Gestational Trophoblastic Neoplasia

David Stanford, M.D.

1
I. Spectrum of Gestational Trophoblastic Pathology One of the great success in oncology has been in the treatment of
trophoblastic diseases. Trophoblastic diseases are a spectrum of
A. Gestational trophoblastic disease (GTD): “benign”
disease going from GTD, which includes transitional mole, partial
trophoblastic disease mole/incomplete mole, and the hydatidiform mole. The malignant
1. Transitional mole form of trophoblast disease GTN which is hydatidiform mole is in
both groups because you cannot determine whether this going to
2. Incomplete mole/partial mole have a benign course or whether this will follow a malignant course.
3. Hydatidiform mole You have an embryo and membranes are present, and you also have
minimal trophoblastic proliferation. There is no cistern formation
B. Gestational trophoblastic neoplasia (GTN): "malignant" on the villa. The villi are only slightly enlarged. Genetically these
trophoblastic disease re abnormal pregnancies. The partial mole or the incomplete mole
usually there is identifiable fetus or amniotic membranes. Mole or
1. Hydatidiform mole degeneration of the placenta. The villi are enlarged but only
2. Invasive mole moderately. Occasionally you will find cistern formation in the
villi. You’ll have trophoblastic proliferation but without atypia.
3. Placental site rumor This becomes the problem because it is extremely difficult for the
4. (Trophoblastic pseudotumor) pathologist, especially in a less than a center, trying to determine
whether or not that trophoblast is atypical or whether or not it is just
5. Choriocarcinoma proliferate. It is a difficult call. That has been made easier recently
II. Definitions by either using Chromosome analysis if you can get the tissue to
grow, or just doing special chemistry staining. A partial mole with
A. Blighted ovum: transitional mole
stain weekly for hCG but it will have a large amount of pick up of
1. Embryo or membranes present placental alkaline phosphatase, so just doing the stains allows you
tell whether or not it is a partial mole.
2. Minimal trophoblastic proliferation
3. No cistern formation The complete mole has absence of cord, membrane, or embryo.
4. Villi only slightly enlarged Marked trophoblastic proliferation with atypia. All the villi are
enlarged with cisterns. It has a strongly positive hCG. If you were
5. Genetically abnormal to do the chromosome analysis, this was unusual because in the
F. Placental site trophoblastic tumor (trophoblastic pseudotumor) complete mole all of the chromosomes are all of the paternal origin.
There are no maternal chromosomes present in a complete mole.
1. An indolent neoplasm composed of the intermediate Apparently the maternal chromosomes are stopped past from the
trophoblast egg at the second mitotic division. The egg is then empty and
fertilized by either one or two sperm. This accounts for all of the
2. Usually confined to the uterus chromosomes being from the father. The majority of 46 xx 89%.
3. Does not have biphasic pattern of CT and ST 10% are 46xy clearly indicating you have to have two sperm
fertilizing that egg 1% of 45 single x. Invasive mole can be a
4. Chorionic villi are absent sequella of either a partial or complete mole. Diagnosis is made
III. Epidemiology looking at mole or villi invading the myometrium on hysterectomy
specimen. True choriocarcinoma was a chorioepithelioadenoma.
A. Theories of pathogenesis Chorionic villi are not present, and this is usually associated with
1. Failure of development of fetal circulation with resultant hemorrhage and necrosis. Finally there is the placental site tumor
or what used to be called trophoblastic tumor. This is a malignancy
hydropic swelling of villi
of the intermediate trophoblast. It is confined to the uterus. It
2. Overgrowth of the villous trophoblast with secondary doesn’t have the biphasic pattern, and chorionic villi are absent in
this particular disease process. The epidemiology of trophoblastic
hydropic swelling
disease is very interesting. There is a huge variation worldwide.
B. Age The highest incidences are in the Third World countries, and they
1. There is an increased risk of complete hydatidiform mole are any numbers of different theories of protein, malnutrition, and
inter-marriage in isolated communities. In any event, it is much
at both ends of the more common in Asia, Africa, and Latin America compared to there
reproductive age spectrum, ie, teenagers and women industrialized Western countries. The incidences in hydatidiform
mole in the United States between 1 and 800 to 1 and 1,000
over 40 years of age pregnancies compared to Asia, which is 1 and 500. This number
2. Malignant sequelae after complete hydatidiform mole actually decreased slightly, and this had to do with 1970’s and
1980’s of the increasing numbers of teenagers becoming pregnant
occur more frequently in women over 40 years of age because trophoblastic disease is more prevalent at both ends of the
3. Maternal age appears to have no effect on the risk of reproductive spectrum. This is a disease you see more commonly
in the teenager or in the woman after the age of 40.
complete hydatidiform mole or partial mole
4. Paternal age does not appear to have an effect on the There is no question that age of the mother has a major impact on
trophoblastic disease. The age of the father of the pregnancy does
risk of complete hydatidiform mole or partial mole not appear to have any effect at all on either complete mole risk or
C. Geographic incidence of GTN partial mole risk. The English Cross Hospital have done an
extensive amount of work on trophoblastic disease, and you can find
1. Wide variation throughout the world
any number of research papers looking at blood groups and HLA

2
 2. Highest incidence antigen patterns in trying to predict outcomes of trophoblastic
neoplasia. You can prove whatever you want from this research.
a. Asia
The bottom line is there are multiple studies, and you can pick
b. Africa which studies you want to prove whatever points you want. There
c. Latin America is no conclusive result of all of this research as to whether HLA
antigens or blood group antigens allow you to project the success in
3. Lowest incidence treating our patients. There does appear to be some benefit in
a. North America looking at the antecedent pregnancy. There is a higher risk of
trophoblastic disease if the mother has a history of multiple
b. Europe spontaneous AB’s. There also appears to be a relative protective
c. Australia effect with a past history of successful live and term pregnancies.
There are two theories of pathogenesis of complete moles, and this
4. Incidence of hydatidiform mole in the United States is is argued in the pathology literature. It is still argued. The
between one in 800 to one in 1,000 pregnancies, com- markedly large dilated villi and the proliferation of trophoblast
around the sides of the villi, which is a standard typical
pared to Asia, which has an incidence of one in 500 hydatidiform mole. That is contra-distinction to choriocarcinoma.
5. Choriocarcinoma has an incidence in the United States of That is the biphasic pattern that you have to see in choriocarcinoma.
one in 20,000 to one in 40,000 pregnancies. Estimated
Asian, African, and Latin American incidence of 1/500 to There are three types of trophoblasts. They all have different
staining patterns and that helps us to make the diagnosis.
1/1,000
syncytiotrophoblast is a very small cell. It has significant mitotic
D. Antecedent pregnancy activity. You can electron microscopy, and it does look different.
Cells don’t stain for hCG or HPO. Intermediate cells you begin to
1. There appears to be a higher risk of GTD with a previous
see HPL and a little hCG, and that is the easiest way to tell the
history of multiple spontaneous abortions difference between the two cells because when you start looking at
2. There appears to be a relative protective effect for a past size it is very difficult. Syncytiotrophoblast is much easier to
diagnose because this is a larger cell. It is usually multi-nucleated.
history of live births and term pregnancies As Dr. Hammond noted many years ago in patients with
E. Blood groups and human leukocyte antigen (HLA) patterns hydatidiform mole the probability of malignancy probably is
increased with trophoblastic proliferation and anaplasia; however,
1. There have been several reports of increased risks of no choriocarcinoma has developed from hydatidiform mole, which
GTN in blood group A women, especially those whose appear to be entirely benign. The pathologist really can’t give you
a handle on what the clinical cause of this disease is going to be
husbands are blood group O, or blood group O women with hydatidiform mole. He will not be able to tell you whether you
whose husbands are blood group A can follow patient routinely and without doing surveillance. The
best thing is to just to follow all the moles with a surveillance
2. Although patients who have had blood group B or AB regimen.
appear less likely to have GTD, when they do develop
Partial mole usually 25-40% of all trophoblastic disease. Usually
GTN, they appear to have a worse prognosis this is diagnosed between the 9th and 34th week of pregnancy.
3. The children from gestations associated with a Preeclampsia usually appears late in partial moles. HCG levels are
low to normal. The easiest way to diagnose a partial mole is on the
choriocarcinoma do not appear to have a pattern of blood
basis of the immunohistochemistry because these moles have only
group distribution a small hCG and a very large pick up of placental alkaline
phosphatase. Partial moles have a very low malignancy and usually
4. It should be noted that there are multiple studies which
have a prompto fracture in a hCG titer. This becomes important
demonstrate no consistent patterns of risk for develop- because if you are dealing with a woman in her late 30’s or 40’s
ment of GTD or GTN in ABO blood group antigens and who is very much interested in trying to get pregnant as quickly as
possible. It is important to know that you don’t have to really go the
HLA antigens full route of surveillance. It does make a difference in this particu-
IV. Cytogenetics lar group to have it stained to make sure that you have partial mole
or get the chromosomes done if you have that capacity.
A. The partial mole karyotype is most frequently a triploidy (69
chromosomes) with a demonstrable maternal chromosome Complete mole is much different and again the easiest way to
follow this if you need to make a diagnosis between partial and
complement complete, there is a significantly different immunohistologic
1. The chromosome content for the triploidy is usually XXY chemistry. The standard pathology laboratory can order the kit in
and can do the standing, but the kits are expensive. The pathologist
in 70% of the cases, XXX in 27%, and XYY in 3% will be resistant to order it and do the staining. It is just easier to
2. There are rare cases of a partial mole being associated send the blocks and slides out to one of the centers and have it done
as a consultation.
with a fetus with a 46 XX or a tetraploidy chromosome
pattern Trophoblastic pseudotumor is a pure intermediate trophoblastic
tumor. Here there is different immunohistochemistry. The reason
B. Complete moles have a chromosome complement that is
it is important to diagnose this is because these tumors don’t

3
 entirely of paternal origin respond as well as either invasive mole or choriocarcinoma to
chemotherapy. If you have persistence of the disease then you are
(androgenic)
basically looking at hysterectomy because once the disease
1. 89% of complete moles are 46 XX; both X chromosomes metastasizes outside of the uterus this has a significant mortality
are androgenic rate. In this particular disease the staining is important because you
have to be aggressive because the response to chemotherapy is so
2. 10% are 46 XY with the X chromosome also being of poor.
androgenic origin
There are significant differences between hydatidiform moles,
3. Less than 1% are 45 X with the chromosomes being of invasive moles, and choriocarcinoma in terms of overall morbidity
androgenic origin and mortality. Even with choriocarcinoma it is unique because
aggressive chemotherapy we did have spontaneous remission for
V. Morphology of the Trophoblast this so that tells you that you are dealing with a tumor which is a
A. Three distinct types of trophoblastic cells little bit different than the standard solid tumor. You have a better
chance of having some type of immunologic response from the
1. CT, ST, and intermediate trophoblast (IT) mother and that probably accounts for the spontaneous remissions
2. Surrounding the villous are primarily CTs and STs with that were well documented prior to aggressive chemotherapy.
small amounts of ITs The diagnosis of trophoblastic disease has been completely changed
3. The extravillous trophoblastic tissue in the decidua by the ability of OBGYN’s to do ultrasounds in the office. The
ability to do an ultrasound has really changed this around totally.
myometrium and spiral arteries of the uterus is primarily
It is rare that we see the 18 to 20 week size uterus pull a mole or
ITs with a very minor component of CT and ST tissue presenting on aberrant delivery. Most of the time these are
picked usually in the 8th or 10th week. It is a completely different
4. The CT (the Langhan's cell) is the primordial
scenario because of the availability of ultrasound. The MRI and the
trophoblastic cell. The IT is an intermediate cell, whereas CT are basically part of staging. There is really no reason to do this
the ST is the most differentiated of the trophoblastic cells as part of the initial work-up. Primarily history and physical, serum
hCG, and pelvic ultrasound should be done if you have any
B. CTs suspicion of late stage disease or invasion. Chest x-ray, CBC, liver
1. A primordial epithelial cell which is uniform and polygonal function, renal function, and thyroid dysfunction tests should be
done. We always get thyroid function tests because of the risk of
to oval in shape thyroid storm when you diagnose a molar pregnancy. The problem
2. Single nucleus with this is in most laboratories it takes several days to get thyroid
function tests back. That is very typical of Hopkins. It takes three
3. Clear-to-granular cytoplasm days to get thyroid tests back. What you do is look at the resting
4. Well defined cell borders pulse. If the patient has a pulse under 100 at rest and with a normal
hematocrit she is not going to be at risk for thyroid storm. On the
5. Significant mitotic activity other hand, if the patients has a resting pulse over 100 when you go
6. On electron microscopy (EM), electron-lucent cytoplasm to do the DNC on that patient you want to make sure that the
anesthesiologist is present, and he has the appropriate bets-blockers
is noted with free cytoplasmic ribosomes and aggregates to handle a thyroid storm. Because that patient with an elevated
of particulate glycogen. Cytoplasmic filaments are not pulse is the patient that will go into thyroid storm. I have only seen
one thyroid storm that occurred back in 1977 when Georgina Jones
present
was doing a DNC to terminate a molar pregnancy. Everything went
7. On immunohistochemistry, CTs do not stain for hCG or wrong. We were dealing with an anesthesia resident. The attend-
ing was in a different room. They have no Papanicolaou on the
human placental lactogen (HPL)
floor. The nurse her had the keys for the medicine cabinet at lunch.
C. ITs Fortunately the patient survived it was a major hassle. The resting
1. Generally mononucleate pulse is the critical thing here. Persistent recurrent disease is where
you do the imaging studies because you need to know where the
2. Vary in shape from round- to spindle-shaped disease is because that can modify your treatment significantly.
3. Abundant cytoplasm, staining eosinophilic-to-amphophilic Clinical factors that allow you to predict whether or not you are
going to have malignancy or molar pregnancy. Usually it is the fetal
4. Small vacuoles may be present in the cytoplasm cysts in the uterus have the greatest prediction of malignancy
5. The nuclei may be irregular and hyperchromatic with combined with delayed post evacuation hemorrhage.

coarse chromatin The classification we use in this country for trophoblast disease is
6. Nuclei are smaller and less prominent a classification that was developed at Duke back in the 1970’s. It
is a very simple classification. It divides non-metastatic disease and
7. The cell is larger than the CT metastatic disease. The board usually has a trick question of where
8. On EM, the cytoplasm is denser with more organelles they will try top put these prognostic factors into the non-metastatic
group. you have to realize that the prognostic factors only apply to
that the CT cytoplasm, but is not as complex as the ST metastatic disease category. They don’t apply to non-metastatic
cytoplasm disease. The prognostic factor is duration of disease, pretreatment,
metastasis, site of metastases, and history of previous chemother-
9. The cells contain HPL and very little, if any, hCG
apy. There is also a concern as to where do you put the antecedent

4
 D. STs pregnancy. If the antecedent pregnancy is a term pregnancy that has
occurred that would probably put this into the poor prognosis group
1. The cell is a larger size
because the duration of the disease is probably greater than 4
2. Multinucleation is usually present months. You are dealing with a term pregnancy you probably
3. The cytoplasm is extremely dense and eosinophilic would be in this group of poor prognosis. If you are looking at the
urine hCG is less than 100,000. If it is outside of metastasis you
4. Extensive vacuolization of the cytoplasm is present don’t want brain or liver metastases. FIGO for years had a
5. The nucleus usually has coarse, granular chromatin classification, which was only used in Eastern Europe. He then has
modified and now looks art the following risk factors, hCG using
6. The cells are usually multinucleated but with only very the urine greater than 100,000, duration of disease greater than 6
rare mitosis months, noted but not used in the staging, prior chemotherapy,
placental site tumors, and histologic verification is not required.
7. On EM, the cytoplasm is extremely complex with multiple The original FIGO stage of classification was basically an anatomic
organelles and vacuoles staging classification. Stage 1 confines to uterus, stage 2 confined
to the pelvis, stage 3 confined to the lungs with or without genital
8. On immunohistochemistry, STs are positive for hCG and tract involvement, and stage 4 metastatic disease. Then they
for HPL developed this complicated modification using their prognostic
factors. It is the anatomic staging classification now with these
VI. Clinical Features different risk factors. This is a staging classification that is not user
A. Partial mole friendly, but it is pushed by FIGO, and if any of the major journals
in this country require results to be reported in FIGO classification
1. 25%-40% of all GTD
this would be the one that would be used. In this country the two
2. Usually presents between the ninth and thirty-fourth classifications has done very well, and it is user friendly and it
works. Further more, it is really questionable as to how they
weeks of pregnancy
arrived at these risk factors because it is not well documented in the
3. Usually a small-for-date uterus European literature. The six months is valid or using of the urine
4. Frequently present as missed abortions hCG is more valid than using a beta subunit. FIGO being an
international group they want to make sure that the Third World
5. Preeclampsia (when it occurs) usually occurs late in countries where this disease has a major incidence can use these
partial moles staging classifications. The diagnosis is completely different
between a partial mole and a complete mole and again if you go
6. Serum hCG levels are often low to normal for gestational back partial mole function hCG is negative. The patient is basically
age over this disease and can proceed with trying to get pregnant as
quickly as possible. With a complete mole hCG need to be down
7. On immunocytochemistry, partial moles have only a to wards negative and then you need to continue to follow the hCG
minimal staining for hCG and a very large pick up of stain for between 6 to 12 months to make sure that the patient in deed is
in remission.
for PLAP
8. Partial moles have a very low incidence of malignant Management of an hydatidiform mole uterine evacuation used to be
a major problem. There is a technique to evacuating a large 18-20
sequelae and usually prompt regression in hCG titer week size uterus. The evacuation is like a D&E type of evacuation.
B. Complete hydatidiform mole What you need to do is you need to use some type of dilatation on
the cervix. Under controlled circumstances you want to dilate the
1. Account for 60-75 % of all GTDs
cervix before you start Pitocin. You want to put the suction in the
2. Usually presents between the eleventh and twenty-fifth uterine segment. The suction cannula is on and then you start the
Pitocin. You don’t want to start the Pitocin on a closed cervix.
weeks of pregnancy
That is where you have a problem with immobilization of
3. Patients usually have a uterus which is appropriate or trophoblastic tissue into the uterine blood vessels and then to the
large for gestational age (in less than one-third of the lung. It is a very simple procedure. The curettage is a little bit
different on a large uterus. The suction cannula stays in the lower
cases, the uterus is small for gestational age) uterine segment, and you let the uterus collapse to the cannula. You
4. Preeclampsia occurs in approximately 25 % of the don’t vacuum the walls with a suction cannula. This is where you’ll
have a posterior perforation. That happens periodically. It is one of
patients the oncologist’s nightmares when you get called usually by the fetal
5. Complete mole has been associated with signs of maternal fellow because they have attempted to do one of these
things in labor and delivery in the middle of the night, and they
hyperemesis and hyperthyroidism, pulmonary didn’t want to bother anyone. It is not something that you really
embolization of trophoblastic tissue, and massive ovarian want to do, and it can be avoided. If you haven’t done a lot of these
large DNC’s, get someone in who has. It is an easy technique, but
enlargement due to thecal luetin cysts it gets forgotten. This whole idea of vacuuming out the wall isn’t
6. The serum hCG is usually normal or greater than ex- needed. This goes back into the actual history of trophoblastic
disease because when you talk to the older OBGYN’s they will tell
pected for gestational age you need to have two specimens on a DNC for hydatidiform mole.
7. Approximately 25 % will develop malignant sequelae of One was the standard uterine curettage and the second was the deep
curettage. Prior to chemotherapy it made a difference in terms of
GTN
management if you had villi invading into the myometrium. That

5
 8. On immunohistochemistry, the tissue stains very posi- made a difference because that was the patient who is probably is
going to require a hysterectomy to be cured of the disease for
tively for hCG and stain poorly for placental alka-
invasive mole. Now with chemotherapy it doesn’t matter whether
line/phosphatase or not this invasion presents at the time of the DNC. It is what
VII. Diagnosis happens to the titers. That determines whether or not the patients
are going to require chemotherapy. You don’t need that information
A. Signs and symptoms about villi being in the myometrium.
1. Bleeding during pregnancy
Hysterectomy can be used to manage trophoblastic disease,
2. Discordant uterine size for gestational age especially in the older patient. There is no question you’ll reduce
3. Ovarian enlargement the risk of needing chemotherapy by using primary hysterectomy.
If you are going to do prophylactic chemotherapy you should use
4. Preeclampsia during the first trimester VP16, Actinomycin D, or methotrexate with rescue. You should not
5. Severe hyperemesis gravidum use the standard methotrexate regimen because of the risk of liver
failure. It really depends on how the curve was going. If you get
6. Pelvic pain out to 12 weeks you are dealing with a hCG level of 10-12, and if
7. Hyperthyroidism the curve is still going down I will still follow that patient to 14, 16
weeks as long as it is heading down. When you start to get a
8. Respiratory failure plateau I use the bigger subunit twice a week so just so I have more
B. Diagnosis points on the curve. If you start to get a significant plateau what I
would do then at that point is I would get a sonogram of the uterus.
1. Passage of vesicles
2. Serum hCG levels/urine hCG levels
The malignancy is associated with high titers of hCG is erroneous
3. Pelvic ultrasound
and results in unacceptable treatment delay. Again low titers can
4. Pelvic MRI be just as troublesome, and if you get stuck in this what happens is
5. Pelvic CT scan you end up waiting, and the disease then becomes establishes and
then it requires more chemotherapy to get that patient adequately
6. Amniogram treated. Chemotherapy is used for non-metastatic and the good
VIII. Staging prognosis to lower risk metastatic disease. The agents that are used
are actinomycin, methotrexate, and BP16. There are two regimens
A. International Federation of Gynecology and Obstetrics (FIGO) for actinomycin a five-day regimen and a bolus regimen. The bolus
staging is based on a clinical group staging system. This is regimen was developed by the GOG to make it a little bit easier to
treat younger patients because coming in for 5 days really effects
not commonly used in most treatment centers schoolwork and the ability to kind of get back into a normal
lifestyle. The bolus does work very well and has the same success
rate as the five-day regimen. The methotrexate the two regimens
Table 1 that are used are the standard maximum 25 mg IV or IM given
FIGO Clinical Staging of Gestational Trophoblastic Tumors every five days repeated every two to three weeks and the
methotrexate with rescue. The rescue has much less liver toxicity.
Stage I: tumor strictly contained to the uterine corpus It is much better tolerated, but it also has a higher rate of resistant
Stage II: tumor extends to the adnexae, outside the disease. As you would expect because when you are rescuing the
patient cells you are also rescuing the tumor cells. BP 16 is
uterus, but is limited to the genital structures extremely effective for trophoblastic disease 200 mg per meter
Stage III: tumor extends to the lungs with or without square orally give over five days and repeated every two to three
weeks. The problem with this regimen is the cost of the BP 16. BP
genital tract involvement
16 is incredibly expensive. You are looking at 200 mg per meter
Stage IV: tumor metastatic to any other site(s) square you are probably looking at a cost of somewhere between
1600 to 2000 dollars depending on the pharmacy. Unless the
patient has a drug plan this particular is cost prohibited to the
B. Clinical classification of gestational trophoblastic neoplasia, average patient. Single agent therapy is you start with a single
Southeastern Trophoblastic Center (the clinical classification agent. If you have resistance to titers plateau then you change to
another single agent regimen. If you have progression that means
generally used by most treatment centers in the United States you have signs of metastasis to the chest or other place. If you have
progression then you need to change to multi-agent regimen. The
type of multi-agent regimen that you change to really would depend
Table 2 on what has happened. The standard multi-agent regimen used to
Clinical Classification of Gestational Trophoblastic Tumors be the Mack regimen, and this was a combination of methotrexate,
actinomycin, and Cytoxan. If you have already failed with
methotrexate and actinomycin as single agents there is no reason to
I. Nonmetastatic go to the Mack regimen. You would go on to another multi-agent
regimen. The other multi-agent regimens are either a modified
II. Metastatic einhorn regimen or the modified Bagshawe regimen. The bagshawe
A. Low risk regimen is extremely good. It is very high dosed methotrexate
followed by rescue, hydroxyurea, actinomycin, vincristine,
1. hCG <100,000 IU/247 hour urine or <40,000 mIU/mL methotrexate, Cytoxan, and then finishing up with adriamycin and

6
 serum Cytoxan. It is sequential, and it does a very good job and has a
good remission rate. The einhorn type regimen for GTN is a little
2. Symptoms present for <4 months
bit different than the regimen for germ cell tumors. Here the dose
3. No brain or liver metastases of platinum is decreased and the dose of vinblastine is increased.
4. No prior chemotherapy The bleomycin stays the same. For the modifications to the einhorn
regimen people are presently using the BP16 replacing the Vinca
5. Pregnancy event is not term delivery (ie, mole, ectopic, or alkaloids. It has a troublesome side effect of causing the paralytic
spontaneous abortion) ileus. You end up with patients, who sometimes have to go to TPN
because of this ileus problem, so by adding BP 16 you improve the
B. High risk side effects. There is no loss in terms of treatment, but the side
1. hCG >100,000 IU/24-hour urine or >40,000 mlU/mL effects are much better tolerated with this regimen. The most
recent advance in trophoblastic disease treatments is a development
serum of the EMA-CO regimen. This is a salvage regimen for people who
2. Symptoms present for >4 months have failed previous multi-drug regimens. It is treated at different
times with different combinations of drugs. It makes a huge
3. Brain or liver metastases difference, and people who would have otherwise died of the
4. Prior chemotherapeutic failure disease are now routine to salvage with this regimen. It is a very
toxic regimen, and it really needs to be done at a center where they
5. Antecedent term pregnancy have the capacity to do a massive hemologic support and massive
IX. WORK-UP FOR GTN monitoring of the patients. It is very toxic to both white blood cells
and platelets, and you need to be able to respond with platelet
A. Primary
transfusions since the people begin to bottom out with this regimen.
1. History and physical You can resect trophoblastic disease.
2. Serum hCG
When you go to do the resection you have to remember the tropho-
3. Pelvic ultrasound blasts cells initial job in life is to establish the maternal fetal
4. MRI scan/CT scan/amniogram circulation’s of these cells, which tend to invade blood vessels. You
have to be prepared for massive blood loss when you are trying to
5. Chest x-ray surgically resect these tumors. It is very bloody surgery, but if you
6. CBC/left fronto transversion/right fronto can do it, it can significantly improve the patient’s chance of
survival. If you do see a late disease and you have a small bowel
transversion/thyroid function tests metastasis the reason for that is well understood. The mesentery of
B. Persistent/recurrent the small bowel seems to be one of these privileged sites, which
doesn’t get well perfused by chemotherapy. When they see this
1. History and physical type of metastasis intraperitoneal to the small bowel normally this
2. Serum hCG has to be resected. It just doesn’t respond well to chemotherapy.
If you have an isolated area of trophoblastic disease it is
3. Chest x-ray/CT scan radiosensitive. You can treat it with 2-3000 rads and get control.
4. Pelvic ultrasound/CT scan/MRI You can treat liver metastasis with this. You can also treat brain
metastases for 2000 rads for ten days. In main-stage disease if you
5. Abdominal CT scan are dealing with someone who is at high risk for late stage wide
6. Brain scan spread metastasis using prophylactic radiation therapy does make
the difference in terms of survival for that patient. Routinely those
7. Brain CT scan
patients would get 2000 rads over ten days as they begin the
8. Brain MRI scan chemotherapy. You have to do that because if you have a patient
who has a metastasis in the brain as you treat that patient with
X. Management
chemotherapy that patient becomes at risk for an inter-cranial
A. Uterine evacuation hemorrhage, so you really have to treat the brain metastases first or
B. Hysterectomy at the same time as you being the chemotherapy. Otherwise the
patient will die of an inter-cranial bleed. Specific inter-arterial
C. Prophylactic chemotherapy profusion could be used for selected sites. Inter-fetal chemotherapy
1. Not indicated unless the follow-up/surveillance is ex- does make a difference. There is also from the Duke group
excellent results non-metastatic disease and good remission rates
pected to be extremely poor because of patient noncom- with very good relapse rates. Again this is where the EMA-CO
pliance regimen has made a huge difference. In these poor prognostic
patient who have recurred this is where EMA-CO really has turned
2. If prophylactic chemotherapy is to be used, it should the game around, and these patients now are fairly routinely
probably be done preferably with salvaged from their disease.
a. VP-16
b. Actinomycin-D (ACT-D)
c. Methotrexate with rescue
XI. Surveillance
A. Postevacuation of a complete mole

7
 1. Weekly serum hCG titers until remission
2. Remission is defined as three consecutive negative
weekly serum hCG titers
3. Continued surveillance with monthly examination and
serum hCG titers with repeat chest x-ray and blood
chemistries as indicated
4. Contraception for 6-12 months until follow-up is com-
pleted
B. Surveillance postevacuation of a partial mole
1. Weekly serum hCG titers until remission
2. Remission is defined as three consecutive negative
weekly serum hCG titers
3. Monthly follow-up for 13 months with examination and
serum hCG titers
4. Contraception for several months postnegative hCG titers
XII. Treatment
A. Single-agent chemotherapy
1. Utilized for the treatment of nonmetastatic GTN (NMGTN)
and metastatic low-risk GTN (MGTN low-risk)
2. The agents that are utilized are
a. ACT-D
b. Methotrexate (MTX)
c. VP-16
3. MTX
a. Several different regimens have been utilized for
MTX therapy as a single agent
b. MTX 0.4 mg/kg (maximum 25 kg) IV or IM qd for 5
days every 2-3 weeks
c. MTX-folinic acid: MTX 1 mg/kg on days 1, 3, 5, and
7 IM or IV, followed by folinic acid 0.1 mg/kg on days
2, 4, 6, and 8, po or IM, repeated every 2-3 weeks
4. Dactinomycin (ACT-D)
a. Actinomycin given 9-13 gm/kg (maximum .5 mg qd
for 5 days, cycle repeated every 2-3 weeks)
b. Dactinomycin bolus: 1.25 mg/m2 IV every 2 weeks
5. VP-16 (etoposide) 200 mg/m2 po qd every 5 days, cycle
every 2-3 weeks
6. If resistance occurs on one regimen, then change to
another single-agent regimen is required
7. If progression occurs, then a change to a multi-agent
regimen or other type of therapy is required
B. Multiagent chemotherapy (MAC)
1. Utilized for treatment of persistent, recurrent, and meta-
static high-risk GTN
2. In treatment of persistent or recurrent GTN that has

8
 previously been treated with single-agent MTX or ACT-D,
the MAC regimen should not be used. Instead, use
a. Vinblastine, platinum, and bleomycin (VPB)-modified
Bagshawe
b. Etopside, MTX, ACT-D, cyclophosphamide, and
vincristine (EMA-CO) regimens
3. Regimens and therapies
a. MAC; cycle interval 10-15 days
(1) MTX 10-15 mg IV qd for 5 days
(2) ACT-D 0.5 mg IV qd for 5 days
(3) Cytoxan 150-250 mg IV qd for 5 days
b. Modified Bagshawe

Table 5
Day Time Chemotherapy
1 Hydroxyurea 500 mg po qid
ACT-D 0.2 mg IV
2 0700 Vincristine 1 mg/m2
1900 MTX 100 rag/m2 IV push
MTX 200 mg/m2 IV over 12 hours
ACT-D 0.2 mg IV
3 1900 ACT-D 0.2 nag IV
Cytoxan 500 mg/m2 IV
Folinic acid 14 mg IM
4 0100 Folinic acid 14 mg IM
0700 Folinic acid 14 mg IM
1300 Folinic acid 14 mg IM
1900 Folinic acid 14 mg IM
ACT-D 0.5 mg IV
5 0100 Folinic acid 14 mg IM
1900 ACT-D 0.5 mg IV
6 No treatment
7 No treatment
8 Cytoxan 400 mg/m2 IV
Adriamycin 30 mg/m2 IV
c. VPB for GTN
(1) Vinblastine 0.2 mg2/kg IV day 1-2, repeat every 3
weeks
(2) Platinum 20 mg/m2 IV over 15 min day 1-5, repeat
every 3 weeks
(3) Bleomycin 30 IU IV day 2 repeat every week for 12
weeks
d. EMA-CO
(1) Course I: EMA
(a) Day 1

9
 i. Dactinomycin 0.5 mg IV
ii. Etoposide 100 mg IV infusion in 250 mg of
normal saline
iii. MTX 100 mg/m2 IV
iv. MTX 200 mg/m2 IV 12-hour infusion
(b) Day 2
i. Dactinomycin 0.5 mg IV
ii. Etoposide 100 mg/m2 IV infusion in 250
mL of normal saline
iii. Folinic acid 15 mg/m2 IM or orally every 12
hours for 4 doses starting 24 hours after
MTX
(2) Five-day drug-free interval to course II
(3) Course ll: CO (day one)
(a) Vincristine 1.0 mg/m2 IV (maximum 2 mg)
normal saline
(b) Cyclophosphamide 600 mg/m2 IV infusion in
normal saline
(4) Six-day drug-free interval to next course
4. Radiation therapy (RT)
a. GTN is radiosensitive
b. External RT (XRT) utilized for brain metastasis (2,000-
3,000 Rads over 10 days) and liver metastasis (2,000
Rads over 10 days)
c. XRT can be used for isolated metastasis
5. Surgical resection: can be very helpful to control metastatic
complications and to resect areas of chemotherapy-resistant
disease
a. Lumpectomy
b. Thoracotomy
c. Craniotomy
d. Bowel resection
6. Other therapies
a. Interarterial perfusion
b. Intrathecal chemotherapy
XIII. Results
The best results in treatment of GTN are the reported results from the
Southeast
Trophoblastic Center
Table 6
Remission Recurrence
NMGTN 139/139 (100%) 3/139 (2.1%)
MGTN: good prognosis 55/55 (100%) 3/55 (5.4%)
MGTN: poor prognosis 42/63 (66%) 13/63 (21.0%)
236/257 (92%) 19/257 (7.8%)

10
XIV. Placental Site Trophoblastic Tumor
A. Atypical chorioepithelioma/trophoblast pseudotumor
B. Tumor is due to the IT
C. Clinical presentation is usually a missed abortion
D. Serum hCG is positive but titer is low
E. Disease is usually confined to the uterus but may have
significant myometrial invasion or extension to the adnexae,
rarely metastasis to lung, liver, abdominal cavity, or brain
F. Immunocytochemistry of placental site trophoblastic tumor
hCG + but hPL ++++
G. Response to chemotherapy is poor
H. Hysterectomy may be curative if disease is confined to the
uterus

11