Chorionic tumors, or gestational trophoblastic diseases, originate from placental

tissues and are among the rare human tumors that can be cured even in the presence of
widespread metastasis.1-4 Gestational trophoblastic diseases include a spectrum of
interrelated tumors, including complete and partial hydatidiform mole, placental-site
trophoblastic tumor, and choriocarcinoma, that vary in their propensity for local
invasion and spreading. Although persistent gestational trophoblastic tumors develop
most commonly after a molar pregnancy, they may follow any gestation. This article
concentrates on recent advances in the understanding of the pathogenesis, natural
history, and treatment of gestational trophoblastic diseases and describes our current
approach to their management.
Hydatidiform moles can be categorized as either complete or partial on the basis of
karyotype, gross morphology, and histopathology (Table 1Table 1Features of
Complete and Partial Hydatidiform Moles.).5-8 Complete moles lack identifiable
embryonic or fetal tissues, the chorionic villi exhibit generalized hydropic swelling
and diffuse trophoblastic hyperplasia, and the implantation-site trophoblast has diffuse
and marked atypia (Figure 1AFigure 1Photographs Showing Mature Chorionic Villi
from a Normal Full-Term Placenta (Panel A, 100); Diffusely Hydropic Chorionic
Villi, with Diffuse Trophoblastic Hyperplasia, from a Complete Mole (Panel B, 50);
and Sheets of Anaplastic Cytotrophoblast and Syncytiotrophoblast from a
Choriocarcinoma (Panel C, 400)., Figure 1B, and Figure 1C).

Cytogenetic studies have demonstrated that most complete moles (90 percent) have a
46,XX karyotype, and the chromosomes are entirely of paternal origin.9 A complete
mole appears to arise from an ovum that has been fertilized by a haploid (23,X)
sperm, which then duplicates its own chromosomes; the nucleus of the ovum may be
either absent or inactivated.10 About 10 percent of complete moles have a 46,XY
chromosomal pattern.11 The chromosomes in a 46,XY complete mole also appear to
be entirely of paternal origin and probably result from dispermy. Although the
chromosomes of complete moles are entirely of paternal origin, mitochondrial DNA is
of maternal origin.12

Partial moles usually contain identifiable embryonic or fetal tissues, and the chorionic
villi vary in size, with focal swelling, cavitation, and trophoblastic hyperplasia. The
chorionic villi characteristically have marked scalloping and prominent stromal
trophoblastic inclusions, and the implantation-site trophoblast may exhibit focal, mild
atypia.
Most partial moles (90 to 93 percent) have a triploid karyotype (69 chromosomes),
with the extra haploid set of chromosomes derived from the father.13,14 Thus, both
complete and partial moles are characterized by an excessive number of paternal
chromosomes. When a fetus is present with a partial mole, it generally has growth
retardation and multiple congenital malformations.15

Epidemiology and Risk Factors

The incidence of gestational trophoblastic disease has been reported to vary
dramatically in different regions of the world.16 For example, the incidence of molar
pregnancy in Japan (2.0 per 1000 pregnancies) is reported to be about three times
higher than the incidence in Europe or North America (about 0.6 to 1.1 per 1000
pregnancies).17 Variations in the worldwide incidence rates of molar pregnancy may
result in part from discrepancies between population-based and hospital-based data. In
Ireland, the incidence of complete and partial moles has been determined to be 1 per
1945 pregnancies and 1 per 695 pregnancies, respectively, on the basis of a review of
pathological studies of all products of conception from first- and second-trimester
abortions.18
Careful casecontrol studies have been undertaken to identify risk factors for
complete and partial molar pregnancy. The high incidence of molar pregnancy in
some populations has been attributed to nutritional and socioeconomic factors. Case
control studies in both Italy and the United States suggest that low dietary intake of
carotene and animal fat may be associated with an increased risk of a complete
mole.19,20 Vitamin A deficiency causes abnormal spermatogenesis in male rhesus
monkeys and spontaneous abortion in female rhesus monkeys.21 Regions with a high
incidence of molar pregnancy correspond to the geographic areas with a high
frequency of vitamin A deficiency.22
A maternal age over 35 years has consistently been demonstrated to be a risk factor
for a complete mole. Parazzini et al. reported that, as compared with younger women,
the risk of a complete mole was 2 times higher for women over the age of 35 years
and 7.5 times higher for women over 40 years.23 Ova from older women may be
more susceptible to abnormal fertilization.
The risk of a complete or partial mole is increased in women with a previous
spontaneous abortion.24 After one spontaneous abortion, the risk of a complete or
partial mole is three and two times higher, respectively, than the risk in the absence of
a previous spontaneous abortion. Acaia et al. reported that after two consecutive
spontaneous abortions, the risk of a complete mole is increased by a factor of 32.25

Certain epidemiologic characteristics of complete and partial moles differ markedly.

For example, Parazzini et al. observed that there was no association between maternal
age and the risk of a partial mole.23 Furthermore, the risk of a partial mole has been
reported to be associated with a history of irregular menstrual periods and the use of
oral contraceptives for more than four years but not with dietary factors.26 Thus, the
risk of a partial mole appears to be associated with the reproductive history rather than
dietary factors.

Clinical Presentation
Complete Molar Pregnancy
The clinical presentation of a complete mole has changed considerably over the past
two decades. Vaginal bleeding was the most common presenting symptom in 89 to 97
percent of patients during the 1960s and 1970s.27-29 Because bleeding was often
prolonged, about half the patients presented with anemia (hemoglobin, <10 per
deciliter). The uterine size was palpably larger than the gestational age in 38 to 51
percent of the patients and was usually associated with markedly elevated levels of
human chorionic gonadotropin.27-29 Theca-lutein ovarian cysts were reported in 20
to 46 percent of patients, depending on whether the diagnosis was based on clinical or
ultrasonographic examination.29,30 Theca-lutein cysts result from ovarian
hyperstimulation by high circulating blood levels of human chorionic gonadotropin.31
Preeclampsia and hyperemesis were reported in 12 to 27 percent and 20 to 26 percent
of patients, respectively, and occurred almost exclusively in those with markedly
elevated human chorionic gonadotropin values and excessive uterine size.27-29
Hyperthyroidism and respiratory insufficiency were medically important but
infrequent complications (occurring in 7 percent and 2 percent of patients,
respectively) and were both associated with high human chorionic gonadotropin
values and excessive uterine enlargement.32 Thyroid storm sometimes developed at
the time of molar evacuation in patients with untreated hyperthyroidism. Respiratory
insufficiency infrequently resulted from the cardiopulmonary complications of
trophoblastic emboli, preeclampsia, thyroid storm, and massive fluid replacement.
Respiratory distress usually resolved within 72 hours with appropriate
cardiopulmonary support.
In the 1960s and 1970s, a complete mole was generally diagnosed in the second
trimester (mean gestational age, 16 to 17 weeks), but in recent years the diagnosis has
been made earlier in gestation (mean gestational age, 12 weeks).33,34 The earlier
diagnosis is due in large part to the availability of accurate and sensitive tests for
measuring human chorionic gonadotropin and the widespread use of both
transabdominal and transvaginal ultrasonography.

Vaginal bleeding continues to be the most common presenting symptom, occurring in

84 percent of patients with complete moles.33 However, now the diagnosis is often
made before the other classic clinical signs and symptoms develop. With the earlier
diagnosis, excessive uterine enlargement, hyperemesis, anemia, and preeclampsia
have been observed at presentation in only 28, 8, 5, and 1 percent of patients,
respectively. Between 1988 and 1993, none of our 74 patients with complete moles
had hyperthyroidism or respiratory distress. However, patients have continued to
present with markedly elevated human chorionic gonadotropin levels before
evacuation of the mole.

Partial Hydatidiform Molar Pregnancy

Patients with partial moles usually do not present with the dramatic clinical features
that were characteristic of complete moles in the past. In general, such patients
present with the signs and symptoms of incomplete or missed abortion, and the
diagnosis of a partial mole is usually made after a histologic review of curettage
specimens.35
The main presenting sign in patients with partial moles is vaginal bleeding (occurring
in 73 percent of patients).35 Excessive uterine enlargement and preeclampsia are
present in only 4 to 11 percent and 1 to 4 percent of patients, respectively.35-37
Theca-lutein ovarian cysts, hyperemesis, and hyperthyroidism develop infrequently.
The clinical diagnosis at presentation was an incomplete or missed abortion in more
than 90 percent of our patients with partial moles.35 Pre-evacuation human chorionic
gonadotropin levels, which were measured in 30 of our patients, exceeded 100,000
mIU per milliliter in only 2 of the patients (6.7 percent).

Diagnosis of Complete and Partial Molar Pregnancy

Ultrasonography is a reliable and sensitive technique for the diagnosis of a complete
mole. Because the chorionic villi exhibit diffuse hydropic swelling, complete moles
produce a characteristic vesicular ultrasonographic pattern. However, current cases of
complete moles are commonly diagnosed in the first trimester, which may be too
early to identify small molar villi or distinguish an early mole from degenerating
chorionic villi by ultrasonographic examination.33,38 Correlating the
ultrasonographic findings with the human chorionic gonadotropin level may aid in
differentiating a complete mole from a missed abortion.39
Ultrasonography may also facilitate the diagnosis of a partial mole by demonstrating
focal cystic spaces in the placenta and an increase in the transverse diameter of the
gestational sac.40 When both these features are present, the positive predictive value
of ultrasonography in diagnosing a partial mole is 90 percent.

Treatment of Molar Pregnancy

After a molar pregnancy has been diagnosed, the patient should be evaluated carefully
for the presence of associated medical complications, including preeclampsia,
hyperthyroidism, electrolyte imbalance, and anemia. After the patient has been
evaluated and her condition stabilized, the most appropriate method of molar
evacuation must be determined.
Suction curettage is the preferred method of evacuation, regardless of the uterine size,
in patients who wish to remain fertile.41 When suction evacuation is thought to be
complete, careful sharp curettage is performed to remove any residual molar tissue.
Because trophoblastic cells express the RhD factor, patients who are RhD-negative
should receive Rh immune globulin at the time of evacuation.
If the patient wants to undergo surgical sterilization, a hysterectomy may be
performed, with preservation of the ovaries, even if prominent theca-lutein cysts are
present. Large ovarian cysts may be decompressed by aspiration. Since hysterectomy
does not prevent metastasis, human chorionic gonadotropin levels must be monitored
after surgery.

Follow-up after a Molar Pregnancy

After molar evacuation, human chorionic gonadotropin levels should be monitored
weekly until they have been undetectable for three consecutive weeks, followed by
monthly monitoring until they have been undetectable for six consecutive months.
The average time to the first undetectable human chorionic gonadotropin level after
evacuation of a complete or partial mole is 9 to 11 weeks.34,42 At the completion of
follow-up, the patient may choose to conceive at any time.
Patients are encouraged to use effective contraception during the entire interval of
follow-up. An intrauterine device should not be inserted until the human chorionic
gonadotropin level is undetectable because of the risk of uterine perforation if an
invasive mole is present. If the patient does not desire surgical sterilization, the choice
is limited to oral or systemic contraceptives or barrier methods.
The incidence of postmolar persistent tumor has been reported to be increased among
patients who use oral contraceptives before gonadotropin levels have returned to
undetectable values.43 Data from both our center and the Gynecologic Oncology
Group, however, indicate that oral contraceptives do not increase the risk of postmolar
trophoblastic disease.44,45 It appears that oral contraceptives may be safely
prescribed during the entire interval of hormonal follow-up after molar evacuation.

Persistent Gestational Trophoblastic Tumors

Persistent gestational trophoblastic tumors have been reported to develop after a
complete molar pregnancy in 18 to 29 percent of patients in the United
States.27,28,46-48 Although complete moles are now being diagnosed earlier in
pregnancy, the incidence of postmolar tumors has not been affected.33,34 Most
centers in the United States diagnose postmolar tumors on the basis of reelevation or
persistent plateau of human chorionic gonadotropin values for at least three

consecutive weeks. However, there is a lack of uniformity in the definition of a

persistent plateau. The diagnostic criteria are less stringent in the United States than in
Europe, partly because of the concern that some patients may be lost to follow-up if
stricter criteria are used.
Several studies have reported that the risk of a postmolar tumor is increased in
patients with signs of marked trophoblastic overgrowth, such as markedly elevated
human chorionic gonadotropin values and excessive uterine enlargement. Patients
with these signs are considered to have high-risk complete moles, because the risk of
persistent tumors in such patients has been reported to be 40 to 57 percent.28,32,49
The risk of a postmolar tumor has also been observed to be increased in older patients
and in those with multiple molar pregnancies. Postmolar tumors have been reported in
33 and 37 percent of patients over 40 years of age50,51 and in 56 percent of patients
over 50 years.52 The risk of a postmolar tumor is three to four times higher in patients
who have had repeated molar pregnancies than in those who have had only one.53,54
The use of prophylactic chemotherapy at the time of evacuation of a complete molar
pregnancy is controversial.55 However, several authors have reported that
chemoprophylaxis reduces the incidence of postmolar tumor.56-58
Kim et al. performed a prospective, randomized trial of prophylactic chemotherapy in
patients with complete molar pregnancies.59 Prophylactic chemotherapy reduced the
incidence of postmolar tumors from 47 percent to 14 percent in patients with high-risk
complete moles. Similarly, we reported that chemoprophylaxis reduced the incidence
of postmolar tumors from 40 percent to 11 percent in patients with high-risk complete
moles.60 Chemoprophylaxis may therefore be considered in patients with high-risk
complete moles, particularly if hormonal testing is unavailable or follow-up is
unreliable.
After a partial molar pregnancy, only about 2 to 4 percent of patients have persistent
tumors.61-64 There are no pathological or clinical features that distinguish such
patients from those with partial moles who do not have persistent tumors.65
After molar evacuation, a persistent gestational trophoblastic tumor may have the
histologic features of either a hydatidiform mole or choriocarcinoma. After a
nonmolar pregnancy, however, a persistent tumor always has the histologic pattern of
choriocarcinoma, which is characterized by sheets of anaplastic cytotrophoblast and
syncytiotrophoblast without chorionic villi (Figure 1A, Figure 1B, and Figure 1C).
When a persistent tumor develops, tissue is often not obtained, and a precise
histopathological diagnosis may therefore not be possible. The diagnosis is usually
based on a rising human chorionic gonadotropin level or a plateau in the level that
persists for more than three weeks, as well as radiologic and clinical findings. A
persistent tumor is generally exquisitely sensitive to chemotherapy, even in the
presence of metastases, and a precise pathological diagnosis infrequently alters the
management of the tumor.

A trophoblastic tumor at the placental site is an uncommon variant of

choriocarcinoma that consists predominantly of intermediate trophoblast.66 Such
tumors tend to remain within the uterus, disseminate late in their course, and produce
low levels of human chorionic gonadotropin relative to their mass.67 In contrast to
other types of gestational trophoblastic tumor, placental-site tumors are relatively
insensitive to chemotherapy.

Nonmetastatic Disease
Locally invasive tumors develop in about 20 percent of patients after a complete
molar pregnancy, in 2 to 4 percent after a partial molar pregnancy, and very
infrequently after any other gestation.27,28,46-48,61-64 Patients with locally invasive
tumors present with a persistent plateau in the human chorionic gonadotropin level or
a reelevation in the level and may have irregular vaginal bleeding, uterine
subinvolution, or theca-lutein ovarian cysts. If the diagnosis is delayed, the
trophoblastic tumor may cause vaginal hemorrhage, intraperitoneal bleeding, or
uterine sepsis.

Metastatic Disease
Metastatic tumors develop in about 4 percent of patients after a complete molar
pregnancy but develop more commonly after a nonmolar pregnancy.1 Metastasis is
often associated with choriocarcinoma, a tumor that disseminates widely.
Trophoblastic tumors are highly vascular and prone to severe hemorrhage either
spontaneously or during biopsy. The most common sites of metastasis are the lungs
(in 80 percent of patients), vagina (30 percent), pelvis (20 percent), liver (10 percent),
and brain (10 percent).32
Patients with pulmonary metastases may have asymptomatic lesions on chest
radiographs or may present with cough, dyspnea, hemoptysis, or signs of pulmonary
hypertension. The early development of respiratory failure requiring intubation is
associated with a poor outcome.68,69
Hepatic or cerebral involvement is encountered almost exclusively in patients who
have had a nonmolar pregnancy with a protracted delay in the diagnosis. Virtually all
patients with hepatic or cerebral metastases have concurrent pulmonary or vaginal
involvement, or both, and their tumors have the histopathological features of
choriocarcinoma.
Some patients with extensive pulmonary and other systemic involvement have
minimal gynecologic symptoms or none. The diagnosis of gestational trophoblastic
tumor should therefore be considered in any woman of reproductive age who has
unexplained systemic symptoms.

Anatomical Staging and Prognostic Scoring Systems

An anatomical staging system for gestational trophoblastic tumor has been adopted by

the International Federation of Gynecology and Obstetrics (Table 2Table 2

Staging of Gestational Trophoblastic Tumors.). In addition to anatomical staging, it is
useful to consider other variables in selecting appropriate chemotherapy.2 The World
Health Organization has proposed a prognostic scoring system that reliably predicts

the potential for resistance to chemotherapy (Table 3Table 3

Scoring
System for Determining Resistance to Chemotherapy.).70 Currently, however, there is
a lack of uniformity in the use of these staging and scoring systems.
A patient is considered to have a high risk of chemotherapy-resistant disease if the
prognostic score is higher than 7. Although patients with stage I (nonmetastatic)
disease infrequently have a high-risk score, those with stage IV disease (hepatic or
cerebral involvement) invariably have a high-risk score. The distinction between lowand high-risk disease therefore mainly applies to patients with stage II disease
(vaginal metastasis) or stage III disease (lung metastasis). A high-risk score is
generally associated with a large tumor burden (large metastases, multiple metastases,
and high human chorionic gonadotropin levels), a protracted delay in the diagnosis, a
nonmolar antecedent pregnancy, or the failure of prior chemotherapy. Patients with
high-risk scores are more likely to have tumors that are resistant to single-agent
chemotherapy and should therefore be treated initially with combination
chemotherapy.

Diagnostic Evaluation
Patients with persistent tumors should undergo a thorough pretreatment assessment of
the extent of disease. If the pelvic examination and chest radiograph are normal, other
sites of metastasis are uncommon.71,72 Other radiologic tests that may help detect
metastasis include computed tomography (CT) of the head, chest, and abdomen and
pelvis.71 Measurement of human chorionic gonadotropin levels in the cerebrospinal
fluid may be useful in detecting cerebral involvement, since the ratio of plasma values
to cerebrospinal fluid values tends to be less than 60 in the presence of cerebral
metastases.73,74 Pelvic ultrasonography may also detect extensive uterine tumors and
thus help identify patients who may benefit from hysterectomy.75

Management
Stage I Tumor

In stage I disease, the selection of treatment is based on whether the patient wishes to
remain fertile. Hysterectomy with adjuvant single-agent chemotherapy may be
performed in patients who do not wish to remain fertile. Single-agent chemotherapy is
administered perioperatively because of the risk of occult micrometastases. Chest CT
has revealed micrometastases in about 40 percent of patients with presumably
nonmetastatic disease.76 At our center all 29 patients with stage I disease who have
been treated with hysterectomy and adjuvant single-agent chemotherapy have had a
remission with no further therapy. Hysterectomy is also performed in all patients with
stage I placental-site trophoblastic tumors, because these tumors are resistant to
chemotherapy. Because placental-site trophoblastic tumors are rare and difficult to
diagnose on the basis of uterine curettage, curettage specimens should be reviewed by
a pathologist with expertise in trophoblast pathology before a hysterectomy is
performed.
Single-agent chemotherapy is the preferred treatment in patients with stage I disease
who wish to remain fertile. A complete remission was induced in 393 of 424 patients
(92.7 percent) with stage I disease who received single-agent chemotherapy at our
center between 1965 and 1994. The other 31 patients subsequently had a remission
with either combination chemotherapy or surgical intervention (hysterectomy or local
uterine resection).

Stage II or III Tumor

Patients with low- or moderate-risk stage II or III disease may be treated with primary
single-agent chemotherapy. Patients with high-risk stage II or III disease require
primary intensive combination chemotherapy. At our center, a complete remission was
achieved in all 27 patients with stage II tumors and in 130 of 131 patients (99.2
percent) with stage III tumors. Primary single-agent chemotherapy induced a
complete remission in 16 of 19 patients (84.2 percent) with low- or moderate-risk
stage II disease and in 71 of 85 (83.5 percent) with low- or moderate-risk stage III
disease. Similarly, other authors have reported that primary single-agent
chemotherapy induces a complete remission in about 85 to 90 percent of patients with
low- or moderate-risk metastatic disease.77-80
Vaginal metastases may bleed profusely, requiring local packing, wide excision, or
arteriographic embolization of the hypogastric arteries. Thoracotomy may also be
performed to excise a site of resistant tumor. However, fibrotic nodules may persist
indefinitely on chest radiographs, even after a sustained remission has been achieved.
In patients with metastatic disease, hysterectomy may be necessary to control uterine
sepsis or hemorrhage. Hysterectomy may also substantially reduce the tumor burden
and thereby limit the need for chemotherapy.81

Stage IV Tumor
All patients with stage IV disease receive primary intensive combination
chemotherapy, with radiation therapy and surgery used selectively as required. Since
1975, 14 of 18 patients (78 percent) with stage IV disease treated at our center have
had a complete remission. Patients with stage IV disease are most likely to have
rapidly progressive and unresponsive tumors, despite intensive multimodal therapy.
Surgery may be required to treat acute complications, such as hepatic or intracerebral
bleeding. Weed and Hammond reported the use of craniotomy to control bleeding in
six patients, three of whom subsequently had a complete remission.82 Occasionally,
resistant sites of disease are amenable to local resection.
Whole-brain irradiation is generally administered in patients with cerebral metastases.
Brain irradiation may lessen the risk of cerebral hemorrhage, because it may have a
hemostatic effect, as well as a tumoricidal effect.83 However, intensive combination
chemotherapy alone, including high-dose intravenous and intrathecal methotrexate,
induced a complete remission in 13 of 15 patients (87 percent) with cerebral
metastases.84

Follow-up
Follow-up for patients with stage I, II, or III disease consists of weekly human
chorionic gonadotropin measurements until the level has been undetectable for 3
weeks, followed by monthly measurements until the level has been undetectable for
12 months. For patients with stage IV disease, follow-up consists of monthly human
chorionic gonadotropin measurements until the level has been undetectable for 24
months, because such patients are at greater risk for a late relapse. Patients are
encouraged to use effective contraception during the entire follow-up period.

Selection of Chemotherapy
Single-Agent Chemotherapy
Single-agent chemotherapy with either methotrexate or dactinomycin has resulted in
high and similar remission rates among patients with nonmetastatic disease and those
with low- or moderate-risk metastatic disease.85,86 Several regimens of methotrexate
and dactinomycin have been effective, but no study has compared all these
protocols.80,87,88 Moreover, there have been no prospective, randomized studies to
determine the most effective means of administering chemotherapy. Single-agent
chemotherapy may be administered either at a fixed interval or on the basis of the
human chorionic gonadotropin regression curve. At our center, further single-agent
chemotherapy is withheld after the first treatment as long as the human chorionic
gonadotropin level is falling progressively. If the tumor is resistant to the initial
regimen of single-agent chemotherapy, the patient may be switched to an alternative
single-agent regimen.

Combination Chemotherapy
Triple therapy (methotrexate, dactinomycin, and cyclophosphamide or chlorambucil)
was the preferred combination chemotherapy in the past. However, triple therapy
induces a remission in only about half the patients with high-risk metastatic
disease.77-79,89-91
Treatment with etoposide was demonstrated to be highly effective in the 1980s.
Etoposide used as primary therapy induced a complete remission in 56 of 60 patients
(93 percent) with nonmetastatic or low-risk metastatic tumors.92 A new combination
regimen was subsequently developed that included etoposide, methotrexate,
dactinomycin, cyclophosphamide, and vincristine. This combination is currently the
preferred treatment in patients with high-risk metastatic tumors. Treatment with
etoposide, methotrexate, dactinomycin, cyclophosphamide, and vincristine has
induced remission in 70 to 75 percent of patients with high-risk metastatic disease.9396
If the tumor is resistant to etoposide, methotrexate, dactinomycin, cyclophosphamide,
and vincristine, cisplatin and etoposide may be substituted for cyclophosphamide and
vincristine on day 8 of the regimen. This modified regimen, either alone or in
conjunction with surgery, induced a remission in 74 percent of patients who had
tumors that were resistant to etoposide, methotrexate, dactinomycin,
cyclophosphamide, and vincristine.94
Second-line therapy with cisplatin, vinblastine, and bleomycin may also be effective.
Azab et al. and DuBeshter et al. reported a complete remission with this regimen in
five of eight and four of seven patients, respectively, who had drug-resistant
tumors.97,98
Patients who require combination chemotherapy must be treated intensively to induce
a remission. When possible, patients with high-risk metastatic disease should be
referred to a regional center with specialized expertise and experience in the treatment
of trophoblastic disease. Because gestational trophoblastic tumors are rare, it is
difficult for clinicians outside regional referral centers to acquire extensive experience
in the treatment of these tumors. Combination chemotherapy is administered as
frequently as the toxic effects permit, until the patient has undetectable human
chorionic gonadotropin values. Once the human chorionic gonadotropin level is
undetectable, additional chemotherapy must be administered to reduce the risk of a
relapse. In the past, gestational trophoblastic tumors were often fatal, but with modern
chemotherapy, this disease is now curable in most cases.

Subsequent Pregnancies
A woman who has had a complete or partial molar pregnancy can anticipate a normal
reproductive outcome of subsequent conceptions.54 However, about 1 percent of
subsequent conceptions result in molar gestation. Similarly, a woman with a persistent
tumor who has had a remission with chemotherapy should be reassured that the
probability of a subsequent normal pregnancy is about the same as that for the average
American woman.54 There is no increase in the risk of a spontaneous abortion,
congenital anomalies, or the need for a cesarean section.

Secondary Tumors
Contrary to their previous report, investigators in England recently reported an
increased risk of secondary cancers, including leukemia, colon cancer, melanoma, and
breast cancer, in patients treated with chemotherapy for gestational trophoblastic
tumors.99,100 The authors attributed the increased risk of secondary tumors to the
inclusion of etoposide in the chemotherapeutic regimen. The increased incidence of
colon cancer, melanoma, and breast cancer did not become apparent until more than
5, 10, and 25 years after treatment, respectively.

Source Information
From the New England Trophoblastic Disease Center, Division of Gynecologic
Oncology, Brigham and Women's Hospital and DanaFarber Cancer Institute, and the
Department of Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical
School all in Boston.
Address reprint requests to Dr. Berkowitz at the Division of Gynecologic Oncology,
Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115.