Gestational trophoblastic neoplasia: Epidemiology, clinical features, diagnosis, staging, and risk stratification

INTRODUCTION — Gestational trophoblastic neoplasia (GTN) refers to a group of malignant neoplasms that consist of abnormal proliferation of trophoblastic tissue, and may follow a hydatidiform mole or a nonmolar pregnancy. GTN is comprised of the following histologic types:

●Invasive mole

●Choriocarcinoma

●Placental site trophoblastic tumor (PSTT)

●Epithelioid trophoblastic tumor (ETT)

Invasive mole and choriocarcinoma are characterized by high levels of human chorionic gonadotropin (hCG), while PSTT and ETT typically have low hCG levels.

Prior to the development of effective chemotherapy for GTN, the majority of patients with disease localized to the uterus were cured with hysterectomy, but metastatic disease was almost uniformly fatal [1]. With the use of sensitive quantitative assays for hCG and appropriate management with highly effective chemotherapy, most patients with GTN can be cured and their reproductive function preserved [2].

The clinical manifestations, diagnosis, staging, and risk stratification of GTN are reviewed here. Treatment of GTN and molar pregnancy are discussed separately:

●(See "Initial management of low-risk gestational trophoblastic neoplasia" and "Initial management of high-risk gestational trophoblastic neoplasia".)

●(See "Gestational trophoblastic disease: Pathology".)

●(See "Hydatidiform mole: Epidemiology, clinical features, and diagnosis".)

●(See "Hydatidiform mole: Treatment and follow-up".)

TERMINOLOGY

●Gestational trophoblastic disease (GTD) – Lesions characterized by abnormal proliferation of trophoblast of the placenta. This category is comprised of benign, nonneoplastic lesions, including placental site nodule (both typical and atypical), exaggerated placental site, and hydatidiform mole.

●Gestational trophoblastic neoplasia (GTN) – Gestational neoplasms include: choriocarcinoma, placental site trophoblastic tumor (PSTT), epithelioid trophoblastic tumor (ETT), and invasive mole. In the absence of tissue for a definitive histopathologic diagnosis, disease diagnosed as a result of persistent elevation of human chorionic gonadotropin (hCG) after evacuation of a molar pregnancy is termed GTN.

EPIDEMIOLOGY — The incidence of GTN is difficult to establish with certainty because data regarding the incidence of pregnancies and subsequent trophoblastic events are not available in most countries. However, representative estimates are as follows:

●Approximately 50 percent of cases of GTN arise from molar pregnancy, 25 percent from pregnancy loss or tubal pregnancy, and 25 percent from term or preterm pregnancy [3,4].

●When GTN develops after a molar pregnancy, it may have the histology of either molar tissue or choriocarcinoma, and rarely, placental site trophoblastic tumor (PSTT) or epithelioid trophoblastic tumor (ETT). Approximately 15 percent of patients after complete hydatidiform mole will develop local invasion, and 5 percent will develop metastatic disease. GTN, usually nonmetastatic, occurs in 1 to 4 percent of patients after partial hydatidiform mole [2].

●GTN after a nonmolar pregnancy, usually choriocarcinoma but rarely PSTT or ETT, occurs in approximately 2 to 7 per 100,000 pregnancies in Europe and North America, whereas in Southeast Asia and Japan, the incidence is higher at 5 to 200 per 100,000 pregnancies, respectively [5,6].

●The incidence of GTN after pregnancy loss is estimated at 1 in 15,000 pregnancies, while the incidence after a term pregnancy is estimated at 1 per 150,000 pregnancies. The overall incidence of GTN following all types of pregnancies is estimated at 1 in 40,000 pregnancies [3-6].

RISK FACTORS — The main risk factors for the development of gestational trophoblastic disease (GTD) are prior molar pregnancy, advanced maternal age (>40 years), and Asian and American Indian ancestry [7-11]. The risk factors for molar pregnancy are discussed in detail separately. (See "Hydatidiform mole: Epidemiology, clinical features, and diagnosis", section on 'Epidemiology'.)

CLASSIFICATION AND CLINICAL BEHAVIOR — There are several histologic types of GTN. GTN histopathology is discussed in detail separately. (See "Gestational trophoblastic disease: Pathology".)

Invasive mole — Invasive mole develops after a molar pregnancy and is characterized by the presence of edematous chorionic villi with trophoblastic proliferation invading the myometrium. (See "Gestational trophoblastic disease: Pathology", section on 'Invasive mole'.)

Postmolar GTN develops in approximately 15 to 20 percent of patients following complete hydatidiform mole and in 1 to 4 percent of patients following partial hydatidiform mole [4,12]. In complete mole, postmolar GTN occurs more frequently (40 to 50 percent) in patients with one or more high-risk features, including [13,14]:

●Pre-evacuation uterine size larger than dates

●Human chorionic gonadotropin (hCG) levels >100,000 milli-international units/mL

●Bilateral ovarian enlargement caused by excess hCG stimulation (theca lutein cysts)

●Previous cesarean birth [15]

Approximately 15 percent of patients with complete hydatidiform mole will develop local uterine invasion, and 5 percent will develop metastatic disease [2,14]. Deep myometrial invasion may occur, and molar villi may be observed on the uterine serosa. Uterine rupture and severe intraperitoneal hemorrhage may occur if deep myometrial invasion is left untreated.

Metastases of invasive moles spread hematogenously; the lungs and vagina are the most common sites [16].

Choriocarcinoma — Choriocarcinoma consists of invasive, highly vascular, and anaplastic trophoblastic tissue made up of cytotrophoblasts and syncytiotrophoblasts without villi. (See "Gestational trophoblastic disease: Pathology", section on 'Choriocarcinoma'.)

Choriocarcinoma can follow any type of pregnancy:

●Following a molar pregnancy, choriocarcinoma is more common after a complete mole rather than a partial mole.

●Following a nonmolar pregnancy, choriocarcinoma is the most common type of GTN; placental site trophoblastic tumor (PSTT) or epithelioid trophoblastic tumor (ETT) makes up only 1 to 2 percent of GTN following nonmolar pregnancy [2,4,17,18]. Diagnosis is often delayed following a nonmolar pregnancy and thus, metastases are more common than after a molar pregnancy [19].

Choriocarcinoma is the most aggressive histologic type of GTN and is characterized by early vascular invasion and widespread metastases. The clinical presentation of choriocarcinoma depends upon extent of disease and location of metastases. Choriocarcinoma metastasizes hematogenously. The clinical presentation is often due to bleeding from a metastatic site [20].

Placental site trophoblastic tumor — PSTTs are malignant and develop from extravillous, intermediate trophoblasts. They are usually diploid and monomorphic. Microscopically, these tumors show no chorionic villi and are characterized by a proliferation of mononuclear intermediate trophoblast cells with oval nuclei and abundant eosinophilic cytoplasm. (See "Gestational trophoblastic disease: Pathology", section on 'Placental site trophoblastic tumors'.)

PSTT occurs most commonly after a nonmolar abortion or pregnancy, although it can also occur after a molar gestation. A PSTT may be diagnosed several months or even years after the pregnancy [21]. This time interval from antecedent pregnancy is highly prognostic for PSTT [22].

A key difference between PSTT and invasive mole or choriocarcinoma is that it secretes very low levels of hCG [23].

PSTT is associated with less vascular invasion, necrosis, and hemorrhage than choriocarcinoma. In addition, unlike choriocarcinoma, PSTT tends to remain localized in the uterus for long periods before metastasizing to regional lymph nodes or other metastatic sites [24-26]. Approximately 30 percent of patients present with metastatic disease [27].

Epithelioid trophoblastic tumor — ETT is a rare variant of GTN. It develops from neoplastic transformation of chorionic-type extravillous trophoblasts [28]. ETT typically presents as a discrete, hemorrhagic, solid, and cystic lesion that is located either in the fundus, lower uterine segment, or endocervix. Like PSTT, it forms tumor nodules in the myometrium. Microscopically, the tumor is composed of a relatively uniform population of mononucleate intermediate trophoblastic cells forming nests and solid masses. (See "Gestational trophoblastic disease: Pathology", section on 'Epithelioid trophoblastic tumor'.)

The clinical behavior of ETT is similar to PSTT. Diagnosis is typically late in the course of disease due to slow growth, paucity of symptoms, and low or absent hCG production [28-32]. Due to late diagnosis, approximately 50 percent of patients with ETT present with metastatic disease [33]. ETT cells show diffuse expression of immunohistochemical markers, including cytokeratin and inhibin A. Approximately 15 percent of those diagnosed with atypical placental site nodule will develop, or have concurrent, ETT within 16 months of diagnosis [34]. Cyclin E staining is higher in ETT than placental site nodules, which can help differentiate between the two [35,36]. Like PSTT, time interval from antecedent pregnancy is highly prognostic [22].

Metastatic sites — The risk of metastases varies depending on the histologic type and the duration of disease. The clinical behavior of each type of GTN is described above. (See 'Classification and clinical behavior' above.)

In general, the sites of GTN metastases and the rate of spread to each site (among patients with metastases) include [12,37,38]:

●Pulmonary (80 percent) (image 1).

●Vagina (30 percent) (picture 1).

●Central nervous system (CNS) metastases (10 percent) are usually in the brain and, rarely, in the meninges (image 2). Virtually all patients with CNS metastases have concurrent pulmonary and/or vaginal involvement [39].

●Hepatic (10 percent) (image 3).

●Other sites (kidney, gastrointestinal tract (picture 2), spleen).

OVERVIEW OF DIAGNOSTIC APPROACH — GTN has a varied presentation depending upon the antecedent pregnancy, extent of disease, and histopathology. GTN may follow a molar pregnancy (complete or partial) or any other pregnancy event (pregnancy loss, induced abortion, preterm or term pregnancy).

GTN most commonly presents following evacuation of a complete hydatidiform mole, with the following characteristics: pre-evacuation uterine size is larger than gestational age and human chorionic gonadotropin (hCG) level >100,000 milli-international units/mL. Bilateral ovarian enlargement is frequently present when the hCG level is markedly elevated. Signs suggestive of GTN after complete molar pregnancy are an enlarged uterus, abnormal uterine bleeding (AUB), and persistent bilateral enlarged ovaries. Rarely, a metastatic nodule will be present in the vagina, which can bleed vigorously, particularly if biopsied [14,16].

In contrast, clinical signs and symptoms of GTN following a partial hydatidiform mole include persistent AUB and a boggy, but not significantly enlarged uterus, without evidence of bilateral enlarged ovaries. Metastatic disease is rare after partial mole [14,16,40].

GTN following a term or preterm gestation may present with amenorrhea, but usually presents with AUB due to invasion of uterine tumor or bleeding from a metastatic site. Bleeding from uterine perforation or metastatic lesions may result in abdominal pain, hemoptysis, or melena. Patients with central nervous system (CNS) metastases often exhibit evidence of increased intracranial pressure from intracerebral hemorrhage, leading to headaches, dizziness, seizures, or hemiplegia. Patients who develop extensive pulmonary metastases may present with dyspnea, cough, or chest pain [19]. Rapid growth, widespread dissemination, and a high propensity for hemorrhage makes this tumor a medical emergency.

Placental site trophoblastic tumors (PSTT) and epithelioid trophoblastic tumors (ETT) almost always cause irregular bleeding or amenorrhea, frequently long after the antecedent pregnancy. There are rare reported cases of nephrotic syndrome and virilizing syndrome associated with these conditions [18,32,41]. Following a nonmolar antecedent pregnancy, choriocarcinoma is the most common histopathologic type of GTN that develops. Choriocarcinoma may present with nonspecific signs and symptoms, making the diagnosis difficult. This frequently accounts for a delay in diagnosis, which often adversely affects prognosis. Patients who develop rising hCG values following a nonmolar pregnancy should be considered to have choriocarcinoma until proven otherwise. However, serum hCG levels are routinely monitored in patients who have a previous molar pregnancy, but not in other patients (except following ectopic pregnancies). Thus, a persistently elevated hCG does not generally come to medical attention unless it is measured to evaluate symptoms (eg, AUB) [2].

Any reproductive-age female with unexplained persistently elevated or rising hCG levels should be considered to potentially have GTN. Other sources of persistent levels of hCG should be excluded, such as normal pregnancy, pituitary hCG, phantom hCG, and ectopic hCG production from other tumors. (See 'Differential diagnosis' below and "Human chorionic gonadotropin: Biochemistry and measurement in pregnancy and disease".)

When the diagnosis of GTN is made, patients must be evaluated for extent of disease. All patients should have a chest radiograph and pelvic examination to identify possible lung and vaginal involvement. In the absence of lung and vaginal metastases, involvement of other metastatic sites is uncommon and additional imaging is not warranted unless other symptoms are present [19,42].

CLINICAL PRESENTATION — GTN has a varied clinical presentation depending upon the antecedent pregnancy, extent of disease, and histologic type.

Elevated human chorionic gonadotropin (hCG) — An elevated hCG is what brings GTN to medical attention after molar pregnancy. This is true for patients with a prior molar pregnancy, in whom weekly hCG measurement is part of posttreatment surveillance. An hCG level that does not return to undetectable suggests the development of GTN. (See 'hCG' below.)

For patients with no history of molar pregnancy, an elevated hCG is most often noted as part of the evaluation for other presenting symptoms.

hCG stimulation effects — Patients with GTN, particularly invasive mole or choriocarcinoma, may have high hCG levels. At levels >100,000 milli-international units/mL, hCG stimulation effects may develop. They may develop endocrine symptoms. These include symptoms or findings of hyperthyroidism, ovarian theca lutein cysts, and rarely, hyperemesis or preeclampsia. (See "Diagnosis of hyperthyroidism", section on 'Symptoms' and "Adnexal mass: Differential diagnosis", section on 'Theca lutein cysts' and "Nausea and vomiting of pregnancy: Clinical findings and evaluation" and "Preeclampsia: Clinical features and diagnosis".)

Abnormal uterine bleeding or amenorrhea — Abnormal uterine bleeding (AUB) may be part of the clinical presentation after a molar or nonmolar pregnancy. For GTN after a nonmolar pregnancy, AUB or amenorrhea is often the presenting symptom.

In some cases, uterine bleeding from GTN can be severe and may require hysterectomy for resection of disease. If surgery is planned in this situation, selective angiography may be utilized to limit blood loss and allow the extent of disease to be evaluated. Alternatively, selective angiography and embolization may be employed as an alternative to tumor resection to control bleeding [43,44]. (See "Managing an episode of acute uterine bleeding", section on 'Therapeutic measures'.)

Pelvic pain or pressure — If an enlarged uterus or ovarian cysts are present, the patient may report pelvic pain or pressure. (See 'Physical examination' below.)

Symptoms of metastases

Pulmonary — Dyspnea, chest pain, cough, or hemoptysis may occur due to lung metastases. The extent of and severity of symptoms due to pulmonary metastases may vary substantially, depending upon when in the course of the disease the metastases are detected. In our practice, the New England Trophoblastic Disease Center (NETDC), we generally detect pulmonary metastases radiographically, before respiratory symptoms develop. In contrast, for patients who do not present to a trophoblastic disease center, detection may be delayed. As an example, in one study of 79 patients with GTN and with pulmonary metastases, 33 percent displayed >50 percent opacification of their lung at presentation, 48 percent had evidence of a prominent pleural effusion, and 11 percent developed respiratory failure [45].

Trophoblastic emboli may cause pulmonary arterial occlusion leading to right heart strain and pulmonary hypertension, which may lead to a false diagnosis of primary pulmonary disease [46]. This is especially true if the antecedent pregnancy is remote and the gynecologic symptoms are minimal to absent.

Vaginal — Vaginal metastases are identified in 4.5 to 11 percent of patients with GTN and typically present with vaginal bleeding or purulent vaginal discharge [47,48]. Hemorrhage can be severe and may require packing or angiographic embolization. The presence of vaginal metastases does not increase the risk of resistance to chemotherapy [49].

Central nervous system — Central nervous system (CNS) involvement may be asymptomatic initially, but as the disease progresses, patients develop neurologic signs and symptoms due to increased intracranial pressure or hemorrhage, including: headache, neuropathy, dizziness, nausea, slurred speech, visual disturbances, and/or hemiparesis [50,51]. Neurologic symptoms are reported to occur in 87 to 100 percent of patients with brain metastases [52-54].

Hepatic — Jaundice, epigastric, or back pain may occur in patients with liver metastases, but fewer than one-third of patients with liver metastases are symptomatic [55].

Patients with liver metastases may be at risk for intra-abdominal hemorrhage if the tumors rupture, which represents a medical emergency [55]. Hepatic lesions should not be biopsied because of risk of hemorrhage.

Other — GTN is rarely associated with nephrotic syndrome or virilization [18,41]. Virilization may be due to long-standing stimulation of ovary by hCG, causing theca cell hyperplasia with subsequent elevated testosterone levels [41].

DIAGNOSTIC EVALUATION — The key elements of the diagnostic evaluation are to confirm an elevated human chorionic gonadotropin (hCG) and evaluate for metastatic disease or hCG stimulation effects. The most common metastatic site is the vagina or lungs. Uterine curettage or other biopsies have a limited role in the diagnosis of GTN, because of risk of hemorrhage and because GTN is a clinical diagnosis. (See 'Metastatic sites' above and 'Diagnosis' below.)

History — Symptoms associated with GTN should be elicited. (See 'Clinical presentation' above.)

An obstetric history is taken. The obstetric history should include the dates, duration, and outcome of all pregnancies. A history of a molar pregnancy is, of course, the most important risk factor for GTN, particularly invasive mole. As noted, however, GTN may occur after any pregnancy, including spontaneous or induced abortion, preterm delivery, or term delivery.

A medical, gynecologic, and surgical history should also be taken.

Physical examination — A complete pelvic examination should be performed as well as a focused general physical examination to evaluate for metastases.

On speculum examination, the vagina should be examined for metastases. These are generally identifiable as a vascular implant (picture 1), most commonly located in the suburethral area or fornices. Pigmented lesions on the cervical portio may also be seen. These lesions should not be biopsied because they are extremely vascular and hemorrhage may occur.

On bimanual examination, the uterus may be enlarged due to the presence of tumor as well as hCG stimulation. Uterine enlargement occurs in many conditions (eg, normal pregnancy, uterine leiomyomas, other uterine malignancies), and imaging is required for further evaluation. The uterus is usually mobile rather than fixed.

Bilateral adnexal masses may be present if ovarian theca lutein cysts have developed due to hCG stimulation. A unilateral adnexal mass suggests another type of adnexal mass.

A general physical examination with a focus on likely site of metastases should be performed (ie, lungs, liver, central nervous system [CNS]).

Rarely, GTN is associated with virilization, which may include male pattern hair growth on the body or head, deepening of the voice, or clitoromegaly [18,41].

Laboratory evaluation

hCG — An elevated human chorionic gonadotropin (hCG) is often the first evidence of possible GTN. A serum quantitative hCG should be drawn in all patients with suspected GTN, including patients with a prior molar pregnancy, nonmolar pregnancy, no known history of pregnancy, and any female of reproductive age with evidence of metastatic disease without an obvious primary site of malignancy.

●For patients with a prior molar pregnancy, serial measurement of hCG is part of posttreatment surveillance, and an elevation, plateau, or persistence of hCG suggests the development of GTN. (See 'Following a molar pregnancy' below.)

●For patients with no prior history of a molar pregnancy, an elevated hCG may be initially presumed to be a normal pregnancy. GTN may be suspected if pelvic ultrasound does not confirm a nonmolar pregnancy (viable intrauterine pregnancy, spontaneous abortion, or ectopic pregnancy), or in some cases, if the patient is certain that she has not conceived recently.

Patients with an elevated hCG should be evaluated with ultrasound. For hCG levels below the discriminatory zone (level above which a gestational sac should be visualized by transvaginal ultrasound if an intrauterine pregnancy is present; 1500 or 2000 milli-international units/mL in most institutions), a gestation will not be visualized, and the patient should be evaluated again based upon the clinical setting. Serial hCG levels should be determined at 48 to 72 hour intervals until it is determined that the pregnancy is either normal or abnormal. If the hCG levels or ultrasound suggest that the pregnancy is abnormal, further evaluation should be carried out to exclude GTN. Other laboratory tests or imaging studies should be performed to assess for metastatic disease. (See 'Liver function tests' below and 'Other imaging studies' below.)

The diagnosis of a normal pregnancy and evaluation of patients for early pregnancy complications is discussed in detail separately. (See "Clinical manifestations and diagnosis of early pregnancy" and "Evaluation and differential diagnosis of vaginal bleeding before 20 weeks of gestation" and "Pregnancy loss (miscarriage): Terminology, risk factors, and etiology" and "Ectopic pregnancy: Clinical manifestations and diagnosis".)

The level of serum hCG varies across histologic types of GTN:

●Invasive mole and choriocarcinoma develop from the cytotrophoblast and syncytiotrophoblast cells of the villous trophoblast (figure 1). These neoplasms produce abundant amounts of hCG, which can typically range from 100 to over 100,000 milli-international units/mL depending on the extent of disease. hCG levels are particularly high in patients with a nonmolar antecedent pregnancy due to delays in diagnosis, whereas they tend to be lower following molar evacuation when GTN is usually diagnosed early due to postmolar hCG monitoring. For these histologies, hCG serves as a tumor marker for diagnosis (even in the absence of histologic confirmation), as well as for monitoring treatment response, and posttreatment surveillance [19].

●Placental site trophoblastic tumors (PSTT) and epithelioid trophoblastic tumors (ETT) originate from the intermediate cells of extravillous trophoblast, rather than the syncytiotrophoblast, and produce low levels of hCG, making the use of hCG as a tumor marker less reliable [56-58]. hCG levels in these patients are usually <1000 milli-international units/mL but are infrequently undetectable. As an example, in one report of patients with PSTT, serum levels of hCG were raised in all patients, but in 41 of 62 (69 percent), the level was only moderately increased (<1000 milli-international units/mL) [56].

In patients with PSTT, measurement of the free beta-subunit of hCG may be useful to establish the diagnosis. Assays for the free beta-subunit of hCG measure the beta chain of hCG without the alpha chain and carbohydrate moiety. PSTT may be characterized by an elevated free beta-subunit to total hCG ratio or percent. As an example, in a retrospective study of 13 cases of PSTT and 12 nontrophoblastic malignancies, an hCG free beta-subunit percent >35 percent had a 100 percent sensitivity and specificity for PSTT [59]. Further study is needed to evaluate the performance of an hCG free beta-subunit percent as a diagnostic test for PSTT.

●On rare occasions following molar evacuation, the hCG level will fail to normalize and remain elevated at low levels (<200 milli-international units/mL). One cause of persistent (present for at least three months) low-level hCG is quiescent GTN that most commonly follows a complete mole. Quiescent GTN is thought to be due to the presence of highly differentiated, noninvasive syncytiotrophoblast cells [60].

The physiology of hCG and the evaluation of patients with persistent low hCG levels is discussed in detail separately.

Thyroid function tests — Thyroid function tests should be ordered if the hCG level is >100,000 milli-international units/mL to determine if the patient may be hyperthyroid. This is particularly important in patients with unevacuated molar pregnancy who are about to undergo anesthesia because of the risk of thyroid storm.

Liver function tests — Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) should be drawn to assess for metastases.

Renal function tests — Renal function tests should also be determined prior to initiation of chemotherapy. Also, in rare cases, PSTT or ETT is associated with nephrotic syndrome [18,32]. (See "Overview of heavy proteinuria and the nephrotic syndrome".)

Other tests — Virilization, while infrequent, can occur in patients with GTN. If present, serum testosterone levels (free and total) should be measured [18,41]. (See "Overview of androgen deficiency and therapy in females".)

Imaging studies — A pelvic ultrasound is performed in all patients with suspected GTN. A chest radiograph is also ordered because the lungs are the most common site of metastases. Other imaging studies are performed if the chest radiograph or vaginal examination shows evidence of metastatic disease, or if other metastatic sites are suspected based upon symptoms or laboratory findings.

Pelvic ultrasound — Pelvic ultrasound is the imaging modality used to evaluate the uterus and adnexa if GTN is suspected [61]. Sonographic findings in patients with GTN include:

●Invasive mole – Invasive mole typically appears as one or more poorly defined masses in the uterus with anechoic areas. Color Doppler of the anechoic areas reveals high vascular flow. Invasion into the myometrium may be visualized.

●Choriocarcinoma – Choriocarcinoma appears as a mass enlarging the uterus, with a heterogeneous appearance that correlates with areas of necrosis and hemorrhage (image 4). The tumor is usually markedly hypervascular on color Doppler (image 5). The tumor may extend into the parametrium.

●Placental site trophoblastic tumor – PSTT also appears as a hyperechoic-intrauterine mass, usually with less hemorrhage than observed with choriocarcinoma. Both cystic and solid lesions can be present, with or without a central component. The mass usually invades the myometrial wall.

●Epithelioid trophoblastic tumor – Early in the course of the disease, transvaginal ultrasound reveals irregular anechoic lacunae within the myometrium, some of them filled with low-resistance, turbulent blood flow on Doppler examination, suggestive of the diagnosis of gestational trophoblastic disease (GTD). Late in the course of the disease, transvaginal ultrasound reveals a well-circumscribed echogenic lesion in the uterine fundus, frequently with no detectable blood flow on Doppler imaging. Most reported cases of ETT show solitary nodules with sharp margins on ultrasound. Ultrasound may be helpful in differentiating ETT from PSTT, which shows infiltrative growth insinuating between muscle fibers [62].

Chest imaging — All patients should have a baseline chest radiograph to evaluate for lung metastases (image 1) rather than chest computed tomography (CT), since a chest radiograph, not CT, is the basis for International Federation of Gynecology and Obstetrics (FIGO) staging. In addition, although micrometastases are detected in 40 percent of chest CT scans performed on patients with a negative chest radiograph, they do not appear to affect outcome and are not considered to be a risk factor for resistance to chemotherapy [63,64]. Chest CT or positron emission tomography (PET)-CT may be useful in patients with chemotherapy resistance to help identify sites of resistant tumor [42,63,64]. (See 'Staging and risk assessment' below.)

On chest imaging, four principal pulmonary radiographic patterns are seen in patients with GTN: 1) discrete rounded densities; 2) an alveolar or "snowstorm" pattern; 3) pleural effusion; or 4) embolic pattern caused by pulmonary arterial occlusion [65-68].

Other imaging studies — For patients with no vaginal metastases on examination, a normal chest radiograph, and normal liver function tests, additional imaging is not necessary since distant metastases are unlikely.

If there is evidence of metastatic disease on initial evaluation, the evaluation should be expanded to include one or more of the following studies:

●CT of the abdomen and pelvis (image 3). Alternatively, whole-body 18-fluorodeoxyglucose positron emission tomography (18-FDG-PET) scan can be used (image 6) [42].

●Magnetic resonance imaging (MRI) or CT scan of the brain (with and without contrast) (image 2) [52-54]. If brain imaging is equivocal or negative and the patient’s symptoms are highly suspicious of brain involvement, a lumbar puncture may be indicated in order to measure the plasma-to-cerebrospinal fluid hCG ratio (normal value is <60:1) to rule out occult cerebral or meningeal disease [69,70].

Imaging of the pelvis, abdomen, and head should also be performed in patients with symptoms suggestive of metastases at these sites (eg, neurologic symptoms) or in patients with histologic evidence of choriocarcinoma, since the likelihood of metastases is high in this type of GTN. (See 'Metastatic sites' above.)

Uterine curettage — Uterine curettage has a limited role in the evaluation of GTN. Its use has generally been reserved for patients who present with postpartum or postabortal bleeding and an elevated hCG level to determine whether the diagnosis is GTN or retained products of conception. Other indications include a clinical presentation that includes uterine enlargement or uterine disease on pelvic imaging.

Histopathologic criteria for the diagnosis of GTN are discussed in detail separately. (See "Gestational trophoblastic disease: Pathology", section on 'Gestational trophoblastic neoplasia'.)

The role of uterine curettage in the management of GTN is also limited. This is discussed separately. (See "Initial management of low-risk gestational trophoblastic neoplasia", section on 'Limited role for second curettage'.)

DIAGNOSIS — GTN is a clinical diagnosis made based upon elevation of serum human chorionic gonadotropin (hCG), after a nonmolar pregnancy and after other etiologies of an elevated hCG have been excluded. Imaging findings of uterine enlargement or pathology consistent with GTN, bilateral ovarian theca lutein cysts, or metastatic disease support the diagnosis. Unlike other solid tumors, a tissue diagnosis is not required prior to treatment.

The interpretation of hCG levels is based upon whether the patient has had a prior molar pregnancy.

Following a molar pregnancy — Following evacuation of a complete or partial molar pregnancy, serial serum hCG levels are measured, typically on a weekly schedule, until an undetectable level is reached. If hCG levels rise or remain elevated over several weeks, the diagnosis of postmolar GTN is based upon the following International Federation of Gynecology and Obstetrics (FIGO) criteria [71-73]:

●Weekly hCG levels plateau (remain within ±10 percent of the previous result) over a three-week period

●hCG level increases >10 percent across three values recorded over a two-week duration

The persistence of detectable serum hCG for more than six months after molar evacuation is no longer a criterion for diagnosing GTN.

Studies have indicated that it may not be necessary to administer chemotherapy in patients with persistent but falling hCG levels six months after molar evacuation [74,75]. The occurrence of persistent but falling hCG levels six months after molar evacuation was reported in 76 (0.5 percent) of 13,960 patients and in 96 (0.8 percent) of 12,526 patients. Spontaneous hCG remission was observed in 66 (87 percent) and 65 (80.2 percent) patients followed with expectant management. Among patients who developed late GTN, there was no worsening of their extent of disease [75].

The above criteria are internationally accepted to make the diagnosis of GTN for patients who had a prior molar pregnancy. However, FIGO also accepts the diagnosis of GTN based on a histologic diagnosis of choriocarcinoma or invasive mole (eg, made by examination of uterine curettings) and/or the identification of clinical or radiological evidence of metastases (table 1).

Following a nonmolar pregnancy — Serum hCG monitoring is not routinely performed, with the exception of ectopic pregnancy, after nonmolar pregnancies. For this reason, patients who develop GTN after a nonmolar pregnancy typically undergo evaluation with serum hCG and ultrasound only after they become symptomatic. This may be weeks or months after the antecedent pregnancy or months or years in the case of placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT).

●The diagnosis is made based upon an elevated hCG, with the exclusion of any other explanation than GTN. This is sufficient for diagnosis even if there is no uterine enlargement and no evidence of metastatic disease. It is critical to exclude a normal viable pregnancy and abnormal pregnancies (eg, spontaneous abortion, ectopic pregnancy), ectopic hCG production by a nontrophoblastic tumor, or other causes of persistent low-level hCG [76]. (See 'Differential diagnosis' below.)

●If there are findings on examination or imaging that suggest metastatic disease, this supports the diagnosis. Biopsies should not be performed because GTN lesions are highly vascular and may cause vigorous bleeding. Thus, hemorrhage is common, particularly from the uterus due to repeated trauma by dilation and curettage. Life-threatening hemorrhage may necessitate embolization or resection of the affected organ [44]. Unlike other tumors, histologic confirmation is not necessary for diagnosis, although on rare occasions, a biopsy may be needed if there is significant question about the diagnosis of GTN.

●Another exception to obtaining a histologic diagnosis is in patients who present with postpartum or postabortal bleeding, uterine enlargement, or evidence of uterine disease on imaging. In these patients, a uterine curettage may be performed and the diagnosis can be confirmed based upon the pathology evaluation of the curettage specimen. (See 'Uterine curettage' above.)

Following a nonmolar pregnancy, the most common histologic type of GTN is choriocarcinoma, and this should be presumed to be the diagnosis, unless proven otherwise. (See 'Choriocarcinoma' above.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis for GTN depends upon the history and clinical presentation. The key issue is to determine whether the antecedent pregnancy was a molar pregnancy or nonmolar pregnancy, and when that pregnancy terminated. Following a molar pregnancy, the diagnosis of GTN is usually clearly established by doing weekly human chorionic gonadotropin (hCG) monitoring. Following a nonmolar pregnancy, however, the differential diagnosis of GTN is more challenging. Pregnancy or other sources of hCG must be excluded. (See "Hydatidiform mole: Epidemiology, clinical features, and diagnosis".)

The obstetric differential diagnosis of elevated hCG includes normal pregnancy, spontaneous abortion, and ectopic pregnancy. During a nonmolar gestation, an atypically high level of hCG may be due to multiple gestation. The diagnosis of a normal pregnancy and evaluation of patients for early pregnancy complications is discussed in detail separately. (See "Clinical manifestations and diagnosis of early pregnancy" and "Evaluation and differential diagnosis of vaginal bleeding before 20 weeks of gestation" and "Pregnancy loss (miscarriage): Terminology, risk factors, and etiology" and "Ectopic pregnancy: Clinical manifestations and diagnosis".)

An elevated hCG level in the absence of a pregnancy may occur due to other neoplasms. These conditions may also have metastatic disease, similar to GTN:

●An hCG-producing germ cell tumor of the ovary. (See "Ovarian germ cell tumors: Pathology, epidemiology, clinical manifestations, and diagnosis".)

●Ectopically-produced hCG from nontrophoblastic tumors has been described in connection with a wide variety of neoplasms, including stomach, liver, pancreas, breast, as well as myeloma and melanoma [77]. (See "Serum tumor markers in testicular germ cell tumors" and "Intracranial germ cell tumors" and "Extragonadal germ cell tumors involving the mediastinum and retroperitoneum" and "Pineal gland masses", section on 'Germ cell tumors'.)

Other etiologies of an elevated hCG in the absence of pregnancy include pituitary hCG or a false-positive test (phantom hCG). (See "Human chorionic gonadotropin: Biochemistry and measurement in pregnancy and disease", section on 'Nonpathologic causes of low-level hCG elevations' and "Human chorionic gonadotropin: Biochemistry and measurement in pregnancy and disease", section on 'Analytical causes of erroneous results; antibody-related interference'.)

Regarding other clinical signs and symptoms of GTN:

●An enlarged uterus may be due to benign or malignant pathology, including leiomyomas, adenomyosis, or uterine malignancy. (See "Uterine fibroids (leiomyomas): Epidemiology, clinical features, diagnosis, and natural history" and "Uterine adenomyosis" and "Endometrial carcinoma: Clinical features, diagnosis, prognosis, and screening" and "Uterine sarcoma: Classification, epidemiology, clinical manifestations, and diagnosis".)

●Ovarian theca lutein cysts may also occur in ovarian hyperstimulation syndrome during ovulation induction for assisted reproduction. (See "Pathogenesis, clinical manifestations, and diagnosis of ovarian hyperstimulation syndrome".)

●Hyperthyroidism symptoms should be evaluated and the etiology determined. (See "Diagnosis of hyperthyroidism".)

PRETREATMENT EVALUATION — Patients diagnosed with GTN should undergo evaluation prior to treatment to assess stage and ability to tolerate chemotherapy; for many patients, these tests will have been performed during the diagnostic evaluation (see 'Diagnostic evaluation' above):

●Complete history and physical examination.

●Baseline laboratory testing, including a pretreatment baseline quantitative serum human chorionic gonadotropin (hCG), complete blood count, and hepatic, renal, and thyroid function tests.

●Pelvic ultrasound – This is important to ensure that the patient is not pregnant, to obtain measurements of the uterine size and volume, to evaluate the degree of pelvic spread, and to see if there is evidence of retained tumor or invasion. The use of transvaginal ultrasound and color flow Doppler is particularly useful when the uterus is enlarged to identify patients at risk of perforation or who might be candidates for hysterectomy to reduce tumor burden (image 4 and image 5) [78-84].

●Chest radiograph – A plain film of the chest rather than chest computed tomography (CT) is the basis for International Federation of Gynecology and Obstetrics (FIGO) staging and the World Health Organization (WHO) Prognostic Score (image 1).

●Review of available pathology specimens – Although histologic confirmation is not required for treatment of GTN, if a uterine curettage or other biopsy specimen is available, it should be reviewed prior to treatment. This may be useful in determining the approach to treatment. Pathology can differentiate between invasive mole, choriocarcinoma, placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT). The management of PSTT and ETT differs significantly from the management of invasive mole or choriocarcinoma [29]. (See "Initial management of low-risk gestational trophoblastic neoplasia" and "Initial management of high-risk gestational trophoblastic neoplasia".)

STAGING AND RISK ASSESSMENT — For patients with GTN, both a stage and a risk score are assigned prior to treatment. Although the American Joint Committee on Cancer has developed a staging system for GTN [85], GTN is typically staged using a combination of the International Federation of Gynecology and Obstetrics (FIGO) staging system and the World Health Organization (WHO) Prognostic Scoring System. This system takes into account eight risk factors that have been shown to predict the potential for the development of resistance to single-agent chemotherapy with methotrexate (MTX) or actinomycin D (ActD); this is the system used by the authors (table 1). It is described below:

●Stage I – Persistently elevated human chorionic gonadotropin (hCG) levels; tumor confined to the uterine corpus

●Stage II – Tumors extending to the adnexa or to the vagina, but limited to the genital structures

●Stage III – Pulmonary metastases on chest radiograph, with or without uterine, pelvic, or vaginal involvement

●Stage IV – Metastatic disease outside of the lungs and pelvis and/or vagina

In the WHO Prognostic Scoring System, the FIGO stage is followed by the modified WHO Score designated by an Arabic number separated by a colon (eg, II:6) [71-73,86-88]. The risk score is based on the following variables (table 1):

●Age.

●Antecedent pregnancy.

●Interval from last pregnancy.

●Pretreatment serum hCG level – It is critical to use the hCG level at the time of treatment for GTN and not the hCG level at the time of diagnosis or evacuation of a molar pregnancy.

●Largest tumor (including uterine).

●Site of metastases.

●Number of metastases.

●Prior chemotherapy treatment.

The use of the WHO Prognostic Scoring System is more predictive of clinical outcome than the use of individual risk factors [89-93]:

●A score of 0 to 6 suggests low risk of resistance to single-agent chemotherapy.

●A score of ≥7 predicts a high risk of resistance to monotherapy and requires combination chemotherapy.

●A score ≥12 is considered as ultra high risk and particularly associated with nonmolar antecedent pregnancy, brain metastases, and failed prior multiagent chemotherapy. Kong et al reported that the five-year overall survival in this group was 68 percent [94].

The prognostic significance of this system was shown in a study that included 21 patients with a WHO score ≤7 [95]. All patients attained a complete remission to chemotherapy, with 67 percent (n = 14) doing so with monotherapy. Patients with a prognostic score of 5 and 6 are at higher risk of resistance to single-agent chemotherapy; however, approximately 60 percent of these patients will achieve remission with first- or second-line single-agent chemotherapy. Primary multiagent chemotherapy should be given to all patients with a score of 5 and 6 with metastatic disease and choriocarcinoma; for the remainder of patients, pretreatment hCG is predictive of resistance to single-agent therapies [96].

The benefit of using the modified WHO Prognostic Scoring system applies primarily to FIGO stages II and III, since essentially all patients with FIGO stage I GTN are low risk, and >90 percent achieve remission with single-agent chemotherapy. Furthermore, patients with FIGO stage IV disease have high risk scores, which indicate probable resistance to single-agent chemotherapy and the need for primary treatment with multiagent chemotherapy to optimize outcomes. Unfortunately, the modified WHO Prognostic Scoring System is not particularly useful for patients with placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT), and therefore, treatment is based on the FIGO stage and time from antecedent pregnancy. Patients with stage III or IV disease and/or ≥48 months from previous pregnancy are considered high risk and thus are treated with chemotherapy [29,31].

INDICATIONS FOR REFERRAL — GTN is a rare disease, and patients should be managed by a gynecologic oncologist and/or medical oncologist experienced with GTN. Ideally, patients should be referred to a trophoblastic disease center whenever possible. These centers provide sufficient clinical experience to allow opportunities for research and improved outcomes. Initial treatment outside of a specialty center is strongly associated with the risk of death from GTN [97].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gestational trophoblastic disease".)

SUMMARY AND RECOMMENDATIONS

●Terminology – Gestational trophoblastic neoplasia (GTN) refers to a group of malignant neoplasms that consist of abnormal proliferation of trophoblastic tissue, and may follow a hydatidiform mole or a nonmolar pregnancy. GTN is comprised of the following histologic types: invasive mole, choriocarcinoma, placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT). (See 'Introduction' above and 'Terminology' above.)

●Epidemiology – Approximately 50 percent of cases of GTN arise from molar pregnancy, 25 percent from pregnancy loss or tubal pregnancy, and 25 percent from term or preterm pregnancy. The estimated incidence of GTN after a term pregnancy is 1 per 150,000 pregnancies and after a pregnancy loss is 1 in 15,000 pregnancies. (See 'Epidemiology' above.)

●Risk factors – The main risk factors for the development of GTD are prior molar pregnancy, advanced maternal age (>40 years), and Asian and American Indian ancestry. The risk factors for molar pregnancy are discussed in detail separately. (See 'Risk factors' above and "Hydatidiform mole: Epidemiology, clinical features, and diagnosis", section on 'Epidemiology'.)

●Clinical presentation – Presenting symptoms and signs of GTN depend upon whether the antecedent pregnancy was molar or nonmolar. The clinical presentation may include: elevated serum human chorionic gonadotropin (hCG), hyperthyroidism, ovarian theca lutein cysts, abnormal uterine bleeding, pelvic pain or pressure, or symptoms of metastatic disease. (See 'Clinical presentation' above.)

●Diagnostic evaluation – The key elements of the diagnostic evaluation are to confirm an elevated hCG and evaluate for metastatic disease or hCG stimulation effects. The vagina and lungs are the most common metastatic sites. (See 'Diagnostic evaluation' above and 'Metastatic sites' above.)

•An elevated hCG is often the first evidence of possible GTN. A serum quantitative hCG should be drawn in all patients with suspected GTN or any female of reproductive age who presents with metastatic disease. (See 'hCG' above.)

•All patients should have a chest imaging to evaluate for lung metastases. We suggest a chest radiograph (image 1) rather than chest computed tomography (CT). A chest radiograph, not CT, is the basis for International Federation of Gynecology and Obstetrics (FIGO) staging, and additional findings on CT do not typically contribute to treatment planning. (See 'Chest imaging' above.)

•Uterine curettage has a limited role in the diagnosis of GTN. Biopsy is avoided given the significant hemorrhage that can occur with these lesions. (See 'Uterine curettage' above and 'Following a nonmolar pregnancy' above.)

●Diagnosis – GTN is a clinical diagnosis made based upon elevation of serum hCG, after a nonmolar pregnancy and other etiologies of an elevated hCG have been excluded. Imaging findings of uterine enlargement or pathology consistent with GTN, bilateral ovarian theca lutein cysts, or metastatic disease support the diagnosis. Unlike other solid tumors, a tissue diagnosis is not required prior to treatment. (See 'Diagnosis' above.)

●Staging – The GTN staging and risk stratification system is a combination of the FIGO staging system and the World Health Organization (WHO) Prognostic Scoring System (table 1). (See 'Staging and risk assessment' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Donald Peter Goldstein, MD, who contributed to an earlier version of this topic review.