Gestational Trophoblastic Neoplasia

Gestational Trophoblastic Neoplasia David Stanford, M.D.

1

I.

Spectrum of Gestational Trophoblastic Pathology A.

Gestational

trophoblastic

disease

(GTD): “benign”

trophoblastic disease

B.

1.

Transitional mole

2.

Incomplete mole/partial mole

3.

Hydatidiform mole

Gestational trophoblastic neoplasia (GTN): "malignant" trophoblastic disease

II.

1.

Hydatidiform mole

2.

Invasive mole

3.

Placental site rumor

4.

(Trophoblastic pseudotumor)

5.

Choriocarcinoma

Definitions A.

F.

Blighted ovum: transitional mole 1.

Embryo or membranes present

2.

Minimal trophoblastic proliferation

3.

No cistern formation

4.

Villi only slightly enlarged

5.

Genetically abnormal

Placental site trophoblastic tumor (trophoblastic pseudotumor) 1.

An indolent neoplasm composed of the intermediate trophoblast

III.

2.

Usually confined to the uterus

3.

Does not have biphasic pattern of CT and ST

4.

Chorionic villi are absent

Epidemiology A.

Theories of pathogenesis 1.

Failure of development of fetal circulation with resultant hydropic swelling of villi

2.

Overgrowth of the villous trophoblast with secondary hydropic swelling

B.

Age 1.

There is an increased risk of complete hydatidiform mole at both ends of the reproductive age spectrum, ie, teenagers and women over 40 years of age

2.

Malignant sequelae after complete hydatidiform mole occur more frequently in women over 40 years of age

3.

Maternal age appears to have no effect on the risk of complete hydatidiform mole or partial mole

4.

Paternal age does not appear to have an effect on the risk of complete hydatidiform mole or partial mole

C. Geographic incidence of GTN 1.

Wide variation throughout the world

One of the great success in oncology has been in the treatment of trophoblastic diseases. Trophoblastic diseases are a spectrum of disease going from GTD, which includes transitional mole, partial mole/incomplete mole, and the hydatidiform mole. The malignant form of trophoblast disease GTN which is hydatidiform mole is in both groups because you cannot determine whether this going to have a benign course or whether this will follow a malignant course. You have an embryo and membranes are present, and you also have minimal trophoblastic proliferation. There is no cistern formation on the villa. The villi are only slightly enlarged. Genetically these re abnormal pregnancies. The partial mole or the incomplete mole usually there is identifiable fetus or amniotic membranes. Mole or degeneration of the placenta. The villi are enlarged but only moderately. Occasionally you will find cistern formation in the villi. You’ll have trophoblastic proliferation but without atypia. This becomes the problem because it is extremely difficult for the 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 proliferate. It is a difficult call. That has been made easier recently by either using Chromosome analysis if you can get the tissue to grow, or just doing special chemistry staining. A partial mole with stain weekly for hCG but it will have a large amount of pick up of placental alkaline phosphatase, so just doing the stains allows you tell whether or not it is a partial mole. The complete mole has absence of cord, membrane, or embryo. Marked trophoblastic proliferation with atypia. All the villi are enlarged with cisterns. It has a strongly positive hCG. If you were to do the chromosome analysis, this was unusual because in the complete mole all of the chromosomes are all of the paternal origin. There are no maternal chromosomes present in a complete mole. Apparently the maternal chromosomes are stopped past from the 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 chromosomes being from the father. The majority of 46 xx 89%. 10% are 46xy clearly indicating you have to have two sperm fertilizing that egg 1% of 45 single x. Invasive mole can be a sequella of either a partial or complete mole. Diagnosis is made looking at mole or villi invading the myometrium on hysterectomy specimen. True choriocarcinoma was a chorioepithelioadenoma. Chorionic villi are not present, and this is usually associated with hemorrhage and necrosis. Finally there is the placental site tumor or what used to be called trophoblastic tumor. This is a malignancy of the intermediate trophoblast. It is confined to the uterus. It doesn’t have the biphasic pattern, and chorionic villi are absent in this particular disease process. The epidemiology of trophoblastic disease is very interesting. There is a huge variation worldwide. The highest incidences are in the Third World countries, and they are any numbers of different theories of protein, malnutrition, and inter-marriage in isolated communities. In any event, it is much more common in Asia, Africa, and Latin America compared to there industrialized Western countries. The incidences in hydatidiform mole in the United States between 1 and 800 to 1 and 1,000 pregnancies compared to Asia, which is 1 and 500. This number actually decreased slightly, and this had to do with 1970’s and 1980’s of the increasing numbers of teenagers becoming pregnant because trophoblastic disease is more prevalent at both ends of the reproductive spectrum. This is a disease you see more commonly in the teenager or in the woman after the age of 40. 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 not appear to have any effect at all on either complete mole risk or partial mole risk. The English Cross Hospital have done an extensive amount of work on trophoblastic disease, and you can find any number of research papers looking at blood groups and HLA

2

2.

3.

4.

Highest incidence a.

Asia

b.

Africa

c.

Latin America

Lowest incidence a.

North America

b.

Europe

c.

Australia

Incidence of hydatidiform mole in the United States is between one in 800 to one in 1,000 pregnancies, compared to Asia, which has an incidence of one in 500

5.

Choriocarcinoma has an incidence in the United States of

antigen patterns in trying to predict outcomes of trophoblastic neoplasia. You can prove whatever you want from this research. The bottom line is there are multiple studies, and you can pick which studies you want to prove whatever points you want. There 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 treating our patients. There does appear to be some benefit in looking at the antecedent pregnancy. There is a higher risk of trophoblastic disease if the mother has a history of multiple spontaneous AB’s. There also appears to be a relative protective effect with a past history of successful live and term pregnancies. There are two theories of pathogenesis of complete moles, and this is argued in the pathology literature. It is still argued. The markedly large dilated villi and the proliferation of trophoblast around the sides of the villi, which is a standard typical hydatidiform mole. That is contra-distinction to choriocarcinoma. 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 1/1,000 D. Antecedent pregnancy 1.

There appears to be a higher risk of GTD with a previous history of multiple spontaneous abortions

2.

There appears to be a relative protective effect for a past history of live births and term pregnancies

E.

Blood groups and human leukocyte antigen (HLA) patterns 1.

There have been several reports of increased risks of GTN in blood group A women, especially those whose husbands are blood group O, or blood group O women whose husbands are blood group A

2.

Although patients who have had blood group B or AB

There are three types of trophoblasts. They all have different staining patterns and that helps us to make the diagnosis. syncytiotrophoblast is a very small cell. It has significant mitotic activity. You can electron microscopy, and it does look different. Cells don’t stain for hCG or HPO. Intermediate cells you begin to see HPL and a little hCG, and that is the easiest way to tell the difference between the two cells because when you start looking at size it is very difficult. Syncytiotrophoblast is much easier to diagnose because this is a larger cell. It is usually multi-nucleated. As Dr. Hammond noted many years ago in patients with hydatidiform mole the probability of malignancy probably is increased with trophoblastic proliferation and anaplasia; however, no choriocarcinoma has developed from hydatidiform mole, which 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 with hydatidiform mole. He will not be able to tell you whether you can follow patient routinely and without doing surveillance. The best thing is to just to follow all the moles with a surveillance regimen.

appear less likely to have GTD, when they do develop GTN, they appear to have a worse prognosis 3.

The children from gestations associated with a choriocarcinoma do not appear to have a pattern of blood group distribution

4.

It should be noted that there are multiple studies which demonstrate no consistent patterns of risk for development of GTD or GTN in ABO blood group antigens and HLA antigens

IV. Cytogenetics A.

The partial mole karyotype is most frequently a triploidy (69 chromosomes) with a demonstrable maternal chromosome complement 1.

The chromosome content for the triploidy is usually XXY in 70% of the cases, XXX in 27%, and XYY in 3%

2.

There are rare cases of a partial mole being associated with a fetus with a 46 XX or a tetraploidy chromosome pattern

B.

Complete moles have a chromosome complement that is

Partial mole usually 25-40% of all trophoblastic disease. Usually this is diagnosed between the 9th and 34th week of pregnancy. Preeclampsia usually appears late in partial moles. HCG levels are low to normal. The easiest way to diagnose a partial mole is on the basis of the immunohistochemistry because these moles have only a small hCG and a very large pick up of placental alkaline phosphatase. Partial moles have a very low malignancy and usually have a prompto fracture in a hCG titer. This becomes important because if you are dealing with a woman in her late 30’s or 40’s 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 full route of surveillance. It does make a difference in this particular group to have it stained to make sure that you have partial mole or get the chromosomes done if you have that capacity. Complete mole is much different and again the easiest way to follow this if you need to make a diagnosis between partial and complete, there is a significantly different immunohistologic chemistry. The standard pathology laboratory can order the kit in and can do the standing, but the kits are expensive. The pathologist will be resistant to order it and do the staining. It is just easier to send the blocks and slides out to one of the centers and have it done as a consultation. Trophoblastic pseudotumor is a pure intermediate trophoblastic tumor. Here there is different immunohistochemistry. The reason it is important to diagnose this is because these tumors don’t

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entirely of paternal origin (androgenic) 1.

89% of complete moles are 46 XX; both X chromosomes are androgenic

2.

10% are 46 XY with the X chromosome also being of androgenic origin

3.

Less than 1% are 45 X with the chromosomes being of androgenic origin

V.

Morphology of the Trophoblast A.

Three distinct types of trophoblastic cells 1.

CT, ST, and intermediate trophoblast (IT)

2.

Surrounding the villous are primarily CTs and STs with small amounts of ITs

3.

The extravillous trophoblastic tissue in the decidua myometrium and spiral arteries of the uterus is primarily ITs with a very minor component of CT and ST

4.

The CT

(the

Langhan's

cell)

is

the

primordial

trophoblastic cell. The IT is an intermediate cell, whereas the ST is the most differentiated of the trophoblastic cells B.

CTs 1.

A primordial epithelial cell which is uniform and polygonal to oval in shape

2.

Single nucleus

3.

Clear-to-granular cytoplasm

4.

Well defined cell borders

5.

Significant mitotic activity

6.

On electron microscopy (EM), electron-lucent cytoplasm is noted with free cytoplasmic ribosomes and aggregates of particulate glycogen. Cytoplasmic filaments are not present

7.

On immunohistochemistry, CTs do not stain for hCG or human placental lactogen (HPL)

C. ITs 1.

Generally mononucleate

2.

Vary in shape from round- to spindle-shaped

3.

Abundant cytoplasm, staining eosinophilic-to-amphophilic

4.

Small vacuoles may be present in the cytoplasm

5.

The nuclei may be irregular and hyperchromatic with coarse chromatin

6.

Nuclei are smaller and less prominent

7.

The cell is larger than the CT

8.

On EM, the cytoplasm is denser with more organelles that the CT cytoplasm, but is not as complex as the ST cytoplasm

9.

The cells contain HPL and very little, if any, hCG

respond as well as either invasive mole or choriocarcinoma to chemotherapy. If you have persistence of the disease then you are basically looking at hysterectomy because once the disease metastasizes outside of the uterus this has a significant mortality rate. In this particular disease the staining is important because you have to be aggressive because the response to chemotherapy is so poor. There are significant differences between hydatidiform moles, invasive moles, and choriocarcinoma in terms of overall morbidity and mortality. Even with choriocarcinoma it is unique because aggressive chemotherapy we did have spontaneous remission for this so that tells you that you are dealing with a tumor which is a little bit different than the standard solid tumor. You have a better chance of having some type of immunologic response from the mother and that probably accounts for the spontaneous remissions that were well documented prior to aggressive chemotherapy. The diagnosis of trophoblastic disease has been completely changed by the ability of OBGYN’s to do ultrasounds in the office. The ability to do an ultrasound has really changed this around totally. It is rare that we see the 18 to 20 week size uterus pull a mole or tissue presenting on aberrant delivery. Most of the time these are picked usually in the 8th or 10th week. It is a completely different scenario because of the availability of ultrasound. The MRI and the CT are basically part of staging. There is really no reason to do this as part of the initial work-up. Primarily history and physical, serum hCG, and pelvic ultrasound should be done if you have any suspicion of late stage disease or invasion. Chest x-ray, CBC, liver function, renal function, and thyroid dysfunction tests should be done. We always get thyroid function tests because of the risk of thyroid storm when you diagnose a molar pregnancy. The problem 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 days to get thyroid tests back. What you do is look at the resting 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 other hand, if the patients has a resting pulse over 100 when you go to do the DNC on that patient you want to make sure that the anesthesiologist is present, and he has the appropriate bets-blockers to handle a thyroid storm. Because that patient with an elevated 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 was doing a DNC to terminate a molar pregnancy. Everything went wrong. We were dealing with an anesthesia resident. The attending was in a different room. They have no Papanicolaou on the floor. The nurse her had the keys for the medicine cabinet at lunch. Fortunately the patient survived it was a major hassle. The resting pulse is the critical thing here. Persistent recurrent disease is where you do the imaging studies because you need to know where the disease is because that can modify your treatment significantly. Clinical factors that allow you to predict whether or not you are going to have malignancy or molar pregnancy. Usually it is the fetal cysts in the uterus have the greatest prediction of malignancy combined with delayed post evacuation hemorrhage. The classification we use in this country for trophoblast disease is a classification that was developed at Duke back in the 1970’s. It is a very simple classification. It divides non-metastatic disease and metastatic disease. The board usually has a trick question of where they will try top put these prognostic factors into the non-metastatic group. you have to realize that the prognostic factors only apply to metastatic disease category. They don’t apply to non-metastatic disease. The prognostic factor is duration of disease, pretreatment, metastasis, site of metastases, and history of previous chemotherapy. There is also a concern as to where do you put the antecedent

4

D. STs 1.

The cell is a larger size

2.

Multinucleation is usually present

3.

The cytoplasm is extremely dense and eosinophilic

4.

Extensive vacuolization of the cytoplasm is present

5.

The nucleus usually has coarse, granular chromatin

6.

The cells are usually multinucleated but with only very rare mitosis

7.

On EM, the cytoplasm is extremely complex with multiple organelles and vacuoles

8.

On immunohistochemistry, STs are positive for hCG and for HPL

VI.

Clinical Features A.

Partial mole 1.

25%-40% of all GTD

2.

Usually presents between the ninth and thirty-fourth weeks of pregnancy

3.

Usually a small-for-date uterus

4.

Frequently present as missed abortions

5.

Preeclampsia (when it occurs) usually occurs late in partial moles

6.

Serum hCG levels are often low to normal for gestational age

7.

On immunocytochemistry, partial moles have only a minimal staining for hCG and a very large pick up of stain for PLAP

8.

Partial moles have a very low incidence of malignant sequelae and usually prompt regression in hCG titer

B.

Complete hydatidiform mole 1.

Account for 60-75 % of all GTDs

2.

Usually presents between the eleventh and twenty-fifth weeks of pregnancy

3.

Patients usually have a uterus which is appropriate or large for gestational age (in less than one-third of the cases, the uterus is small for gestational age)

4.

Preeclampsia occurs in approximately 25 % of the patients

5.

Complete mole has been associated with signs of hyperemesis

and

hyperthyroidism,

pulmonary

embolization of trophoblastic tissue, and massive ovarian enlargement due to thecal luetin cysts 6.

The serum hCG is usually normal or greater than expected for gestational age

7.

Approximately 25 % will develop malignant sequelae of GTN

pregnancy. If the antecedent pregnancy is a term pregnancy that has occurred that would probably put this into the poor prognosis group because the duration of the disease is probably greater than 4 months. You are dealing with a term pregnancy you probably 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 don’t want brain or liver metastases. FIGO for years had a classification, which was only used in Eastern Europe. He then has modified and now looks art the following risk factors, hCG using the urine greater than 100,000, duration of disease greater than 6 months, noted but not used in the staging, prior chemotherapy, placental site tumors, and histologic verification is not required. The original FIGO stage of classification was basically an anatomic staging classification. Stage 1 confines to uterus, stage 2 confined to the pelvis, stage 3 confined to the lungs with or without genital tract involvement, and stage 4 metastatic disease. Then they developed this complicated modification using their prognostic factors. It is the anatomic staging classification now with these different risk factors. This is a staging classification that is not user 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 this would be the one that would be used. In this country the two classifications has done very well, and it is user friendly and it works. Further more, it is really questionable as to how they arrived at these risk factors because it is not well documented in the European literature. The six months is valid or using of the urine hCG is more valid than using a beta subunit. FIGO being an international group they want to make sure that the Third World countries where this disease has a major incidence can use these staging classifications. The diagnosis is completely different between a partial mole and a complete mole and again if you go back partial mole function hCG is negative. The patient is basically over this disease and can proceed with trying to get pregnant as quickly as possible. With a complete mole hCG need to be down to wards negative and then you need to continue to follow the hCG for between 6 to 12 months to make sure that the patient in deed is in remission. Management of an hydatidiform mole uterine evacuation used to be a major problem. There is a technique to evacuating a large 18-20 week size uterus. The evacuation is like a D&E type of evacuation. 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 cervix before you start Pitocin. You want to put the suction in the 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. That is where you have a problem with immobilization of trophoblastic tissue into the uterine blood vessels and then to 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 uterine segment, and you let the uterus collapse to the cannula. You 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 the oncologist’s nightmares when you get called usually by the fetal maternal fellow because they have attempted to do one of these things in labor and delivery in the middle of the night, and they didn’t want to bother anyone. It is not something that you really 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 it gets forgotten. This whole idea of vacuuming out the wall isn’t needed. This goes back into the actual history of trophoblastic disease because when you talk to the older OBGYN’s they will tell you need to have two specimens on a DNC for hydatidiform mole. One was the standard uterine curettage and the second was the deep curettage. Prior to chemotherapy it made a difference in terms of management if you had villi invading into the myometrium. That

5

8.

On immunohistochemistry, the tissue stains very positively for hCG and stain poorly for placental alkaline/phosphatase

VII. Diagnosis A.

B.

Signs and symptoms 1.

Bleeding during pregnancy

2.

Discordant uterine size for gestational age

3.

Ovarian enlargement

4.

Preeclampsia during the first trimester

5.

Severe hyperemesis gravidum

6.

Pelvic pain

7.

Hyperthyroidism

8.

Respiratory failure

Diagnosis 1.

Passage of vesicles

2.

Serum hCG levels/urine hCG levels

3.

Pelvic ultrasound

4.

Pelvic MRI

5.

Pelvic CT scan

6.

Amniogram

VIII. Staging A.

International Federation of Gynecology and Obstetrics (FIGO) staging is based on a clinical group staging system. This is not commonly used in most treatment centers

Table 1 FIGO Clinical Staging of Gestational Trophoblastic Tumors Stage I: tumor strictly contained to the uterine corpus Stage II:

tumor extends to the adnexae, outside the uterus, but is limited to the genital structures

Stage III:

tumor extends to the lungs with or without genital tract involvement

Stage IV:

B.

tumor metastatic to any other site(s)

Clinical classification of gestational trophoblastic neoplasia, Southeastern Trophoblastic Center (the clinical classification generally used by most treatment centers in the United States

Table 2 Clinical Classification of Gestational Trophoblastic Tumors

I.

Nonmetastatic

II.

Metastatic A. Low risk 1.

hCG <100,000 IU/247 hour urine or <40,000 mIU/mL

made a difference because that was the patient who is probably is going to require a hysterectomy to be cured of the disease for invasive mole. Now with chemotherapy it doesn’t matter whether or not this invasion presents at the time of the DNC. It is what happens to the titers. That determines whether or not the patients are going to require chemotherapy. You don’t need that information about villi being in the myometrium. Hysterectomy can be used to manage trophoblastic disease, especially in the older patient. There is no question you’ll reduce the risk of needing chemotherapy by using primary hysterectomy. If you are going to do prophylactic chemotherapy you should use VP16, Actinomycin D, or methotrexate with rescue. You should not use the standard methotrexate regimen because of the risk of liver failure. It really depends on how the curve was going. If you get out to 12 weeks you are dealing with a hCG level of 10-12, and if 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 plateau I use the bigger subunit twice a week so just so I have more 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.

The malignancy is associated with high titers of hCG is erroneous and results in unacceptable treatment delay. Again low titers can be just as troublesome, and if you get stuck in this what happens is you end up waiting, and the disease then becomes establishes and then it requires more chemotherapy to get that patient adequately treated. Chemotherapy is used for non-metastatic and the good prognosis to lower risk metastatic disease. The agents that are used are actinomycin, methotrexate, and BP16. There are two regimens for actinomycin a five-day regimen and a bolus regimen. The bolus 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 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 that are used are the standard maximum 25 mg IV or IM given every five days repeated every two to three weeks and the methotrexate with rescue. The rescue has much less liver toxicity. It is much better tolerated, but it also has a higher rate of resistant disease. As you would expect because when you are rescuing the patient cells you are also rescuing the tumor cells. BP 16 is extremely effective for trophoblastic disease 200 mg per meter 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 16 is incredibly expensive. You are looking at 200 mg per meter 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 average patient. Single agent therapy is you start with a single agent. If you have resistance to titers plateau then you change to another single agent regimen. If you have progression that means 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 on what has happened. The standard multi-agent regimen used to 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 go to the Mack regimen. You would go on to another multi-agent regimen. The other multi-agent regimens are either a modified einhorn regimen or the modified Bagshawe regimen. The bagshawe regimen is extremely good. It is very high dosed methotrexate followed by rescue, hydroxyurea, actinomycin, vincristine, methotrexate, Cytoxan, and then finishing up with adriamycin and

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serum 2.

Symptoms present for <4 months

3.

No brain or liver metastases

4.

No prior chemotherapy

5.

Pregnancy event is not term delivery (ie, mole, ectopic, or spontaneous abortion)

B. High risk 1.

hCG >100,000 IU/24-hour urine or >40,000 mlU/mL serum

IX.

2.

Symptoms present for >4 months

3.

Brain or liver metastases

4.

Prior chemotherapeutic failure

5.

Antecedent term pregnancy

WORK-UP FOR GTN A.

Primary 1.

History and physical

2.

Serum hCG

3.

Pelvic ultrasound

4.

MRI scan/CT scan/amniogram

5.

Chest x-ray

6.

CBC/left

fronto

transversion/right

fronto

transversion/thyroid function tests B.

X.

Persistent/recurrent 1.

History and physical

2.

Serum hCG

3.

Chest x-ray/CT scan

4.

Pelvic ultrasound/CT scan/MRI

5.

Abdominal CT scan

6.

Brain scan

7.

Brain CT scan

8.

Brain MRI scan

Management A.

Uterine evacuation

B.

Hysterectomy

C. Prophylactic chemotherapy 1.

Not indicated unless the follow-up/surveillance is expected to be extremely poor because of patient noncompliance

2.

If prophylactic chemotherapy is to be used, it should probably be done preferably with

XI.

a.

VP-16

b.

Actinomycin-D (ACT-D)

c.

Methotrexate with rescue

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 bit different than the regimen for germ cell tumors. Here the dose of platinum is decreased and the dose of vinblastine is increased. The bleomycin stays the same. For the modifications to the einhorn regimen people are presently using the BP16 replacing the Vinca alkaloids. It has a troublesome side effect of causing the paralytic 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 side effects. There is no loss in terms of treatment, but the side effects are much better tolerated with this regimen. The most recent advance in trophoblastic disease treatments is a development of the EMA-CO regimen. This is a salvage regimen for people who have failed previous multi-drug regimens. It is treated at different times with different combinations of drugs. It makes a huge difference, and people who would have otherwise died of the 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 have the capacity to do a massive hemologic support and massive 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 transfusions since the people begin to bottom out with this regimen. You can resect trophoblastic disease. When you go to do the resection you have to remember the trophoblasts cells initial job in life is to establish the maternal fetal 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 surgically resect these tumors. It is very bloody surgery, but if you 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 metastasis the reason for that is well understood. The mesentery of the small bowel seems to be one of these privileged sites, which doesn’t get well perfused by chemotherapy. When they see this type of metastasis intraperitoneal to the small bowel normally this has to be resected. It just doesn’t respond well to chemotherapy. If you have an isolated area of trophoblastic disease it is radiosensitive. You can treat it with 2-3000 rads and get control. 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 are dealing with someone who is at high risk for late stage wide spread metastasis using prophylactic radiation therapy does make the difference in terms of survival for that patient. Routinely those patients would get 2000 rads over ten days as they begin the 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 chemotherapy that patient becomes at risk for an inter-cranial hemorrhage, so you really have to treat the brain metastases first or at the same time as you being the chemotherapy. Otherwise the patient will die of an inter-cranial bleed. Specific inter-arterial profusion could be used for selected sites. Inter-fetal chemotherapy does make a difference. There is also from the Duke group excellent results non-metastatic disease and good remission rates with very good relapse rates. Again this is where the EMA-CO regimen has made a huge difference. In these poor prognostic patient who have recurred this is where EMA-CO really has turned the game around, and these patients now are fairly routinely salvaged from their disease.

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 completed

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. 5.

Dactinomycin bolus: 1.25 mg/m2 IV every 2 weeks

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 metastatic high-risk GTN

2.

In treatment of persistent or recurrent GTN that has

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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

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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 (2,0003,000 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%)

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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

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