Gestational Trophoblastic Disease
BS. Nguyễn Hồng Anh
KEY POINTS
1 Gestational trophoblastic disease (GTD) is a group of interrelated tumors which
include complete and partial moles, invasive moles, choriocarcinoma, placental-site
trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT).
2 Complete and partial moles differ in terms of chromosomal origin, histopathology,
clinical presentation, and risk of gestational trophoblastic neoplasia (gestational
trophoblastic neoplasia [GTN]-persistent tumor).
3 Human chorionic gonadotropin (hCG) is a critical marker for GTD to diagnose the
development of GTN, monitor response to chemotherapy, and occurrence of relapse.
4 Metastases can occur after any type of GTD but is more common after nonmolar
pregnancies and most commonly occur in the lung and the vagina.
5 Single-agent chemotherapy achieves a high remission rate in nonmetastatic and lowrisk metastatic GTN.
6 High-risk GTN requires primary combination chemotherapy, surgery to control
complications of disease and drug-resistant sites and infrequently radiation therapy.
7 After achieving remission with chemotherapy, patients can anticipate normal future
reproduction.
Gestational trophoblastic disease (GTD) is the term used to describe the
heterogeneous group of interrelated lesions that arise from abnormal
proliferation of placental trophoblasts. GTD lesions are histologically distinct
and can be benign or malignant. Benign lesions consist of hydatidiform
moles, complete and partial, whereas malignant lesions consist of invasive
moles, placental-site trophoblastic tumors (PSTT), epithelioid trophoblastic
tumors (ETT), and choriocarcinoma. [1] This subset of malignant lesions
that have varying propensities for local invasion and metastasis is referred to
as gestational trophoblastic neoplasia (GTN). GTNs are among the rare
human tumors that can be cured even in the presence of widespread
dissemination (1,2). Although GTNs commonly follow a molar pregnancy, they
can occur after any gestational event, including induced or spontaneous abortion,
ectopic pregnancy, or term pregnancy.
HYDATIDIFORM MOLES
Epidemiology
[1] The incidence of molar pregnancy in Japan (2:1,000 pregnancies) is reported
to be about threefold higher than the incidence in Europe or North America (about
0.6 to 1.1 per 1,000 pregnancies) (3). In Taiwan, 1 in 125 pregnancies are molar,
while in the United States the incidence is 1 in 1,500 live births. The incidences
of complete and partial hydatidiform moles in Ireland were investigated by
reviewing all products of conception from first- and second-trimester abortions
(4). [1] Based on a thorough pathologic review, the incidence of complete and
partial hydatidiform moles was 1:1,945 and 1:695 pregnancies, respectively.
Table 41-1 Features of Complete and Partial Hydatidiform Moles
Features Complete Mole Partial Mole
Fetal or embryonic tissue Absent Present
Hydatidiform swelling of chorionic villi Diffuse Focal
Trophoblastic hyperplasia Diffuse Focal
Scalloping of chorionic villi Absent Present
Trophoblastic stromal inclusions Absent Present
Karyotype 46,XX (90%); 46,XY Triploid
While variations in the worldwide incidence of molar pregnancy may result in
part from reporting population-based versus hospital-based data, a number of
studies suggest that the high incidence in some populations can be attributed to
socioeconomic and nutritional factors. The decreasing incidence of molar
pregnancy in South Korea is attributed to a more Western diet and improved
standard of living (5). Case-control studies from Italy and the United States show
that the rate of complete mole increases with decreasing consumption of dietary
carotene (vitamin A precursor) and animal fat (6,7). Maternal age and
reproductive history influence the rate of molar pregnancy. Women older
than 40 years have a 2- to 10-fold greater risk of having a complete mole,
while one in three pregnancies in women older than 50 years results in a molar
gestation (8,9). Similarly, adolescents have a sevenfold increased risk of
developing a complete mole (8). [1] These findings suggest that ova from
adolescent and older women may be more susceptible to abnormal
fertilization, resulting in a complete hydatidiform mole.
Limited information is available concerning risk factors for partial molar
pregnancy. The epidemiologic characteristics of complete and partial moles
appear to differ significantly (8–11). The risk for partial moles is associated with
the use of oral contraceptives and a history of irregular menstruation, but not with
dietary factors (10). Nor does there appear to be a strong association between
maternal age and the risk for partial moles (8,9).
FIGURE 41-1 Photomicrograph of a complete mole demonstrating enlarged villous with central cavitation and surrounding trophoblastic hyperplasia.
Pathology and Cytogenetics
Hydatidiform moles may be categorized as either complete or partial moles
on the basis of gross morphology, histopathology, and karyotype (Table 41-1).
Complete Hydatidiform Mole
Complete hydatidiform moles exhibit characteristic swelling and
trophoblastic hyperplasia (Fig. 41-1). They usually have a 46,XX karyotype,
but about 10% have a 46,XY karyotype (12,13). [2] The molar chromosomes
are entirely of paternal origin, with mitochondrial DNA of maternal origin (Fig.
41-2) (14). Complete moles usually arise from an ovum fertilized by a haploid
sperm, which duplicates its own chromosomes. The ovum nucleus may be absent
or inactivated (15).
FIGURE 41-2 The karyotype of complete hydatidiform mole.
Partial Hydatidiform Mole
Partial hydatidiform moles are characterized by the following pathologic features (Fig. 41-3) (16):
1. Chorionic villi of varying size with focal hydatidiform swelling, cavitation, and trophoblastic hyperplasia
2. Marked villous scalloping
3. Prominent stromal trophoblastic inclusions
4. Identifiable embryonic or fetal tissues
[2] Partial moles have a triploid karyotype (69 chromosomes); the extra
haploid set of chromosomes is derived from the father (Fig. 41-4) (17). It is
possible that nontriploid partial moles do not exist (18). When a fetus is present in
conjunction with a partial mole, it generally exhibits the stigmata of triploidy,
including growth retardation and multiple congenital malformations such as
syndactyly and hydrocephaly (Fig. 41-5).
Advances in Pathologic Diagnosis
When molar pregnancy is diagnosed early in the first trimester, the pathologist
can have difficulty distinguishing complete hydatidiform moles from partial
hydatidiform moles or hydropic abortions because of smaller villi, less
trophoblastic hyperplasia, more primitive villous stroma, and less global necrosis
(19,20). Accurate diagnosis can be facilitated using flow cytometry to determine
ploidy (i.e., diploid versus triploid moles) (21) and through assessment of
biomarkers of paternally imprinted and maternally expressed gene products (22).
Biomarkers that take advantage of imprinted genes to distinguish between
complete moles and hydropic abortions from other gestations are identified.
Because complete moles generally have no maternal chromosomes, paternally
imprinted gene products, normally expressed only by maternal chromosomes,
should be absent. In complete moles, the nuclei of the villous stroma and
cytotrophoblastic cells do not express p57, whereas all other gestations, including
partial moles, are characterized by nuclear immunostaining in these cells. Thus, a
complete mole is diploid and negative for p57, a hydropic abortion is diploid
(sometimes triploid) and positive for p57, and a partial mole is triploid and
positive for p57.
Familial Recurrent Molar Pregnancy
Evaluation of families with recurrent molar pregnancy suggests that dysregulation
of normal parental imprinting of genes, with loss of maternally transcribed genes,
is likely to contribute to the pathogenesis of molar pregnancy. Familial recurrent
hydatidiform moles, is a rare occurrence, characterized by recurrent complete
hydatidiform mole of biparental origin, rather than the more usual androgenetic
origin (23). Genetic mapping shows that in most families the gene responsible,
NLRP7, is located in a 1.1 Mb region on chromosome 19q13.4. Mutations in the
gene result in dysregulation of imprinting in the female germline with abnormal
development of embryonic and extraembryonic tissue.
FIGURE 41-3 Photomicrograph of a partial mole showing marked disparity in the villous
size, trophoblastic inclusions (center), and mild trophoblastic hyperplasia. (From
Berkowitz RS, Goldstein OP. Gestational trophoblastic diseases. In: Ryan KJ, Berkowitz
R, Barbieri R, eds. Kistner’s Gynecology Principles and Practice. 5th ed. Chicago, IL:
Year Book Medical Publishers; 1990:433, with permission.)
FIGURE 41-4 The karyotype of a partial hydatidiform mole.
Clinical Features
Patients with complete molar pregnancy are diagnosed increasingly earlier in
pregnancy and treated before they develop the classic clinical signs and
symptoms. [2] This is the result of many changes in clinical practice, such as the
frequent use of human chorionic gonadotropin (hCG) measurement and
transvaginal ultrasonography in early pregnancy for women with vaginal staining
2764and for determining the gestational dates in asymptomatic women. The following
is a description of the classic and current clinical features of complete molar
pregnancy (24,25).
Complete Hydatidiform Mole
Vaginal Bleeding
[2] Vaginal bleeding is the most common symptom causing patients to seek
treatment for complete molar pregnancy. It is reported to occur in 46% of
patients, rather than the previous reports of 97% of cases. Molar tissues may
separate from the decidua and disrupt maternal vessels, and large volumes of
retained blood may distend the endometrial cavity. Because vaginal bleeding may
be considerable and prolonged, in the past one-half of these patients had anemia
(hemoglobin <10 g/100 mL). Anemia is typically present in only 5% of patients.
Excessive Uterine Size
[2] Excessive uterine enlargement relative to the gestational age is one of the
classic signs of a complete mole, although it was present in only about half of
patients. Excessive uterine size occurs in only 28% of patients. The endometrial
cavity may be expanded by chorionic tissue and retained blood. Excessive uterine
size is generally associated with markedly elevated levels of hCG, because uterine
enlargement results in part from trophoblastic overgrowth.
FIGURE 41-5 Photomicrograph of a fetal hand demonstrating syndactyly. The fetus had a
triploid karyotype, and the chorionic tissues were a partial mole.
Preeclampsia
[2] Preeclampsia was observed in 27% of patients with a complete
2766hydatidiform mole. Preeclampsia is reported in only 1 of 74 patients with
complete mole at the initial visit. Although preeclampsia is associated with
hypertension, proteinuria, and hyperreflexia, eclamptic convulsions rarely occur.
Preeclampsia develops almost exclusively in patients with excessive uterine size
and markedly elevated hCG levels. Hydatidiform moles should be considered
whenever preeclampsia develops early in pregnancy.
Hyperemesis Gravidarum
[2] Hyperemesis requiring antiemetic or intravenous (IV) replacement
therapy historically occurred in one-fourth of women with a complete mole,
particularly those with excessive uterine size and markedly elevated hCG
levels. Severe electrolyte disturbances may develop and require treatment with
parenteral fluids. Typically 8% of patients have hyperemesis.
Hyperthyroidism
[2] Clinically evident hyperthyroidism was observed in 7% of patients with a
complete molar gestation. These women may have tachycardia, warm skin, and
tremor, and the diagnosis can be confirmed by detection of elevated serum levels
of free thyroxine (T4) and triiodothyronine (T3). Clinical evidence of
hyperthyroidism with complete mole is rare.
Anesthesia or surgery may precipitate thyroid storm. Thus, if
hyperthyroidism is suspected before the induction of anesthesia for molar
evacuation, a-adrenergic blocking agents should be administered. Thyroid
storm may be manifested by hyperthermia, delirium, convulsions, tachycardia,
high-output heart failure, or cardiovascular collapse. Administration of β-
adrenergic blocking agents prevents or rapidly reverses many of the metabolic
and cardiovascular complications of thyroid storm. After molar evacuation,
thyroid function test results rapidly return to normal.
[2] Hyperthyroidism develops almost exclusively in patients with very high
hCG levels. Some investigators suggest that hCG is the thyroid stimulator in
women with molar pregnancy because positive correlations between serum hCG
levels and total T4 or T3 concentrations were observed. However, in one study in
which thyroid function was measured in 47 patients with a complete mole, no
significant correlation was found between serum hCG levels and serum values of
free T4 index or free T3 index (26). Although some investigators speculated about
a separate chorionic thyrotropin, this substance is not yet isolated.
Trophoblastic Embolization
Respiratory distress rarely occurs in patients with a complete mole. It is
usually diagnosed in patients with excessive uterine size and markedly elevated
2767hCG levels. These patients may have chest pain, dyspnea, tachypnea, and
tachycardia and may experience severe respiratory distress during and after molar
evacuation. Auscultation of the chest usually reveals diffuse rales, and chest
radiographic evaluation may show bilateral pulmonary infiltrates. Respiratory
distress usually resolves within 72 hours with cardiopulmonary support. In some
circumstances, patients may require mechanical ventilation. Respiratory
insufficiency may result from trophoblastic embolization and the
cardiopulmonary complications of thyroid storm, preeclampsia, and massive fluid
replacement.
Theca Lutein Ovarian Cysts
[2] Prominent theca lutein ovarian cysts (6 cm in diameter) develop in about
one-half of patients with a complete mole (27). Theca lutein ovarian cysts result
from high serum hCG levels, which cause ovarian hyperstimulation (28). Because
the uterus may be excessively enlarged, theca lutein cysts can be difficult to
palpate during physical examination; however, ultrasonography can accurately
document their presence and size. After molar evacuation, theca lutein cysts
normally regress spontaneously within 2 to 4 months.
Prominent theca lutein cysts may cause symptoms of marked pelvic pressure,
and they can be decompressed by laparoscopically or ultrasonographically
directed aspiration. If acute pelvic pain develops, laparoscopy should be
performed to assess possible cystic torsion or rupture.
Partial Hydatidiform Mole
[2] Patients with partial hydatidiform mole usually do not have the dramatic
clinical features characteristic of complete molar pregnancy. These patients have
the signs and symptoms of incomplete or missed abortion, and a partial mole
is diagnosed after histologic review of the tissue obtained by curettage (29).
In a survey of 81 patients with a partial mole, the main initial sign was vaginal
bleeding, which occurred in 59 patients (72.8%) (30). Excessive uterine
enlargement and preeclampsia were present in 3 patients (3.7%) and 2 patients
(2.5%), respectively. No patient had theca lutein ovarian cysts, hyperemesis, or
hyperthyroidism. The initial clinical diagnosis was an incomplete or missed
abortion in 74 patients (91.3%) and hydatidiform mole in 5 patients (6.2%). Preevacuation hCG levels were measured in 30 patients and were higher than
100,000 mIU/mL in 2 patients (6.6%).
Natural History
Complete Hydatidiform Mole
2768[2] Complete moles have a potential for local invasion and dissemination. After
molar evacuation, local uterine invasion occurs in 15% of patients, and
metastasis occurs in 4% (27).
A review of 858 patients with complete hydatidiform mole at the New England
Trophoblastic Disease Center (NETDC) revealed that two-fifths of the patients
had the following signs of marked trophoblastic proliferation at the time they
sought treatment:
1. [2] hCG level greater than 100,000 mIU/mL
2. Excessive uterine enlargement
3. Theca lutein cysts 6 cm in diameter or larger
In this review, patients with any one of these signs were considered at high
risk for developing postmolar tumor. [2] After molar evacuation, local uterine
invasion occurred in 31%, and metastases developed in 8.8% of the 352 high-risk
patients. For the 506 low-risk patients, local invasion was found in only 3.4%,
and metastases developed in 0.6%.
Older patients are at increased risk of developing postmolar GTN. One
study reported that persistent tumor developed after a complete molar pregnancy
in 37% of women older than 40 years (27), whereas in another study this finding
occurred in 60% of women older than 50 years (31).
Partial Hydatidiform Mole
[2] Persistent tumor, usually nonmetastatic, develops in approximately 1% to
4% of patients with a partial mole, and chemotherapy is required to achieve
remission (32). Patients who develop persistent disease have no
distinguishing clinical or pathologic characteristics (33).
Diagnosis
[2] Ultrasonography is a reliable and sensitive technique for the diagnosis of
complete molar pregnancy. Because the chorionic villi exhibit diffuse
hydropic swelling, complete moles produce a characteristic vesicular
ultrasonographic pattern as early as the first trimester (Fig. 41-6).
[2] Ultrasonography may contribute to the diagnosis of partial molar
pregnancy by demonstrating focal cystic spaces in the placental tissues and
an increase in the transverse diameter of the gestational sac (34). When these
criteria are present, the positive predictive value for a partial mole is 90%.
Treatment
2769When molar pregnancy is diagnosed, the patient should be evaluated for the
presence of associated medical complications, including preeclampsia,
hyperthyroidism, electrolyte imbalance, and anemia. After the patient’s condition
is stabilized, a decision must be made concerning the most appropriate method of
evacuation.
Suction Curettage
[2] Suction curettage is the preferred method of evacuation, regardless of
uterine size, for patients who desire to preserve fertility (32). It involves the
following steps:
1. Oxytocin infusion—This procedure is begun before the induction of
anesthesia.
2. Cervical dilation—As the cervix is being dilated, uterine bleeding often
increases. Retained blood in the endometrial cavity may be expelled during
cervical dilation. Active uterine bleeding should not deter the prompt
completion of cervical dilation.
3. Suction curettage—Within a few minutes of commencing suction curettage,
the uterine size may decrease dramatically, and the bleeding will be well
controlled. The use of a 12-mm cannula is strongly advised to facilitate
evacuation. If the uterus is larger than 14 weeks of gestation, one hand should
be placed on top of the fundus, and the uterus should be massaged to stimulate
uterine contraction and reduce the risk of perforation.
4. Sharp curettage—When suction evacuation is believed to be complete, gentle
sharp curettage is performed to remove any residual molar tissue.
FIGURE 41-6 Ultrasonogram of a uterus showing a typical pattern of a complete
hydatidiform mole. Note the characteristic vesicular ultrasonographic pattern.
Because trophoblast cells express the RhD factor, patients who are Rh
negative should receive Rh immune globulin at the time of evacuation.
Hysterectomy
[2] If the patient desires surgical sterilization, a hysterectomy may be
performed with the mole in situ. The ovaries may be preserved at the time of
surgery, even in the presence of prominent theca lutein cysts. Large ovarian
cysts may be decompressed by aspiration. Hysterectomy does not prevent
metastasis; patients still require follow-up with assessment of hCG levels.
2771Prophylactic Chemotherapy
The use of prophylactic chemotherapy at the time of molar evacuation is
controversial. The debate concerns the wisdom of exposing all patients to
potentially toxic treatment when only about 20% are at risk of developing
persistent tumor.
In a study of 247 patients with complete molar pregnancy who prophylactically
received a single course of actinomycin D (ActD) at the time of evacuation, local
uterine invasion developed in 10 patients (4%), and no patients experienced
metastasis (35). All 10 patients with local invasion achieved remission after one
additional course of chemotherapy. Prophylactic chemotherapy, prevented
metastasis and reduced the incidence and morbidity of local uterine invasion.
In two prospective randomized studies of prophylactic chemotherapy in
patients with a complete mole, a significant decrease in persistent tumor was
detected in patients with high-risk moles who received prophylactic
chemotherapy (47% and 50% vs. 14%) (36,37). [2] Prophylaxis may be
particularly useful in the management of high-risk complete molar
pregnancy, especially when hCG assessments for follow-up are unavailable
or unreliable (38).
Follow-Up
Human Chorionic Gonadotropin
[2] After molar evacuation, patients should be monitored with weekly
determinations of a-subunit hCG levels until these levels are normal for 3
consecutive weeks, followed by monthly determinations until the levels are
normal for 6 consecutive months (39). The average time to achieve the first
normal hCG level after evacuation is about 9 weeks (40). After achieving
nondetectable serum hCG levels, the risk of developing GTN approaches
zero (41–43). If these findings are confirmed, it is possible that postmolar hCG
surveillance could be safely abbreviated.
Contraception
Patients are encouraged to use effective contraception during the entire interval of
hCG follow-up. Because of the potential risk of uterine perforation, bleeding, and
infection, intrauterine devices should not be inserted until the patient achieves a
normal hCG level. If the patient does not desire surgical sterilization, either oral
contraceptives or barrier methods should be used.
Increased incidence of postmolar persistent tumor was reported among patients
who used oral contraceptives before gonadotropin remission (44). However, data
2772from a prospective trial and other centers indicate that oral contraceptive use does
not increase the risk of postmolar trophoblastic disease (45–47). It appears that
oral contraceptives may be used safely after molar evacuation during the
entire interval of hormonal follow-up.
GESTATIONAL TROPHOBLASTIC NEOPLASIA
Nonmetastatic Disease
[2] Locally invasive GTN develops in about 15% of patients after evacuation
of a complete mole and infrequently after other gestations (1). These patients
usually present with the following symptoms:
1. Irregular vaginal bleeding
2. Theca lutein cysts
3. Uterine subinvolution or asymmetric enlargement
4. Persistently elevated serum hCG levels.
The trophoblastic tumor may perforate the myometrium, causing
intraperitoneal bleeding, or erode into uterine vessels, causing vaginal
hemorrhage. Bulky, necrotic tumor may involve the uterine wall and serve as a
nidus for infection. Patients with uterine sepsis may have a purulent vaginal
discharge and acute pelvic pain.
[1] After molar evacuation, persistent GTN may exhibit the histologic
features of either hydatidiform moles or choriocarcinoma. After a nonmolar
pregnancy, persistent GTN always has the histologic pattern of
choriocarcinoma. Histologic characterization of choriocarcinoma depends on
sheets of anaplastic syncytiotrophoblast and cytotrophoblast without chorionic
villi.
Placental-Site Trophoblastic Tumor and Epithelioid Trophoblastic Tumor
PSTT and ETT are uncommon but important variants of GTN that consist
predominantly of intermediate trophoblast (48). Relative to their mass, these
tumors produce small amounts of hCG and human placental lactogen (hPL), and
they tend to remain confined to the uterus, metastasizing late in their course. [1]
In contrast to other trophoblastic tumors, they are relatively insensitive to
chemotherapy.
Metastatic Disease
[4] Metastatic GTN occurs in about 4% of patients after evacuation of a
complete mole, but it is seen more often when GTN develops after nonmolar
2773pregnancies (1). GTN usually metastasizes as choriocarcinoma because of its
tendency for early vascular invasion with widespread dissemination.
Trophoblastic tumors often are perfused by fragile vessels and are frequently
hemorrhagic. Symptoms of metastases may result from spontaneous bleeding at
metastatic foci. [3] The most common sites of metastases are the lungs (80%),
vagina (30%), pelvis (20%), liver (10%), and brain (10%).
Pulmonary
At the time of diagnosis, lung involvement is visible by chest radiography in
80% of patients with metastatic GTN. [4] Patients with pulmonary metastasis
may have chest pain, cough, hemoptysis, dyspnea, or an asymptomatic lesion
visible by chest radiography. Respiratory symptoms may be acute or chronic,
persisting over many months.
GTN may produce four principal pulmonary patterns:
1. An alveolar or “snowstorm” pattern
2. Discrete rounded densities
3. Pleural effusion
4. An embolic pattern caused by pulmonary arterial occlusion.
Because respiratory symptoms and radiographic findings may be
dramatic, the patient may be thought to have a primary pulmonary disease.
Some patients with extensive pulmonary involvement have minimal, if any,
gynecologic symptoms because the reproductive organs may be free of
trophoblastic tumor. The diagnosis of GTN may be confirmed only after
thoracotomy is performed, particularly in patients with a nonmolar antecedent
pregnancy.
Pulmonary hypertension may develop in patients with GTN secondary to
pulmonary arterial occlusion by trophoblastic emboli. The development of early
respiratory failure requiring intubation is associated with a poor clinical outcome
(49).
Vaginal
[4] Vaginal metastases occur in 30% of the patients with metastatic tumor.
These lesions are highly vascular and may bleed vigorously when biopsied.
Metastases to the vagina may occur in the fornices or suburethrally and may
produce irregular bleeding or a purulent discharge.
Hepatic
Liver metastases occur in 10% of patients with disseminated trophoblastic
2774tumor. Hepatic involvement is encountered when there is a protracted delay in
diagnosis and the patient has an extensive tumor burden. Epigastric or right upper
quadrant pain may develop if metastases stretch the hepatic capsule. Hepatic
lesions may be hemorrhagic, causing hepatic rupture and exsanguinating
intraperitoneal bleeding.
Central Nervous System
[4] Metastatic trophoblastic disease involves the brain in 10% of patients.
Cerebral involvement is seen in patients with advanced disease; virtually all
patients with brain metastasis have concurrent pulmonary or vaginal involvement
or both. Because cerebral lesions frequently hemorrhage spontaneously, most
patients develop acute focal neurologic deficits (50,51).
Staging and Prognostic Score
Staging
[5] An anatomic staging system for GTN was adopted by the International
[6] Federation of Gynecology and Obstetrics (FIGO) (Table 41-2). It is hoped
that this staging system will encourage the objective comparison of data from
various centers (52).
Stage I: Patients have persistently elevated hCG levels and tumor confined
to the uterine corpus.
Stage II: Patients have metastases to the genital tract (i.e., adnexa, broad
ligament, vagina).
Stage III: Patients have pulmonary metastases with or without uterine,
vaginal, or pelvic involvement. The diagnosis is based on a rising hCG level in
the presence of pulmonary lesions viewed by plain chest radiography and not
chest computed tomography scans (CT scan).
Stage IV: Patients have advanced disease and involvement of the brain,
liver, kidneys, or gastrointestinal tract. These patients are in the highest risk
category because they are most likely to be resistant to chemotherapy.
Choriocarcinoma is usually present, and the disease commonly follows a
nonmolar pregnancy.
Table 41-2 Staging of Gestational Trophoblastic Tumors
Stage
I
Disease confined to uterus
Stage GTN extending outside uterus but limited to genital structures (adnexa,
2775II vagina, broad ligament)
Stage
III
GTN extending to lungs with or without known genital tract involvement
Stage
IV
All other metastatic sites
Prognostic Scoring System
In addition to anatomic staging, it is important to consider other variables to
predict the likelihood of drug resistance and to assist in selecting the appropriate
chemotherapy (53). [5] A prognostic scoring system proposed by the World
Health [6] Organization reliably predicts the potential for resistance to
chemotherapy (Table 41-3).
When the prognostic score is higher than 6, the patient is categorized as
high risk and requires multimodal therapy, which includes intensive
combination chemotherapy, and may include surgery and radiation to
achieve remission. Patients with stage-I disease usually have a low-risk score,
and those with stage-IV disease have a high-risk score. The distinction
between low and high risk applies mainly to patients with stage-II or III
disease.
Table 41-3 Scoring System Based on Prognostic Factorsa
Diagnostic Evaluation
2776[4] Optimal management of persistent GTN requires a thorough assessment [5] of
the extent of the disease before the initiation of treatment. [6] All patients with
persistent GTN should undergo a careful pretreatment evaluation, including
the following:
1. Complete history and physical examination
2. Measurement of the serum hCG level
3. Hepatic, thyroid, and renal function tests
4. Determination of baseline peripheral white blood cell and platelet counts
The metastatic workup should include the following:
1. Chest radiograph or CT scan (see below regarding micrometastases)
2. Ultrasonography or CT scan of the abdomen and pelvis
3. CT or magnetic resonance imaging (MRI) scan of the head as indicated
When the pelvic examination and chest radiographic findings are negative,
metastatic involvement of other sites is uncommon.
Liver ultrasonography and CT or MRI scanning will disclose most hepatic
metastases in patients with abnormal liver function tests. CT or MRI scan of the
head facilitates the early diagnosis of asymptomatic cerebral lesions. Chest CT
scans may detect micrometastases not visible on chest radiography. Chest CT will
demonstrate pulmonary micrometastases in about 40% of patients with presumed
nonmetastatic disease (54). The presence of pulmonary micrometastases has not
been shown to substantially change the clinical outcome.
In patients with choriocarcinoma or metastatic disease, hCG levels may be
measured in the cerebrospinal fluid (CSF) to exclude cerebral involvement if
the results of CT or MRI scanning of the brain are normal. The ratio of
plasma-to-CSF hCG tends to be lower than 60 in the presence of cerebral
metastases (55). A single plasma-to-CSF hCG ratio may be misleading, because
rapid changes in plasma hCG levels may not be reflected promptly in the CSF
(56).
Pelvic ultrasonography appears to be useful in detecting extensive
trophoblastic uterine involvement and may aid in identifying sites of
resistant uterine tumor (57). Because ultrasonography can accurately and
noninvasively detect extensive uterine tumor, it may help identify patients who
would benefit from hysterectomy.
Management of GTN
A protocol for the management of GTN is presented in Table 41-4.
2777Low-Risk Disease
Low-risk GTN includes patients with both nonmetastatic (stage I) and
metastatic GTN whose prognostic score is less than 7. In patients with stage-I
disease, the selection of treatment is based primarily on whether the patient
desires to retain fertility.
Hysterectomy Plus Chemotherapy
[5] If the patient does not wish to preserve fertility, hysterectomy with
adjuvant single-agent chemotherapy may be performed as primary
treatment. Adjuvant chemotherapy is administered for three reasons:
1. To reduce the likelihood of disseminating viable tumor cells at surgery.
2. To maintain a cytotoxic level of chemotherapy in the bloodstream and tissues
in case viable tumor cells are disseminated at surgery.
3. To treat any occult metastases that may be present at the time of surgery.
Chemotherapy can be administered safely at the time of hysterectomy without
increasing the risk of bleeding or sepsis. In a series of 31 patients treated with
primary hysterectomy and a single course of adjuvant chemotherapy, all achieved
complete remission with no additional therapy (58).
Hysterectomy is performed in all patients with stage-I PSTT and ETT.
Because PSTT and ETT are relatively resistant to chemotherapy, hysterectomy
for presumed nonmetastatic disease is the most certain curative treatment. Patients
with metastatic PSTT may still achieve remission, but their tumors are less
responsive to chemotherapy (59).
Table 41-4 Protocol for Treatment of GTN
Stage I
Initial Single-agent chemotherapy or hysterectomy with adjunctive
chemotherapy
Resistant Combination chemotherapy
Hysterectomy with adjunctive chemotherapy
Local resection
Pelvic infusion
Stages II and III
2778Low riska
Initial Single-agent chemotherapy
Resistant Combination chemotherapy
High riska
Initial Combination chemotherapy
Resistant Second-line combination chemotherapy
Stage IV
Initial Combination chemotherapy
Brain Whole-head radiation (3,000 cGy)
Craniotomy to manage complications
Liver Resection or embolization to manage complications
Resistanta Second-line combination chemotherapy
Hepatic arterial infusion
aLocal resection optional.
Chemotherapy Alone
[5] Single-agent chemotherapy is the preferred treatment in patients with
stage-I disease who desire to retain fertility (60). At the NETDC from July
1965 through December 2016, primary single-agent chemotherapy was
administered to 592 patients with stage-I GTN and 487 patients (82.3%) attained
complete remission. The remaining 105 patients with resistant disease
subsequently achieved remission after combination chemotherapy or surgical
intervention.
[6] When a patient’s disease is resistant to single-agent chemotherapy and
she desires to preserve fertility, combination chemotherapy should be
administered. If the patient’s disease is resistant to single-agent and combination
chemotherapy and she wants to retain fertility, local uterine resection may be
considered. When local resection is planned, a preoperative ultrasonography,
MRI, positron emission tomography (PET) scan, or arteriography may help to
define the site of the resistant tumor.
2779Low-Risk Metastatic GTN (Stages II and III)
Vaginal and Pelvic Metastasis
[5] Low-risk disease treated with primary single-agent chemotherapy has a
high (approximately 80%) rate of remission in contrast to high-risk disease
that usually does not achieve remission with single-agent treatment and
requires treatment with primary intensive combination chemotherapy.
Vaginal metastases may bleed profusely because they are highly vascular
and friable. When bleeding is substantial, it may be controlled by packing the
vagina or by wide local excision. Infrequently, arteriographic embolization of the
hypogastric arteries may be required to control hemorrhage from vaginal
metastases (61).
Pulmonary Metastasis
At the NETDC from July 1965 through December 2016, of the 168 patients with
low-risk stages II or III disease, 130 (77.3%%) attained complete remission with
single-agent chemotherapy. The remaining 38 (22.6%) patients who had disease
resistant to single-agent treatment subsequently achieved remission with
combination chemotherapy.
Thoracotomy
[6] Thoracotomy has a limited but important role in the management of
pulmonary metastases. If a patient has a persistent viable pulmonary
metastasis following intensive chemotherapy, thoracotomy may be indicated
to excise the resistant focus. A thorough metastatic workup should be performed
before surgery is undertaken to exclude other sites of persistent disease. It is
important to realize that fibrotic pulmonary nodules may persist indefinitely on
chest radiography, even after complete gonadotropin remission is attained. In
patients undergoing thoracotomy for resistant disease, chemotherapy should be
administered postoperatively to treat potential occult sites of micrometastases.
Hysterectomy
[6] Hysterectomy may be required in patients with metastatic disease to
control uterine hemorrhage or sepsis. [6] In patients with extensive uterine
tumor, hysterectomy may substantially reduce the trophoblastic tumor burden and
limit the need for multiple courses of chemotherapy (62).
Follow-Up
[3] All patients with GTN should undergo follow-up with:
1. Weekly measurement of hCG levels until they are normal for three
2780consecutive weeks.
2. Monthly measurement of hCG values until levels are normal for twelve
consecutive months.
3. Effective contraception during the entire interval of hormonal follow-up.
High-Risk Metastatic GTN (Stages II to IV)
[6] All patients with high-risk GTN (stages II to IV) should be treated with
primary intensive combination chemotherapy and the selective use of
radiation therapy and surgery. Between July 1965 and December 2016, of the
144 patients with high-risk GTN stages II to IV treated at the NETDC, 121 (84%)
achieved complete remission. Before 1975, when single-agent therapy was used
primarily to treat patients with stage-IV GTN, only 6 of 20 patients (30%)
attained complete remission. Since 1975, 25 of 33 patients (75.7%) achieved
remission. This improvement in survival resulted from the use of multimodal
therapy, including primary combination chemotherapy in conjunction with
radiation and surgical treatment. Patients with stage-IV disease are at the greatest
risk of developing rapidly progressive and unresponsive tumors despite intensive
multimodal therapy. They should be referred to centers with special expertise in
the management of trophoblastic disease.
Hepatic Metastasis
The management of resistant hepatic metastasis is particularly difficult (63). If a
patient becomes resistant to systemic chemotherapy, hepatic arterial infusion of
chemotherapy may induce complete remission in selected cases. Hepatic resection
may be required to control acute bleeding or to excise a focus of resistant tumor.
New techniques of arterial embolization may reduce the need for surgical
intervention.
Cerebral Metastasis
At the NETDC, cerebral metastases are treated with either whole-brain radiation
(3,000 cGy in 10 fractions) or stereotactic radiosurgery in conjunction with
combination chemotherapy. [6] Because irradiation may be hemostatic and
tumoricidal, the risk of spontaneous cerebral hemorrhage may be lessened
by the concurrent use of combination chemotherapy and brain irradiation.
Excellent remission rates (86%) were reported in patients with cranial metastases
treated with intensive IV combination chemotherapy and intrathecal methotrexate
(MTX) (64).
Craniotomy
[6] Craniotomy may be required to provide acute decompression or to
2781control bleeding. It should be performed to manage life-threatening
complications so that the patient ultimately will be cured with chemotherapy. In a
study of six patients (65), the use of craniotomy to control bleeding resulted in
complete remission in three patients. Infrequently, cerebral metastases that are
resistant to chemotherapy may be amenable to local resection (66). Patients with
cerebral metastases who achieve sustained remission generally have no residual
neurologic deficits.
Follow-Up
An algorithm for the management of persistent GTN is presented in Figure 41-7.
CHEMOTHERAPY
Single-Agent Treatment
[5] Single-agent chemotherapy with either ActD or MTX achieved
comparable and excellent remission rates in both nonmetastatic and low-risk
metastatic GTN (67). Several protocols using these agents are available. ActD
can be given every other week as a 5-day regimen or in a pulsatile fashion;
similarly, MTX can be given either in a 5-day or 8-day regimen or pulsatile
weekly (68,69). No study to date has compared these various protocols with
regard to success. An optimal regimen should maximize the response rate while
minimizing morbidity and cost.
An important phase III randomized trial examining MTX and ActD in the
treatment of low-risk GTN was published by the Gynecologic Oncology Group
(GOG) (70). Two hundred sixteen patients were randomized to receive either
biweekly ActD 1.25 mg/m2 IV bolus or weekly MTX 30 mg/m2 intramuscular
(IM). The remission rate was 58% in the MTX arm and 73% in the ActD arm.
These results suggest that ActD is superior to the weekly MTX regimen in treating
low-risk GTN. Before recommending pulse ActD as the primary modality in the
treatment of patients with low-risk GTN, it is important to be aware of the
potential for significant toxicity of this regimen compared to those receiving
MTX. All patients with low-risk disease in this study ultimately achieved
remission, regardless of their initial response. Regarding the true comparative
effectiveness of these agents, it would be prudent to compare the biweekly ActD
regimen to the more commonly used 5-day or 8-day MTX regimens, which offer a
high initial remission rate with minimal toxicity. The GOG attempted to repeat a
randomized trial using these regimens but the trial was closed early as a result of
lack of accrual. A 2016 meta-analysis of seven randomized controlled trials
indicated that substantial heterogeneity made it difficult to be confident which
was the preferred single agent (67).
2782The administration of methotrexate with folinic acid (MTX-FA) in GTN to limit
systemic toxicity was first reported in 1964 (71). It has been confirmed that MTXFA is effective and safe in the management of GTN.
FIGURE 41-7 Management of gestational trophoblastic tumor. GTN, gestational
trophoblastic neoplasia; hCG, human chorionic gonadotropin; RT, radiotherapy. (From
Berkowitz RS, Goldstein DP. Gestational trophoblastic disease. In: Berek JS, Hacker NF.
Berek & Hacker’s Gynecologic Oncology. 6th ed. Philadelphia, PA: Wolters Kluwer;
2015;642.)
An evaluation of 185 patients treated with 8-day MTX-FA revealed that
2784complete remission was achieved in 162 patients (87.6%); of these patients, 132
(81.5%) required only one course of MTX-FA to attain remission (72). MTX-FA
induced remission in 147 of 163 patients (90.2%) with stage-I GTN and in 15 of
22 patients (68.2%) with low-risk stages II and III GTN. [5] Resistance to
therapy was more common in patients with choriocarcinoma, metastasis, and
pretreatment serum hCG levels higher than 50,000 mIU/mL. After treatment
with MTX-FA, thrombocytopenia, granulocytopenia, and hepatotoxicity
developed in 3 (1.6%), 11 (5.9%), and 26 (14.1%) patients, respectively. [5]
Thus, MTX-FA achieved an excellent therapeutic outcome with minimal
toxicity and attained this goal with limited exposure to chemotherapy.
Technique of Single-Agent Treatment
[5] Administration of single-agent chemotherapy (generally 8-day [6] MTXFA) every 2 weeks until hCG is undetected and then three consolidation
courses to reduce the risk of relapse is recommended (73,74). Resistance to
chemotherapy is diagnosed if the hCG level plateaus +/- 10% over the course
of 2 weeks or re-elevates in at least one measurement of hCG level. If the
patient is diagnosed as having resistance to the primary chemotherapy,
treatment is promptly changed to the alternative single-agent regimen
(generally ActD).
Combination Chemotherapy
Triple Therapy
Prior to the introduction of etoposide in combination with MTX, ActD,
cyclophosphamide, and vincristine (EMA-CO), triple therapy with MTX, ActD,
and cyclophosphamide was the treatment of choice as initial therapy for patients
with low-risk disease resistant to single-agent therapy and as primary therapy for
high-risk patients. Triple therapy is no longer indicated in patients with highrisk disease. It may be useful in selected patients with low-risk scores
resistant to single agents.
EMA-CO
Etoposide induces complete remission in 56 (95%) of 60 patients with
nonmetastatic and low-risk metastatic GTN (75). The use of EMA-CO induced
an 83% remission rate in patients with metastasis and a high-risk score (76).
Another study confirmed that primary EMA-CO induced complete remission in
76% of the patients with metastatic GTN and a high-risk score (77). Another
study reported that EMA-CO induced complete sustained remission in 87 (90.6%)
of 96 patients with high-risk (score >6) GTN (78). Remission occurred with
2785EMA-CO in 30 (86%) of 35 patients with brain metastasis (64).
[6] The EMA-CO regimen is well tolerated, and treatment seldom is
suspended because of toxicity. The EMA-CO regimen is the preferred
primary treatment in patients with metastasis and a high-risk prognostic
score >6.
EMA-EP
[6] Patients resistant to EMA-CO can be treated successfully by substituting
etoposide and cisplatin on day 8 (EMA-EP). EMA-EP induced remission alone
or with surgery in 16 (76%) of 21 patients who were resistant to EMA-CO
(79). The optimal combination drug protocol will most likely include etoposide,
MTX, and ActD and perhaps other agents administered in the most dose-intensive
manner.
Management of Refractory GTN
Efforts continue to identify new agents and regimens effective in treating
patients who prove resistant to all standard chemotherapy regimens. A
combination of cisplatin, vinblastine, and bleomycin (PVB) was used effectively
in patients with drug-resistant tumor (80). Although ifosfamide and paclitaxel
were used successfully, further studies are needed to define their potential role in
either primary or second-line therapy (81,82). Wang et al. reported that a novel
three-drug doublet regimen consisting of paclitaxel, etoposide, and cisplatin
(TE/TP) induced response in seven patients (three complete, four partial) who
were resistant to EMA-CO (83). Wan et al. demonstrated that floxuridine
(FUDR)-containing regimens induced complete remission in all of 21 patients
with drug-resistant GTN (84). Matsui et al. found that 5-fluorouracil (5-FU) in
combination with ActD induced remission in 9 of 11 (82%) patients with drug
resistance (85). [6] The potential role for autologous bone marrow transplantation
or stem cell rescue in conjunction with ultra–high-dose chemotherapy has yet to
be defined, although complete remissions were reported in patients with
refractory GTN (86,87).
Duration of Therapy
[6] Patients who require combination chemotherapy must be treated
intensively to attain remission. Combination chemotherapy should be given
as often as toxicity permits until the patient achieves three consecutive
normal hCG levels. After normal hCG levels are attained, at least three
additional courses of chemotherapy are administered to reduce the risk of
relapse.
2786False-Positive hCG Tests
The concept of false-positive hCG tests caused by heterophile antibodies is
critical to remember when following patients with molar gestation or GTN. Some
assay systems used by commercial laboratories are particularly vulnerable to
false-positive tests resulting from the presence of heterophilic antibodies in the
test kits they were using (88). For the most part this problem was corrected by
adding blocking antibodies to the test systems. Since the hCG molecules in GTN
are significantly more degraded or heterogeneous than in normal pregnancy, with
higher proportions of free β-hCG, nicked hCG, and β-core fragments, it is
important to use an assay that detects intact hCG and its metabolites and
fragments in order to accurately assess the tumor burden (89–91). Cross-reactivity
with luteinizing hormone (LH) can cause confusion when dealing with women in
the perimenopausal age group whose hCG level may plateau above assay, even
when there is no longer active tumor. The pituitary normally produces low hCG
levels which may increase into the measurable range when chemotherapy induces
ovarian failure. The use of hormone suppression will suppress LH and pituitary
hCG and prevent unnecessary treatment. False-positive hCG tests caused by
heterophile agglutinins or LH release may cause confusion in the diagnosis of
early pregnancy, ectopic pregnancy, and the so-called phantom choriocarcinoma.
When there is concern about the possibility of a false-positive serum hCG test, a
urine sample should be tested, because patients with phantom hCG generally have
no measurable hCG in a parallel urine sample.
Persistent Low-Level “Real” hCG
Some patients with molar pregnancy and GTN have persistent (weeks to months)
very low levels of real hCG (usually <500 mIU/mL). In these women, extensive
radiologic and clinical evaluations fail to reveal any lesions, and chemotherapy is
usually not effective. This condition of “real” low-level hCG, where hCG is not
hyperglycosylated, is called “quiescent GTN.” These patients should be managed
with careful follow-up, because 6% to 10% ultimately will relapse into active
disease and rising hCG levels. The risk of relapse to active disease is correlated
with the amount of hyperglycosylated hCG. If relapse does occur, chemotherapy
usually proves effective (92).
Subsequent Pregnancies
Pregnancies After Uncomplicated Hydatidiform Mole
[7] Patients with hydatidiform moles can anticipate normal reproduction in
the future (93). At the NETDC from 1965 until 2014, patients with
2787uncomplicated complete mole had 1,388 subsequent pregnancies that resulted in
949 term live births (68.4%), 103 premature deliveries (7.4%), 11 ectopic
pregnancies (0.8%), 7 stillbirths (0.5%), and 20 repeat molar pregnancies (1.4%).
First- and second-trimester spontaneous abortions occurred in 256 (18.4%)
pregnancies. Major and minor congenital malformations were detected in 40
infants (3.8%).
Although data regarding pregnancies after a partial mole are limited (357
subsequent pregnancies), the information is reassuring (93). [7] Patients with
complete or partial moles should be reassured that they are generally at no
increased risk of complications in later gestations.
[7] When a patient has had a molar pregnancy, either partial or complete,
she should be informed of the increased risk of having a molar gestation in
subsequent conceptions. After one molar pregnancy, the risk of having molar
disease in a future gestation is about 1% to 1.5%. Of 37 patients with at least
two documented molar pregnancies, every possible combination of repeat molar
pregnancy was observed. After two molar gestations, these 37 patients had 40
later conceptions resulting in 25 (62.5%) term deliveries, 7 (17.5%) moles (6
complete, 1 partial), 3 spontaneous abortions, 3 therapeutic abortions, 1
intrauterine fetal death, and 1 ectopic pregnancy. In 6 patients, the medical
records indicated that the patient had a different partner at the time of different
molar pregnancies (93).
[7] For any subsequent pregnancy, it seems prudent to undertake the
following approach:
1. Perform pelvic ultrasonographic examination during the first trimester to
confirm normal gestational development.
2. Obtain an hCG measurement 6 weeks after completion of the pregnancy
to exclude occult trophoblastic neoplasia.
Pregnancies After GTN
[7] Patients with GTN who are treated successfully with chemotherapy can
expect normal reproduction in the future. Patients who were treated with
chemotherapy at the NETDC from 1965 to 2014 had 667 subsequent pregnancies
that resulted in 446 term live births (66.9%), 44 preterm deliveries (6.6%), 7
ectopic pregnancies (1.0%), 10 stillbirths (1.5%), and 9 repeat molar pregnancies
(1.3%) (93). First- and second-trimester spontaneous abortions occurred in 123
(18.4%) pregnancies. Major and minor congenital malformations were detected in
12 infants (2.4%). The frequency of congenital anomalies is not increased,
although chemotherapeutic agents have teratogenic and mutagenic potential.
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