Gestational trophoblastic disease (GTD) is a group of tumors defined by abnormal trophoblastic proliferation. Trophoblast cells produce human chorionic gonadotropin (hCG). GTD is divided into hydatidiform moles (contain villi) and other trophoblastic neoplasms (lack villi). 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. These malignancies can occur weeks or years following any pregnancy but occur most commonly after a molar pregnancy.
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. 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. 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. 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.
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.
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.
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.
Partial and complete hydatidiform moles have distinct pathological and clinical features which are outlined below.
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.
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.
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:
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:
Among women with molar pregnancy, the risk factors for developing GTN include:
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. 
GTD is best managed by an interprofessional team that includes nurses and pharmacists. 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. 
|||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 PMID: 20728069]|
|||Practice bulletin No. 53--Diagnosis and treatment of gestational trophoblastic disease., Kohorn E,, Obstetrics and gynecology, 2004 Dec [PubMed PMID: 15572508]|
|||Histopathological diagnosis of hydatidiform mole: contemporary features and clinical implications., Sebire NJ,, Fetal and pediatric pathology, 2010 [PubMed PMID: 20055560]|
|||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 PMID: 11117091]|
|||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 PMID: 31047719]|
|||Ning F,Hou H,Morse AN,Lash GE, Understanding and management of gestational trophoblastic disease. F1000Research. 2019; [PubMed PMID: 31001418]|
|||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 PMID: 30997658]|
|||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 PMID: 10985885]|
|||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 PMID: 30773233]|
|||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 PMID: 30618041]|
|||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 PMID: 31110626]|