operative from a dilation and evacuation procedure for a molar pregnancy, presents to the emergency department with sudden onset, intermittent, right-sided pelvic pain. The pain is 10 out of 10 and worse with ambulation and when her legs are straight. The patient receives intravenous hydromorphone with minimal relief. What is the increased risk for this patient?



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Gestational Trophoblastic Disease - References

References

Gestational trophoblastic disease I: epidemiology, pathology, clinical presentation and diagnosis of gestational trophoblastic disease, and management of hydatidiform mole., Lurain JR,, American journal of obstetrics and gynecology, 2010 Dec     [PubMed]
Practice bulletin No. 53--Diagnosis and treatment of gestational trophoblastic disease., Kohorn E,, Obstetrics and gynecology, 2004 Dec     [PubMed]
Gestational trophoblastic disease: a study of mode of evacuation and subsequent need for treatment with chemotherapy., Tidy JA,Gillespie AM,Bright N,Radstone CR,Coleman RE,Hancock BW,, Gynecologic oncology, 2000 Sep     [PubMed]
Sonographic appearance of first trimester complete hydatidiform moles., Benson CB,Genest DR,Bernstein MR,Soto-Wright V,Goldstein DP,Berkowitz RS,, Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology, 2000 Aug     [PubMed]
Histopathological diagnosis of hydatidiform mole: contemporary features and clinical implications., Sebire NJ,, Fetal and pediatric pathology, 2010     [PubMed]
Gadducci A,Carinelli S,Guerrieri ME,Aletti GD, Placental site trophoblastic tumor and epithelioid trophoblastic tumor: Clinical and pathological features, prognostic variables and treatment strategy. Gynecologic oncology. 2019 Jun;     [PubMed]
Ning F,Hou H,Morse AN,Lash GE, Understanding and management of gestational trophoblastic disease. F1000Research. 2019;     [PubMed]
Gerstl B,Sullivan E,Vallejo M,Koch J,Johnson M,Wand H,Webber K,Ives A,Anazodo A, Reproductive outcomes following treatment for a gynecological cancer diagnosis: a systematic review. Journal of cancer survivorship : research and practice. 2019 Apr;     [PubMed]
Albrecht C,Chamley L,Charnock-Jones DS,Collins S,Fujiwara H,Golos T,Grayo S,Hannan N,Harris L,Ichizuka K,Illsley NP,Iwashita M,Kallol S,Al-Khan A,Lash G,Nagamatsu T,Nakashima A,Niimi K,Nomoto M,Redman C,Saito S,Tanimura K,Tomi M,Usui H,Vatish M,Wolfe B,Yamamoto E,O'Tierney-Ginn P, IFPA meeting 2018 workshop report II: Abnormally invasive placenta; inflammation and infection; preeclampsia; gestational trophoblastic disease and drug delivery. Placenta. 2019 Feb 12;     [PubMed]
Wreczycka-Cegielny P,Cegielny T,Oplawski M,Sawicki W,Kojs Z, Current treatment options for advanced choriocarcinoma on the basis of own case and review of the literature. Ginekologia polska. 2018;     [PubMed]
Al Riyami N,Al Riyami M,Al Hajri AT,Al Saidi S,Salman B,Al Kalbani M, Gestational Trophoblastic Disease at Sultan Qaboos University Hospital: Prevalence, Risk Factors, Histological Features, Sonographic Findings, and Outcomes. Oman medical journal. 2019 May;     [PubMed]

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