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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:
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' and "Hydatidiform mole: Management", section on
'Gestational trophoblastic neoplasia'.)
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 5 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]:
Approximately 15 percent of invasive moles remain localized to the uterus, and 5 percent are metastatic [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.
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.
●
Approximately 50 percent of cases of GTN arise from molar pregnancy, 25 percent from miscarriages 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 5 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 spontaneous miscarriage 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].
●
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)●
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Metastases of invasive moles spread hematogenously; the lungs and vagina are the most common sites [15].
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:
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 [19].
Placental site trophoblastic tumor — PSTTs are malignant and develop from extravillous, intermediate
trophoblast. 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 [20]. This time interval
from antecedent pregnancy is highly prognostic for PSTT.
A key difference between PSTT and invasive mole or choriocarcinoma is that it secretes very low levels of hCG
[21].
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 [22-24]. Approximately 30 percent of patients present with
metastatic disease [25].
Epithelioid trophoblastic tumor — ETT is a rare variant of PSTT. It develops from neoplastic transformation
of chorionic-type extra-villous trophoblast [26]. 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 [26-29]. Due to late diagnosis, approximately 50
percent of patients with ETT present with metastatic disease [30]. ETT cells show diffuse expression of
immunohistochemical markers, including cytokeratin and inhibin a. Cyclin E staining is higher in ETT than
placental site nodules, which can help differentiate between the two [31,32].
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 [2,4,16,17]. Diagnosis is often delayed following a nonmolar pregnancy and
thus, metastases are more common than after a molar pregnancy [18].
●
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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 [12,33,34]:
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 (miscarriage, 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 [14,15].
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 [14,15,36].
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 [18]. 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 [17,27,37]. Following a nonmolar
antecedent pregnancy, choriocarcinoma is the most common histopathologic type of GTN that develops.
Choriocarcinoma may present with non-specific 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 women who have a previous molar pregnancy,
but not in other women (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].
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
[35].
●
Hepatic (10 percent) (image 3).●
Other sites (kidney, gastrointestinal tract (picture 2), spleen).●
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Any reproductive-age woman 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: Testing in pregnancy and gestational trophoblastic disease
and causes of low persistent levels".)
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 [38].
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 "Hydatidiform mole: Management", section on 'Serial hCG' and 'hCG' below.)
For women 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
"Approach to the patient with an adnexal mass", section on 'Medical history' and "Clinical features and evaluation
of nausea and vomiting of pregnancy" 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 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 [39,40]. (See "Managing an episode of severe or prolonged 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 women 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 [41].
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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 [42]. This is especially true if the
antecedent pregnancy is remote and the gynecologic symptoms are minimal to absent.
Vaginal — Vaginal metastases typically present with vaginal bleeding or purulent vaginal discharge.
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 [43,44]. Neurologic symptoms are reported to occur in 87 to 100 percent of patients with brain
metastases [45-47].
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 [48].
Patients with liver metastases may be at risk for intra-abdominal hemorrhage if the tumors rupture, which
represents a medical emergency [48]. Hepatic lesions should not be biopsied because of risk of hemorrhage.
Other — GTN is rarely associated with nephrotic syndrome or virilization [17,27]. Virilization may be due to long-
standing stimulation of ovary by hCG, causing theca cell hyperplasia with subsequent elevated testosterone
levels [37].
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. 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]).
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Rarely, GTN is associated with virilization, which may include male pattern hair growth on the body or head,
deepening of the voice, or clitoromegaly [17,27,37].
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 women with a prior molar
pregnancy, nonmolar pregnancy, no known history of pregnancy, and any woman of reproductive age with
evidence of metastatic disease without an obvious primary site of malignancy.
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 "Overview of the
etiology and evaluation of vaginal bleeding in pregnant women" and "Spontaneous abortion: Risk factors,
etiology, clinical manifestations, and diagnostic evaluation" and "Ectopic pregnancy: Clinical manifestations and
diagnosis".)
The level of serum hCG varies across histologic types of GTN:
For women 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 women 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.)
Invasive mole and choriocarcinoma develop from the cyto and syncytial 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 [18].
●
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 [49-51]. hCG levels in these patients are
usually <1000 milli-international units/mL and 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) [49].
●
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The physiology of hCG and the evaluation of women with persistent low hCG levels is discussed in detail
separately. (See "Human chorionic gonadotropin: Testing in pregnancy and gestational trophoblastic disease and
causes of low persistent levels", section on 'Gestational trophoblastic disease'.)
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 [17,27]. (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 [17,27,37]. (See "Overview of androgen deficiency and therapy in
women".)
Imaging studies — A pelvic ultrasound is performed in all women 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 [54]. Sonographic findings in women with GTN include:
In women 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 non-trophoblastic
malignancies, an hCG free beta-subunit percent >35 percent had a 100 percent sensitivity and specificity for
PSTT [52]. Further study is needed to evaluate the performance of an hCG free beta-subunit percent as a
diagnostic test for PSTT. At this time, an assay for free beta-subunit is not commercially available.
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, non-invasive syncytiotrophoblast cells [53]. (See "Hydatidiform
mole: Management", section on 'Persistent low hCG (quiescent GTN)'.)
●
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.
●
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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 [56,57].
Chest CT or positron emission tomography (PET)-CT may be useful in patients with chemotherapy resistance to
help identify sites of resistant tumor [38,56,57]. (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 [58-61].
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:
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 'Persistent uterine bleeding'.)
DIAGNOSIS — GTN is a clinical diagnosis made based upon elevation of serum human chorionic gonadotropin
(hCG), after a nonmolar pregnancy and other etiologies of an elevated hCG have been excluded. Imaging
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 [55].
●
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) [38].
●
Magnetic resonance imaging (MRI) or CT scan of the brain (with and without contrast) (image 2) [45-47]. 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 [62,63].
●
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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 [64-66]:
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 [67,68]. 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 [68].
The above criteria are internationally accepted to make the diagnosis of GTN for women 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 after nonmolar
pregnancies. For this reason, women 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).
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●
Persistence of detectable serum hCG for more than six months after molar evacuation●
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 [69]. (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 [40].
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.)
●
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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 "Overview of
the etiology and evaluation of vaginal bleeding in pregnant women" and "Spontaneous abortion: Risk factors,
etiology, clinical manifestations, and diagnostic evaluation" 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:
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: Testing in pregnancy and gestational trophoblastic
disease and causes of low persistent levels", section on 'Causes and evaluation of persistent low levels of hCG'.)
Regarding other clinical signs and symptoms of GTN:
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):
An hCG-producing germ cell tumor of the ovary (See "Ovarian germ cell tumors: Pathology, 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 [70].
(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'.)
●
An enlarged uterus may be due to benign or malignant pathology, including leiomyomas, adenomyosis, or
uterine malignancy. (See "Uterine leiomyomas (fibroids): Epidemiology, clinical features, diagnosis, and
natural history" and "Uterine adenomyosis" and "Endometrial carcinoma: Clinical features and diagnosis"
and "Uterine sarcoma: Classification, 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".)
●
Complete history and physical examination.●
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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 [78],
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) and actinomycin D (ActD); this is the system used by the
authors (table 1). It is described below:
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) [64-66,79-81]. The risk score is based on the following variables
(table 1):
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) [71-77].
●
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 (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 [28]. (See "Initial management of low-risk gestational trophoblastic neoplasia" and "Initial
management of high-risk gestational trophoblastic neoplasia".)
●
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●
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●
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The use of the WHO Prognostic Scoring System is more predictive of clinical outcome than the use of individual
risk factors [82-86]:
The prognostic significance of this system was shown in a small study that included 21 patients with a WHO
score ≤7 [87]. 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, and about 70 percent of these patients will require combination chemotherapy to achieve
remission [88,89].
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 multi-agent
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 alone [28].
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.
SUMMARY AND RECOMMENDATIONS
Number of metastases●
Prior chemotherapy treatment●
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●
Gestational trophoblastic neoplasia (GTN) refers to a group of malignant neoplasms that consist of abnormal
proliferation of trophoblastic tissue, and may follow a hydatiform 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.)
●
Approximately 50 percent of cases of GTN arise from molar pregnancy, 25 percent from miscarriages 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 spontaneous miscarriage is 1 in 15,000
pregnancies. (See 'Epidemiology' above.)
●
The main risk factors for the development of GTN are prior molar pregnancy, advanced maternal age (>40
years), and Asian and American Indian ancestry. (See 'Risk factors' above.)
●
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.)
●
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. Uterine
●
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REFERENCES
1. Brewer JI, Eckman TR, Dolkart RE, et al. Gestational trophoblastic disease. A comparative study of the
results of therapy in patients with invasive mole and with choriocarcinoma. Am J Obstet Gynecol 1971;
109:335.
2. Goldstein DP, Berkowitz RS. Current management of gestational trophoblastic neoplasia. Hematol Oncol
Clin North Am 2012; 26:111.
3. Hertig AT, Mansell H. Tumors of the female sex organs. Part 1. Hydatidiform mole and choriocarcinoma. In:
Atlas of Tumor Pathology (1st series), Armed Forces Institute of Pathology, Washington, DC 1956. Fascicle
33.
4. Ngan S, Seckl MJ. Gestational trophoblastic neoplasia management: an update. Curr Opin Oncol 2007;
19:486.
5. Brinton LA, Bracken MB, Connelly RR. Choriocarcinoma incidence in the United States. Am J Epidemiol
1986; 123:1094.
6. Smith HO. Gestational trophoblastic disease epidemiology and trends. Clin Obstet Gynecol 2003; 46:541.
7. Altieri A, Franceschi S, Ferlay J, et al. Epidemiology and aetiology of gestational trophoblastic diseases.
Lancet Oncol 2003; 4:670.
8. Moodley M, Tunkyi K, Moodley J. Gestational trophoblastic syndrome: an audit of 112 patients. A South
African experience. Int J Gynecol Cancer 2003; 13:234.
9. Messerli ML, Lilienfeld AM, Parmley T, et al. Risk factors for gestational trophoblastic neoplasia. Am J
Obstet Gynecol 1985; 153:294.
10. Berkowitz RS, Cramer DW, Bernstein MR, et al. Risk factors for complete molar pregnancy from a case-
control study. Am J Obstet Gynecol 1985; 152:1016.
11. Melamed A, Gockley AA, Joseph NT, et al. Effect of race/ethnicity on risk of complete and partial molar
pregnancy after adjustment for age. Gynecol Oncol 2016; 143:73.
curettage or other biopsies have a limited role in the diagnosis of GTN. (See 'Diagnostic evaluation' above
and 'Metastatic sites' 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.)
●
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.)
●
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.)
●
15. 6/17/2018 Gestational trophoblastic neoplasia: Epidemiology, clinical features, diagnosis, staging, and risk stratification - UpToDate
https://www.uptodate.com/contents/gestational-trophoblastic-neoplasia-epidemiology-clinical-features-diagnosis-staging-and-risk-stratification/print?… 15/29
12. Goldstein DP, Berkowitz RS. Gestational Trophoblastic Neoplasms: Clinical Principles of Diagnosis and Ma
nagement, WB Saunders, Philadelphia 1982.
13. Soto-Wright V, Bernstein M, Goldstein DP, Berkowitz RS. The changing clinical presentation of complete
molar pregnancy. Obstet Gynecol 1995; 86:775.
14. Berkowitz RS, Goldstein DP. Clinical practice. Molar pregnancy. N Engl J Med 2009; 360:1639.
15. Berkowitz RS, Goldstein DP. Gestational trophoblastic diseases. In: Principles and Practice of Gynecologic
Oncology, 3rd ed, Hoskins WJ, Perez CA, Young RD (Eds), Williams and Wilkins, Philadelphia 2000. p.112
7.
16. Seckl MJ, Sebire NJ, Berkowitz RS. Gestational trophoblastic disease. Lancet 2010; 376:717.
17. Feltmate CM, Genest DR, Wise L, et al. Placental site trophoblastic tumor: a 17-year experience at the
New England Trophoblastic Disease Center. Gynecol Oncol 2001; 82:415.
18. Berkowitz RS, Goldstein DP. Chorionic tumors. N Engl J Med 1996; 335:1740.
19. 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;
203:531.
20. Osborne R, Dodge J. Gestational trophoblastic neoplasia. Obstet Gynecol Clin North Am 2012; 39:195.
21. Zhao J, Lv WG, Feng FZ, et al. Placental site trophoblastic tumor: A review of 108 cases and their
implications for prognosis and treatment. Gynecol Oncol 2016; 142:102.
22. Fox H, Sebire NJ. Pathology of the placenta, 3rd ed, Elsevier, Philadelphia 2007.
23. Baergen RN, Rutgers JL, Young RH, et al. Placental site trophoblastic tumor: A study of 55 cases and
review of the literature emphasizing factors of prognostic significance. Gynecol Oncol 2006; 100:511.
24. Hassadia A, Gillespie A, Tidy J, et al. Placental site trophoblastic tumour: clinical features and
management. Gynecol Oncol 2005; 99:603.
25. Lan C, Li Y, He J, Liu J. Placental site trophoblastic tumor: lymphatic spread and possible target markers.
Gynecol Oncol 2010; 116:430.
26. Shih IM, Kurman RJ. Epithelioid trophoblastic tumor: a neoplasm distinct from choriocarcinoma and
placental site trophoblastic tumor simulating carcinoma. Am J Surg Pathol 1998; 22:1393.
27. Allison KH, Love JE, Garcia RL. Epithelioid trophoblastic tumor: review of a rare neoplasm of the chorionic-
type intermediate trophoblast. Arch Pathol Lab Med 2006; 130:1875.
28. Horowitz NS, Goldstein DP, Berkowitz RS. Placental site trophoblastic tumors and epithelioid trophoblastic
tumors: Biology, natural history, and treatment modalities. Gynecol Oncol 2017; 144:208.
29. Davis MR, Howitt BE, Quade BJ, et al. Epithelioid trophoblastic tumor: A single institution case series at the
New England Trophoblastic Disease Center. Gynecol Oncol 2015; 137:456.
30. Zhang X, Lü W, Lü B. Epithelioid trophoblastic tumor: an outcome-based literature review of 78 reported
cases. Int J Gynecol Cancer 2013; 23:1334.
31. Mao TL, Seidman JD, Kurman RJ, Shih IeM. Cyclin E and p16 immunoreactivity in epithelioid trophoblastic
tumor--an aid in differential diagnosis. Am J Surg Pathol 2006; 30:1105.
32. Bamberger AM, Aupers S, Milde-Langosch K, Löning T. Expression pattern of the cell cycle promoter cyclin
e in benign extravillous trophoblast and gestational trophoblastic lesions: correlation with expression of Ki-
67. Int J Gynecol Pathol 2003; 22:156.
33. Berkowitz RS, Goldstein DP. Pathogenesis of gestational trophoblastic neoplasms. Pathobiol Annu 1981;
11:391.
16. 6/17/2018 Gestational trophoblastic neoplasia: Epidemiology, clinical features, diagnosis, staging, and risk stratification - UpToDate
https://www.uptodate.com/contents/gestational-trophoblastic-neoplasia-epidemiology-clinical-features-diagnosis-staging-and-risk-stratification/print?… 16/29
34. Berkowitz RS, Goldstein DP. Current management of gestational trophoblastic diseases. Gynecol Oncol
2009; 112:654.
35. Savage P, Kelpanides I, Tuthill M, et al. Brain metastases in gestational trophoblast neoplasia: an update
on incidence, management and outcome. Gynecol Oncol 2015; 137:73.
36. Berkowitz RS, Goldstein DP, Bernstein MR. Natural history of partial molar pregnancy. Obstet Gynecol
1985; 66:677.
37. Rajatanavin R, Chuahirun S, Chailurkit L, et al. Virilization associated with choriocarcinoma. J Endocrinol
Invest 1995; 18:653.
38. Dhillon T, Palmieri C, Sebire NJ, et al. Value of whole body 18FDG-PET to identify the active site of
gestational trophoblastic neoplasia. J Reprod Med 2006; 51:879.
39. Garner EI, Meyerovitz M, Goldstein DP, Berkowitz RS. Successful term pregnancy after selective arterial
embolization of symptomatic arteriovenous malformation in the setting of gestational trophoblastic tumor.
Gynecol Oncol 2003; 88:69.
40. Lim AK, Agarwal R, Seckl MJ, et al. Embolization of bleeding residual uterine vascular malformations in
patients with treated gestational trophoblastic tumors. Radiology 2002; 222:640.
41. Bakri YN, Berkowitz RS, Khan J, et al. Pulmonary metastases of gestational trophoblastic tumor. Risk
factors for early respiratory failure. J Reprod Med 1994; 39:175.
42. Bagshawe KD, Noble MI. Cardio-respiratory aspects of trophoblastic tumours. Q J Med 1966; 35:39.
43. Jones WB, Wagner-Reiss KM, Lewis JL Jr. Intracerebral choriocarcinoma. Gynecol Oncol 1990; 38:234.
44. Hongzhao S, Baozhen W. Brain metastasis in choriocarcinoma and malignant mole: an analysis of 98
cases. Chin Med J (Engl) 1979; 92:164.
45. Bakri Y, Berkowitz RS, Goldstein DP, et al. Brain metastases of gestational trophoblastic tumor. J Reprod
Med 1994; 39:179.
46. Athanassiou A, Begent RH, Newlands ES, et al. Central nervous system metastases of choriocarcinoma.
23 years' experience at Charing Cross Hospital. Cancer 1983; 52:1728.
47. Liu TL, Deppe G, Chang QT, Tan TT. Cerebral metastatic choriocarcinoma in the People's Republic of
China. Gynecol Oncol 1983; 15:166.
48. Bakri YN, Subhi J, Amer M, et al. Liver metastases of gestational trophoblastic tumor. Gynecol Oncol 1993;
48:110.
49. Schmid P, Nagai Y, Agarwal R, et al. Prognostic markers and long-term outcome of placental-site
trophoblastic tumours: a retrospective observational study. Lancet 2009; 374:48.
50. Hoekstra AV, Keh P, Lurain JR. Placental site trophoblastic tumor: a review of 7 cases and their implications
for prognosis and treatment. J Reprod Med 2004; 49:447.
51. Papadopoulos AJ, Foskett M, Seckl MJ, et al. Twenty-five years' clinical experience with placental site
trophoblastic tumors. J Reprod Med 2002; 47:460.
52. Cole LA, Khanlian SA, Muller CY, et al. Gestational trophoblastic diseases: 3. Human chorionic
gonadotropin-free beta-subunit, a reliable marker of placental site trophoblastic tumors. Gynecol Oncol
2006; 102:160.
53. Kohorn EI. What we know about low-level hCG: definition, classification and management. J Reprod Med
2004; 49:433.
54. Zhou Q, Lei XY, Xie Q, Cardoza JD. Sonographic and Doppler imaging in the diagnosis and treatment of
gestational trophoblastic disease: a 12-year experience. J Ultrasound Med 2005; 24:15.
17. 6/17/2018 Gestational trophoblastic neoplasia: Epidemiology, clinical features, diagnosis, staging, and risk stratification - UpToDate
https://www.uptodate.com/contents/gestational-trophoblastic-neoplasia-epidemiology-clinical-features-diagnosis-staging-and-risk-stratification/print?… 17/29
55. Okumura M, Fushida K, Rezende WW, et al. Sonographic appearance of gestational trophoblastic disease
evolving into epithelioid trophoblastic tumor. Ultrasound Obstet Gynecol 2010; 36:249.
56. Gamer EI, Garrett A, Goldstein DP, Berkowitz RS. Significance of chest computed tomography findings in
the evaluation and treatment of persistent gestational trophoblastic neoplasia. J Reprod Med 2004; 49:411.
57. Ngan HY, Chan FL, Au VW, et al. Clinical outcome of micrometastasis in the lung in stage IA persistent
gestational trophoblastic disease. Gynecol Oncol 1998; 70:192.
58. Sung HC, Wu PC, Hu MH, Su HT. Roentgenologic manifestations of pulmonary metastases in
choriocarcinoma and invasive mole. Am J Obstet Gynecol 1982; 142:89.
59. BAGSHAWE KD, GARNETT ES. RADIOLOGICAL CHANGES IN THE LUNGS OF PATIENTS WITH
TROPHOBLASTIC TUMOURS. Br J Radiol 1963; 36:673.
60. EVANS KT, COCKSHOTT WP, HENDRICKSEPDE V. PULMONARY CHANGES IN MALIGNANT
TROPHOBLASTIC DISEASE. Br J Radiol 1965; 38:161.
61. Libshitz HI, Baber CE, Hammond CB. The pulmonary metastases of choriocarcinoma. Obstet Gynecol
1977; 49:412.
62. Bakri Y, al-Hawashim N, Berkowitz R. CSF/serum beta-hCG ratio in patients with brain metastases of
gestational trophoblastic tumor. J Reprod Med 2000; 45:94.
63. Bagshawe KD, Harland S. Immunodiagnosis and monitoring of gonadotrophin-producing metastases in the
central nervous system. Cancer 1976; 38:112.
64. Kohorn EI. The new FIGO 2000 staging and risk factor scoring system for gestational trophoblastic
disease: description and critical assessment. Int J Gynecol Cancer 2001; 11:73.
65. Kohorn EI. Negotiating a staging and risk factor scoring system for gestational trophoblastic neoplasia. A
progress report. J Reprod Med 2002; 47:445.
66. Ngan HY, Bender H, Benedet JL, et al. Gestational trophoblastic neoplasia, FIGO 2000 staging and
classification. Int J Gynaecol Obstet 2003; 83 Suppl 1:175.
67. Agarwal R, Teoh S, Short D, et al. Chemotherapy and human chorionic gonadotropin concentrations 6
months after uterine evacuation of molar pregnancy: a retrospective cohort study. Lancet 2012; 379:130.
68. Braga A, Torres B, Burlá M, et al. Is chemotherapy necessary for patients with molar pregnancy and human
chorionic gonadotropin serum levels raised but falling at 6months after uterine evacuation? Gynecol Oncol
2016; 143:558.
69. Harvey RA, Mitchell HD, Stenman UH, et al. Differences in total human chorionic gonadotropin
immunoassay analytical specificity and ability to measure human chorionic gonadotropin in gestational
trophoblastic disease and germ cell tumors. J Reprod Med 2010; 55:285.
70. Braunstein GD, Vaitukaitis JL, Carbone PP, Ross GT. Ectopic production of human chorionic gonadotrophin
by neoplasms. Ann Intern Med 1973; 78:39.
71. Mutch DG, Soper JT, Baker ME, et al. Role of computed axial tomography of the chest in staging patients
with nonmetastatic gestational trophoblastic disease. Obstet Gynecol 1986; 68:348.
72. Berkowitz RS, Birnholz J, Goldstein DP, Bernstein MR. Pelvic ultrasonography and the management of
gestational trophoblastic disease. Gynecol Oncol 1983; 15:403.
73. Kohorn EI, McCarthy SM, Taylor KJ. Nonmetastatic gestational trophoblastic neoplasia. Role of
ultrasonography and magnetic resonance imaging. J Reprod Med 1998; 43:14.
74. Kohorn EI. Imaging practices in the diagnosis and management of gestational trophoblastic disease: an
assessment. J Reprod Med 2012; 57:207.
18. 6/17/2018 Gestational trophoblastic neoplasia: Epidemiology, clinical features, diagnosis, staging, and risk stratification - UpToDate
https://www.uptodate.com/contents/gestational-trophoblastic-neoplasia-epidemiology-clinical-features-diagnosis-staging-and-risk-stratification/print?… 18/29
75. Mangili G, Spagnolo D, Valsecchi L, Maggi R. Transvaginal ultrasonography in persistent trophoblastic
tumor. Am J Obstet Gynecol 1993; 169:1218.
76. Dobkin GR, Berkowitz RS, Goldstein DP, et al. Duplex ultrasonography for persistent gestational
trophoblastic tumor. J Reprod Med 1991; 36:14.
77. Long MG, Boultbee JE, Begent RH, et al. Preliminary Doppler studies on the uterine artery and
myometrium in trophoblastic tumours requiring chemotherapy. Br J Obstet Gynaecol 1990; 97:686.
78. Gestational Trophoblastic Neoplasms (Female Reproductive Organs). In: AJCC Cancer Staging Manual, Ei
ghth Edition, Amin MB (Ed), Springer, Chicago 2017.
79. FIGO Committee on Gynecologic Oncology. Current FIGO staging for cancer of the vagina, fallopian tube,
ovary, and gestational trophoblastic neoplasia. Int J Gynaecol Obstet 2009; 105:3.
80. Pecorelli S, Benedet JL, Creasman WT, Shepherd JH. FIGO staging of gynecologic cancer. 1994-1997
FIGO Committee on Gynecologic Oncology. International Federation of Gynecology and Obstetrics. Int J
Gynaecol Obstet 1999; 64:5.
81. Goldstein DP, Zanten-Przybysz IV, Bernstein MR, Berkowitz RS. Revised FIGO staging system for
gestational trophoblastic tumors. Recommendations regarding therapy. J Reprod Med 1998; 43:37.
82. World Health Organization Scientific Group on Gestational Trophoblastic Disease. WHO Tech Rep Ser
1983; 692:1.
83. Lurain JR. Treatment of gestational trophoblastic tumors. Curr Treat Options Oncol 2002; 3:113.
84. Gordon AN, Gershenson DM, Copeland LJ, et al. High-risk metastatic gestational trophoblastic disease:
further stratification into two clinical entities. Gynecol Oncol 1989; 34:54.
85. Mortakis AE, Braga CA. "Poor prognosis" metastatic gestational trophoblastic disease: the prognostic
significance of the scoring system in predicting chemotherapy failures. Obstet Gynecol 1990; 76:272.
86. Dubuc-Lissoir J, Zweizig S, Schlaerth JB, Morrow CP. Metastatic gestational trophoblastic disease: a
comparison of prognostic classification systems. Gynecol Oncol 1992; 45:40.
87. DuBeshter B, Berkowitz RS, Goldstein DP, et al. Metastatic gestational trophoblastic disease: experience at
the New England Trophoblastic Disease Center, 1965 to 1985. Obstet Gynecol 1987; 69:390.
88. Sita-Lumsden A, Short D, Lindsay I, et al. Treatment outcomes for 618 women with gestational
trophoblastic tumours following a molar pregnancy at the Charing Cross Hospital, 2000-2009. Br J Cancer
2012; 107:1810.
89. McNeish IA, Strickland S, Holden L, et al. Low-risk persistent gestational trophoblastic disease: outcome
after initial treatment with low-dose methotrexate and folinic acid from 1992 to 2000. J Clin Oncol 2002;
20:1838.
Topic 95881 Version 7.0
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GRAPHICS
Gestational trophoblastic neoplasia: Lung metastases
Chest radiograph showing pulmonary infiltrates in patient with gestational trophoblastic
neoplasia.
Graphic 96988 Version 1.0
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Gestational trophoblastic neoplasia: Vaginal metastases
Vaginal metastases in a patient with choriocarcinoma.
Graphic 96989 Version 1.0
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Gestational trophoblastic neoplasia: Brain metastasis on MRI
MRI: magnetic resonance imaging.
Graphic 96991 Version 2.0
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Ultrasound choriocarcinoma
Choriocarcinoma: Patient with stage 3 choriocarcinoma after term pregnancy. The
endometrial cavity is filled with a hyperechoic mass measuring 3.0 x 2.9 x 2.8 cm.
Courtesy of Department of Radiology, Santa Clara Valley Medical Center.
Graphic 75900 Version 3.0
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Doppler ultrasound choriocarcinoma
Choriocarcinoma: Ultrasound reveals a hyperechoic mass showing hypervascularity on
color Doppler.
Courtesy of Department of Radiology, Santa Clara Valley Medical Center.
Graphic 52443 Version 3.0
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Gestational trophoblastic neoplasia: Positron emission tomography of
liver metastases
Graphic 97076 Version 1.0
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FIGO Staging of Gestational Trophoblastic Neoplasia (GTN) and modified WHO
Prognostic Scoring System as adapted by FIGO
Stage
I
Disease confined to the uterus
Stage
II
GTN extends outside of the uterus, but is limited
to the genital structures (adnexa, vagina)
Stage
III
GTN extends to the lungs, with
or
without genital tract involvement
Stage
IV
All other metastatic sites
The stage should be followed by the sum of the risk
factors (eg, III:5)
Risk factor
Score
0 1 2 4
Age (years) <40 ≥40 – –
Antecedent
pregnancy
Mole Abortion Term –
Interval (months)* 4 4 to 6 7 to
12
>12
Pretreatment serum
hCG (mIU/mL)
<10 10 to
10
10
to
10
>10
Largest tumor
(including uterus)
<3 cm 3 to 4
cm
≥5
cm
–
Site of metastases Lung Spleen,
kidney
GI
tract
Brain,
liver
Number of
metastases
– 1 to 4 5 to 8 >8
Prior failed
chemotherapy
– – Single
drug
≥2
drugs
FIGO: International Federation of Gynecology and Obstetrics; WHO: World Health Organization; hCG: human chorionic
gonadotropin.
* Interval (in months) between end of antecedent pregnancy and start of chemotherapy.
Original figure modified for this publication. Berkowitz RS, Goldstein DP. Current management of gestational trophoblastic
diseases. Gynecol Oncol 2009; 112:654. Table used with the permission of Elsevier Inc. All rights reserved.
Graphic 98185 Version 3.0
3 3
4
4
5
5
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Contributor Disclosures
Ross S Berkowitz, MD Nothing to disclose Donald Peter Goldstein, MD Nothing to disclose Neil S Horowitz,
MD Grant/Research/Clinical Trial Support: TRACON Pharmaceuticals [Gestational trophoblastic neoplasia
(TRC105)]. Barbara Goff, MD Employment (Spouse): Lilly [General oncology (Gemcitabine, pemetrexed)] - No
relevant conflict on topics. Don S Dizon, MD, FACP Grant/Research/Clinical Trial Support: Merck [Gynecologic
malignancies (None)]. Consultant/Advisory Boards: Pfizer [Gynecologic malignancies (Biosimilars)]; Fuji
Pharmaceuticals [Chemotherapy (Biosimilars)]; Tesaro [Gynecologic malignancies (Niraparib)]. Sandy J Falk,
MD, FACOG Nothing to disclose Sadhna R Vora, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
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