Gestational Trophoblastic Disease

Timothy DeKoninck

Britta Hakkila

Stacey L. Poznanski

OVERVIEW

Background

The term “gestational trophoblastic disease” (GTD) describes a spectrum of disorders that originate from placental trophoblastic tissue following abnormal fertilization.¹ GTD can be categorized into premalignant (hydatidiform mole [HM]) and malignant (invasive moles, choriocarcinoma, placental site trophoblastic tumor [PSTT], and epithelioid trophoblastic tumor [ETT]). The malignant forms are collectively termed gestational trophoblastic neoplasia (GTN).² See Figure 14.1. This disease process was described as early as Hippocrates, although it was first linked to pregnancy in 1895.² Sixty years ago, most women died from this malignant disease; however, in the past two decades there have been significant advancements in the understanding, diagnosis, and management of GTD.¹^,³ Improved recognition, the use of human chorionic gonadotropin (hCG) as a biomarker, effective treatments, and increased coordination of care have led to overall cure rates that exceed 98% with fertility retention.² Despite the improved mortality rates, both molar pregnancies and GTN are associated with various life-threatening clinical presentations; therefore, understanding the pathophysiology, constellation of symptoms, and emergent management is crucial in limiting morbidity and mortality in these patients.

The most common form of GTD is the HM, comprising roughly 80% of cases. It is further subdivided into a complete or partial mole based on gross morphology, histopathologic features, and karyotype.¹^,⁴ GTN most commonly develops following a complete molar pregnancy (50%), although it can develop after any form of pregnancy, with 25% occurring after an ectopic pregnancy or spontaneous abortion and the remaining 25% occurring after a normal pregnancy.⁵^,⁶ It very rarely occurs without a documented preceding gestation.⁷ GTN can be defined by (1) a plateaued or rising hCG level after a molar evacuation⁵; (2) histologic diagnosis of one of the malignant forms of GTD; or (3) metastatic disease identified after a molar evacuation (see Table 14.1).⁸ Of patients with a complete mole, GTN will develop in approximately 15% to 20%, whereas only 2% of patients with a partial mole will develop GTN. Invasive moles comprise 15% of GTD and choriocarcinomas make up 5%. PSTTs, including their rarer variant ETT, occur only 0.2% to 2% of the time; however, they carry the highest mortality rate.¹

Figure 14.1: Types of gestational trophoblastic disease.

TABLE 14.1 Gestational Trophoblastic Neoplasia

GTN can be defined by:

Plateaued or rising, hCG level after a molar evacuation

plateau = less than 10% variation, lasting for at least 4 measurements for 3 wk or longer (days 1, 7, 14, 21)
rising = 10% or greater increase for at least three measurements over 2 wk or longer (days 1, 7, 14)

Histologic diagnosis of one of the malignant forms of GTD

Metastatic disease identified after a molar evacuation

GTD, gestational trophoblastic disease; GTN, gestational trophoblastic neoplasia; hCG, human chorionic gonadotropin.

From Ngan HYS, Seckl MJ, Berkowitz RS, et al. Update on the diagnosis and management of gestational trophoblastic disease. Int J Gynecol Obstet. 2018;143(suppl 2):79-85. https://obgyn.onlinelibrary.wiley.com/doi/pdf/10.1002/ijgo.12615.

Prognosis

Overall cure rates of GTN with retention of fertility are high with current clinical practice.²^,⁹ Most malignant types are extremely susceptible to chemotherapy. Nonmetastatic disease has a nearly 100% cure rate with chemotherapy treatment alone.⁵ Metastatic disease can be classified as low risk or high risk based on a World Health Organization (WHO) and International Federation of Gynecology and Obstetrics (FIGO) prognostic score (see Table 14.2). Patients with low-risk metastatic disease have a cure rate close to 100%, whereas the cure rate of high-risk disease is roughly 75% to 90%.⁹

Epidemiology and Risk Factors

The incidence of GTD varies widely between geographical regions, socioeconomic status, and race.¹ There are linkages to hormonal factors, including association with oral contraceptive use,² as well as dietary associations, such as increased incidence with reduced dietary intake of carotene and animal fat.² For unknown reasons, the incidence appears to be about 3 times higher (1 in 120 to 1 in 400 pregnancies) in Asia than in North America, South America, and Europe (1 in 500 to 1 in 1500 pregnancies), although rates are declining, particularly in Asian populations.¹^,²^,⁴ Up to 10-fold greater rates of molar pregnancy are seen in lower socioeconomic status women in East Asia, the

Middle East, the United States, and Brazil.¹ Race also seems to play a role in determining risk. When subset analysis is done by complete mole versus partial mole, studies show that Asian women are at a greater risk of developing a complete mole but less likely to develop a partial mole, black women were significantly less likely to develop a complete mole but only marginally less likely to develop a partial mole, and Hispanic women were also less likely to develop either a complete or partial mole when compared to Caucasian counterparts.¹⁰

TABLE 14.2 FIGO Anatomical Staging and Modified WHO/FIGO Prognostic Scoring System for GTN

FIGO Anatomic Staging Guide
Stage I	Gestational trophoblastic tumors strictly confined to the uterine corpus
Stage II	Gestational trophoblastic tumors extending to the adnexa or to the vagina, but limited to the genital structures
Stage III	Gestational trophoblastic tumors extending to the lungs, with or without genital tract involvement
Stage IV	All other metastatic sites
Score		0	1	2	4
Age (years)		<40	≥40	–	–
Antecedent pregnancy		Mole	Abortion	Term	–
Pregnancy event to treatment interval (months)		<4	4-6	7-12	>12
Pretreatment hCG (mIU/mL)		<1000	1000-10 000	10 000-100 000	>100 000
Largest tumor mass, including uterus (cm)		–	3-4	≥5	–
Site of metastases		Lung	Spleen, kidney	Gastrointestinal Tract	Liver, brain
Number of metastases		–	1-4	5-8	>8
Previous failed chemotherapy		–	–	Single drug	2 or more drugs
The patient’s stage is represented by the Roman numeral and separated by a colon from the sum of the risk factor scores, expressed in Arabic numerals (e.g., Stage III:9). FIGO, International Federation of Gynecology and Obstetrics; GTN, Gestational trophoblastic neoplasia; hCG, human chorionic gonadotropin; WHO, World Health Organization.
Reprinted with permission from Ngan HYS, Seckl MJ, Berkowitz RS, et al. Update on the diagnosis and management of gestational trophoblastic disease. Int J Gynecol Obstet. 2018;143(suppl 2):79-85. https://obgyn.onlinelibrary.wiley.com/doi/pdf/10.1002/ijgo.12615.

Extremes of maternal age, less than 20 years and greater than 40 years, have been associated with increased incidence of molar pregnancy as well as developing GTN. One explanation is that ova from older women are more susceptible to abnormal fertilization than those of younger women.² Recent data show that although adolescents are at greater risk for developing complications, such as bleeding and increased uterine size for dates, they have no increase in low-risk GTD, stage of disease, or frequency of resistance to initial chemotherapy management.¹¹

Historically, a prior molar pregnancy was felt to be an important risk factor, with studies demonstrating 0.6% to 2.6% of molar pregnancies occurring in females who had a prior molar pregnancy,¹² with the risk of a third molar pregnancy up to 15% to 20%.² Recent studies, however, demonstrate minimal increase, if not similar risk, as compared to the general population for molar pregnancies as well as GTN.¹³^,¹⁴ Of note, patients with prior GTD that received chemotherapy were at slightly greater risk for experiencing a stillbirth as compared to the general population.¹³

Although GTN is the most curable gynecologic malignancy, GTD as a whole is not without morbidity and mortality. If the disease process is undiagnosed and untreated, it can be rapidly fatal. Because GTD can present with vague symptoms that may initially appear similar to several other diseases, the emergency clinician needs to have a high index of suspicion for GTD in order to make an accurate diagnosis.

PATHOPHYSIOLOGY

The placenta serves as a connection between the fetus and the mother and develops via the invasion of healthy trophoblastic tissue into the endometrium. Normally, this is closely controlled; however, in GTD, the mechanisms regulating this invasive behavior fail (akin to malignancy) and result in a prolific disorder of trophoblastic cells that can be extremely invasive, vascular, and metastatic.² Although the etiology of GTD is largely unknown, it likely entails genetic abnormalities involved in fertilization.⁸ Although all types of GTD are derived from the placenta, HMs and choriocarcinoma arise from villous trophoblasts and PSTT and ETT from extravillous (interstitial) trophoblasts.¹⁵

HYDATIDIFORM MOLE

A HM is the most common and only benign type of GTD.¹^,¹⁶ A mole may either be partial or complete, depending on the presence or absence of fetal tissue. See Table 14.3 for a comparison of additional features. Approximately 70% of molar pregnancies are complete moles, whereas 30% are partial moles.⁸ Partial molar pregnancies are rarely associated with a viable fetus, and complications such as fetal abnormalities and anemia as well as maternal complications such as preeclampsia prior to 20 weeks are common.¹⁷ Rarely, a molar pregnancy may have a coexisting normal twin pregnancy.¹⁸ These cases (estimated incidence of 1 in 20 000 to 1 in 100 000 pregnancies) are associated with high risk of obstetric complications and poor perinatal outcome, although up to 40% result in normal viable fetuses if allowed to continue.⁵^,¹⁸^,¹⁹

A complete mole occurs when a spermatozoon fertilizes an empty ovum (the ovum does not contain a nucleus/maternal chromosomes). The genetic material of the spermatozoa then replicates, resulting in a 46 XX androgenetic karyotype, in which all chromosomes are paternally derived.² Another less common type of complete mole may occur when two spermatozoa simultaneously fertilize an empty ovum and may result in the karyotypes of 46 XX, 46 XY, or, theoretically, 46 YY.²⁰ On the other hand, partial HMs are almost always triploid. This occurs after fertilization of an apparently healthy haploid ovum by two spermatozoa simultaneously or by one spermatozoon which then duplicates.² These may have a karyotype of 69 XXX, 69 XXY, or 69 XYY.²⁰ Congenital anomalies associated with triploidy, such as syndactyly and cleft lip, can be found when fetuses with partial moles are identified.²¹

TABLE 14.3 Features of GTD

Type of GTD	Pathologic Features	Clinical Features
Partial mole	Triploid (69, XXX or 69, XXY or 69, XYY) Abnormal fetus often present Variable and focal villi edema	Pre-evacuation diagnosis: missed abortion Usually hCG >100 000 mIU/mL Uterine size small for dates Theca lutein cysts rare Medical complications rare Postmolar GTN 2.5%-7.5%
Complete mole	46, XX (usually); 46, XY Absent fetus Diffuse edema of villi	Pre-evacuation diagnosis: molar gestation Usually hCG >100 000 mIU/mL Uterine size 50% large for dates Theca lutein cysts 25%-30% Medical complications 10%-25% Postmolar GTN 15%-20%
Invasive mole	Myometrial invasion Edema of villi	15% metastatic—lung, vagina Most often diagnosed clinically, rather than pathologically
Choriocarcinoma	Hemorrhage, necrosis Absent villi	Vascular spread to distant sites—lung/brain/liver Malignant disease
PSTT/ETT	Absent villi PSTT: Myometrial infiltration with vascular/lymphatic invasion ETT: solitary mass with necrosis and hemorrhage	Extremely rare hCG levels lower and less reliable Relatively chemoresistant Mainly surgical treatment
ETT, epithelioid trophoblastic tumor; GTD, gestational trophoblastic disease; GTN, gestational trophoblastic neoplasia; hCG, human chorionic gonadotropin; PSTT, placental site trophoblastic tumor.
Adapted with permission from 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):531-539.

Histologically, a complete mole shows trophoblastic proliferation with extensive cistern formation. There is characteristically an absence of fetal parts. This helps to differentiate complete from partial mole, where fetal parts, such as fetal cells, may be visualized.⁵ The chorionic villi in both forms are hydropic with diffuse trophoblastic hyperplasia and generalized swelling, leading to the characteristic “grape-like” appearance.²¹^,²² The chorionic villi of partial moles vary in size and have more focal swelling and mild atypia. This, along with the presence of fetal tissue, can lead to the misdiagnosis of an incomplete or missed abortion, only correctly identified after pathologic review.²³

GESTATIONAL TROPHOBLASTIC NEOPLASIA

Invasive Mole

An invasive mole, also known as chorioadenoma destruens,²⁴ develops in approximately 10% to 15% of molar pregnancies,²⁵ rarely in other types of gestation, and comprises 5% to 15% of total GTDs.¹^,¹⁶ An invasive mole is characterized by persistent and aggressive penetration of the hydropic chorionic villi with proliferating trophoblastic tissue into the myometrium, causing local tissue destruction.⁸ It is considered malignant due to this local invasion and also the ability of the molar vesicles to metastasize. Rarely, the tissue destruction can lead to uterine wall perforation presenting emergently with hemoperitoneum and hemorrhagic shock.⁷^,⁸

Persistently elevated hCG levels after evacuation of a molar pregnancy should prompt investigation into GTN. Patients with invasive moles tend to be asymptomatic.⁵ However, it may occasionally be associated with recurrent vaginal bleeding and a vascular myometrial lesion visualized on ultrasound. In such cases, hysterectomy with tissue pathology can fully confirm the diagnosis.
Given the risk of complications such as recurrent vaginal bleeding, uterine perforation, hemorrhage, and infection, invasive moles are often treated empirically with chemotherapy.⁸ They tend to be very sensitive to chemotherapy, resulting in high cure rates.

Choriocarcinoma

Choriocarcinoma comprise 1% to 2% of GTDs and are composed histologically of abnormal syncytiotrophoblasts and cytotrophoblasts, without the presence of chorionic villi, categorizing it as a solely epithelial malignancy.⁵^,⁸^,¹⁶ Necrosis and hemorrhage may also be present.⁵ It is the most malignant GTN and tends to invade locally into the uterus as well as metastasize hematogenously. Metastatic spread is most commonly to the lungs, but other common sites of metastasis are the gastrointestinal tract (liver, spleen, intestines), kidneys, and brain.⁵ Fifty percent of choriocarcinomas occur after a molar pregnancy and 25% occur following a normal pregnancy.²³

Placental Site Trophoblastic Tumor

PSTT is an extremely rare form of GTN, with only approximately one hundred cases reported in the literature.⁸ These tumors occur most often after nonmolar gestation but can occur after molar evacuation.¹ Histologically, it is characterized by invasion of the uterine myometrium and blood vessels by mononuclear trophoblast cells (cells on the maternal side of the placenta), with occasional syncytiotrophoblast giant cells also visualized.⁵ The malignant cells demonstrate irregularity of nuclear membranes as well as hyperchromatic nuclei.⁵ Similar to choriocarcinoma, chorionic villi are absent.⁵ They tend to invade local tissue but may metastasize to various sites, with a 15% to 20% mortality rate in cases of metastatic disease.⁸ Findings are variable but range from a 5 cm myometrial mass that may be tan or yellow with areas of necrosis, to a large uterine polyp, to invasion into the surrounding abdominopelvic tissues.⁵ PSTT tends to be resistant to chemotherapy and is generally treated definitively by hysterectomy.⁸

PSTTs present with the same initial symptoms as other GTDs, with the most common presenting symptom being vaginal bleeding. hCG levels are elevated, although typically not at the high levels seen in other GTDs.

Epithelioid Trophoblastic Tumor

ETT is the rarest form of GTN. The presentation of ETT is very similar to PSTT, although they differ histologically. Grossly, it tends to appear as a single solid mass with areas of hemorrhage and is generally found in the lower portion of the uterus or in the endocervix but may also present in the uterine fundus or, occasionally, the broad ligament.⁵ Histologically, ETT presents as areas of intermediate trophoblastic cells with surrounding necrosis and a hyaline-like matrix.⁵ ETT tends to invade less deeply than PSTTs, although common clinical features are low levels of hCG production and resistance to chemotherapy.⁸ As with PSTT, localized disease is generally treated by hysterectomy.

CLINICAL FEATURES

History and Physical Examination

The Common Presentation Is No Longer Classic

The clinical presentation of molar pregnancies has changed over the past three decades due to increased sensitivity and availability of hCG monitoring and the use of ultrasonography in the first-trimester evaluation of a pregnancy.²⁶^,²⁷^,²⁸ This has led to the diagnosis of GTD occurring more commonly in the first trimester.²⁷ This trend was reported with complete mole diagnosis at a median gestational age of 12 weeks in 1988 to 1993, down from 16 weeks in 1965 to 1975.²⁷ In 2015, a further decline in gestational age was reported, with complete mole diagnosis at 9 weeks in 1994 to 2013.²⁷ Partial moles are more commonly diagnosed later, in the second trimester (at 18.8 weeks on average), and are more frequently misdiagnosed prior to dilation and curettage compared to complete mole.⁸^,²⁷^,²⁹

With earlier diagnosis, the classic presenting symptoms typically seen in the second trimester, such as hyperemesis, abnormal uterine enlargement, anemia, preeclampsia, hyperthyroidism, and dyspnea from pulmonary trophoblastic embolization, are observed much less frequently.⁵^,²⁷
As a result, the diagnosis can be more challenging, leading to molar pregnancies often being missed clinically and diagnosed only after dilation and curettage for a presumed spontaneous abortion.⁵ This is especially true for partial moles that overall have less overt clinical symptoms at presentation. In one study, only 15% of patients with partial mole presented with vaginal bleeding, 3.6% had increased uterine size, and 4% had hyperemesis, leading to a clinical diagnosis of partial molar disease in only 27% of cases prior to evacuation, compared to 76% of complete mole cases successfully diagnosed prior to evacuation.²⁷ This mirrors other studies in which the pre-evacuation clinical diagnosis of partial mole was either a missed or an incomplete abortion in 92% of cases.²⁷ This has important clinical considerations as misdiagnosis may lead to a failure to conduct the postmolar surveillance required to diagnose GTN.²⁷

All forms of GTD may present with typical symptoms of early pregnancy and, although it may be difficult, it is important to differentiate these potentially life-threatening conditions from a viable, aborting, or ectopic pregnancy. The most common presenting symptom of HM is irregular vaginal bleeding, which occurs in 84% of complete molar pregnancies and may vary from minimal spotting to life-threatening hemorrhage.⁴^,⁸ Anti-D immunoglobulin (RhoGam) is recommended in Rh-negative women with HM.³ Nausea and vomiting are common symptoms of pregnancy and affect 70% to 80% of pregnant women at some point during gestation.³⁰ Increased circulating levels of hCG, particularly in the extremely high levels seen in GTD, increase the potential for nausea and vomiting.³⁰

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