|
INTRODUCTION |
¡@ |
Background: Gestational
trophoblastic neoplasia (GTN) can be benign or malignant. Histologically, it is
classified into a hydatidiform mole, an invasive mole (chorioadenoma destruens),
choriocarcinoma, and a placental site trophoblastic tumor (PSTT). Hydatidiform
mole is the most common form of GTN (see
Image 1). While
invasive mole and choriocarcinoma are malignant, a hydatidiform mole can behave
in a malignant or benign fashion.
No methods exist to accurately predict the clinical behavior of a
hydatidiform mole by histopathology. The clinical course is defined by the
patient’s serum human chorionic gonadotropin (HCG) curve after evacuation of the
mole. In the 80% of patients with a benign hydatidiform mole, serum HCG titers
steadily drop to normal within 8-12 weeks after evacuation of the molar
pregnancy. In the other 20% of patients with a malignant hydatidiform mole,
serum HCG titers either rise or plateau.
The official International Federation of Gynecology and Obstetrics staging of
GTN is as follows:
- Stage I Confined to the uterus
- Stage II Limited to the genital structures
- Stage III Lung metastases
- Stage IV Other metastases
Each stage is subclassified further according to the presence or absence of
risk factors as follows:
¡@
- A - No risk factors
- B - One risk factor
- C - Two risk factors
The risk factors included in the subclassification are serum HCG greater than
100,000 mIU/mL and duration of disease longer than 6 months.
¡@
Pathophysiology: Histologically, hydatidiform moles look
like placental tissue, but edema of the villi demonstrates varying sizes.
Proliferation of the trophoblast occurs, and fetal blood vessels are lacking or
are scarce.
If a fetus or fetal parts are present, this is known as a partial or
incomplete mole. Partial moles also have malignant potential, but only 2% become
malignant. An invasive mole has the same histopathologic characteristics of a
hydatidiform mole, but invasion of the myometrium with necrosis and hemorrhage
occurs or pulmonary metastases are present. Histologically, choriocarcinomas
have no villi, but they have sheets of trophoblasts and hemorrhage.
Choriocarcinomas are aneuploid and can be heterozygous, depending on the type
of pregnancy from which the choriocarcinoma arose. If a hydatidiform mole
preceded the choriocarcinoma, the chromosomes are of paternal origin. Maternal
and paternal chromosomes are present if a term pregnancy precedes the
choriocarcinoma. Of choriocarcinomas, 50% are preceded by a hydatidiform mole,
25% by an abortion, and the other 25% by a full-term pregnancy.
PSTT is a rare form of GTN, with slightly more than 100 cases reported in the
literature. In patients with PSTT, intermediate trophoblasts are found
infiltrating the myometrium without causing tissue destruction. Even though
these trophoblasts contain human placental lactogen (HPL), the serum HPL levels
in patients with PSTT are not elevated. These patients have persistent low
levels of serum HCG (100-1000 mIU/mL). The treatment of PSTT is hysterectomy
with ovarian conservation. If the tumor recurs or metastases are present at
initial diagnosis, chemotherapy is administered, but with uniformly poor
results. Radiation therapy may provide local control.
The most frequent sites of metastases of malignant GTN are the lungs, lower
genital tract, brain, liver, kidney, and gastrointestinal tract.
¡@
Frequency:
¡@
- In the US: Hydatidiform moles occur in 1 in 2000
deliveries, or 1 in 1200 to 1 in 1300 pregnancies, in the United States.
- Internationally: In Mexico, an incidence of 1 in 200
deliveries is reported, while an incidence of 1 in 120 deliveries is reported
in Taiwan. Some believe these international differences are due to differences
in diet. However, in some countries, these differences are due to poor
recording of the total number of deliveries, especially if deliveries are
normal and do not occur in a hospital.
Mortality/Morbidity: Patients who have a malignant
hydatidiform mole, an invasive mole, or a choriocarcinoma should undergo a
systematic search for metastases. Patients who have metastases are classified as
high-risk or low-risk. The criteria for high-risk metastatic GTN include hepatic
or brain metastasis, serum HCG titers greater than 40,000 mIU/mL prior to the
initiation of chemotherapy, duration of disease longer than 4 months, prior
unsuccessful chemotherapy, and malignant GTN following a term pregnancy.
- The World Health Organization (WHO) classification provides points for the
presence of a number of prognostic factors. Patients with a WHO score of 8 or
higher are considered at high risk.
¡@
- Age older than 39 years = 1 point
- Antecedent pregnancy terminated in abortion = 1 point
- Antecedent full-term pregnancy = 2 points
- Interval of 4-6 months between antecedent pregnancy and start of
chemotherapy = 1 point
- Interval of 7-12 months between antecedent pregnancy and start of
chemotherapy = 2 points
- Interval of more than 12 months between antecedent pregnancy and start
of chemotherapy = 4 points
- Beta-HCG level in serum is 1,000-10,000 mIU/mL = 1 point
- Beta-HCG level in serum is 10,000-100,000 mIU/mL = 2 points
- Beta-HCG level in serum is greater than 100,000 mIU/mL = 4 points
- Blood type of woman is type O and man is type A or vice versa = 1 point
- Blood type of woman is type B or AB = 2 points
- Largest tumor is 3-5 cm = 1 point
- Largest tumor is greater than 5 cm = 2 points
- Site of metastases is spleen or kidney = 1 point
- Site of metastases is gastrointestinal tract or liver = 2 points
- Site of metastases is brain = 4 points
- Number of metastases is 1-3 = 1 point
Number of metastases is 4-8 = 2 points
- Number of metastases is more than 8 = 4 points
- Prior chemotherapy with single drug = 2 points
- Prior chemotherapy with multiple drugs = 4 points
- Patients with malignant nonmetastatic or metastatic low-risk GTN have an
almost 100% probability of cure with chemotherapy. The probability of cure
after chemotherapy for patients with metastatic high-risk GTN is approximately
75%.
- The probability of a late recurrence after the patient has been in
remission (normal serum beta-HCG titers) for 1 year is less than 1%.
Race:
- International reports are conflicting as to whether ethnicity is an
independent risk factor for the development of GTN.
- In the United States, race does not appear to be a risk factor.
Sex:
- GTN affects women during their reproductive years. However, PSTTs have
been diagnosed when patients were postmenopausal.
Age:
- Hydatidiform mole is more frequent in teenagers and in women older than 40
years. The potential for malignant change is higher when a hydatidiform mole
occurs in a woman older than 40 years.
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|
CLINICAL |
¡@ |
History:
- Patients with a hydatidiform mole present with signs and symptoms of
pregnancy.
- The most frequent symptom is abnormal uterine bleeding.
- A history of amenorrhea exists. Occasionally, the typical hydatid
vesicles (edematous villi) are passed through the vagina.
- Signs and symptoms of preeclampsia occur in one third of patients.
- Prolonged hyperemesis gravidarum also is common.
- Hyperthyroidism is found in 3% of patients. This is due to the production
of human molar thyrotropin by the molar tissue and the similarities between
HCG and thyroid-stimulating hormone (TSH).
- If metastases exist, signs and symptoms associated with the metastatic
disease, such as hematuria, hemoptysis, abdominal pain, and neurologic
symptoms, may be present.
Physical:
- Suspect GTN when a positive pregnancy test occurs in the absence of a
fetus.
- Uterine size is larger than estimated by the patient’s last menstrual
period in half the patients, smaller in a fourth of the patients, and equal to
the estimated gestational age in a fourth of the patients.
- The identification of hydatid vesicles in the vagina is diagnostic for
hydatidiform mole.
- Enlarged ovaries secondary to theca lutein cysts are found in 30% of
patients with hydatidiform mole.
- These cysts are the result of stimulation of the ovaries by the high
circulating levels of HCG.
- The cysts regress after evacuation of the hydatidiform mole, but this
process can take as long as 12 weeks.
Causes:
- A hydatidiform mole occurs when a haploid sperm fertilizes an egg that has
no maternal chromosomes and then duplicates its chromosomal complement.
- Most complete hydatidiform moles are 46,XX, and all the chromosomes come
from the male.
- Of hydatidiform moles, 10-15% are 46,XY. This occurs when 2 sperm, 1
carrying an X and the other carrying a Y, fertilize an “empty?egg.
- Partial moles are 69,XXY, and the 2 sets of chromosomes are of paternal
origin.
|
|
DIFFERENTIALS |
¡@ |
Abortion
Ectopic Pregnancy
Other Problems to be Considered: Intrauterine pregnancy
Tubal pregnancy
|
|
WORKUP |
¡@ |
Lab Studies:
- Serum HCG is elevated and frequently higher than expected for the
estimated gestational age. A serum HCG greater than 100,000 mIU/mL should
raise the suggestion of GTN.
- CBC count may help detect anemia secondary to vaginal bleeding.
- Liver enzymes may become elevated in the presence of metastasis to the
liver.
Imaging Studies:
¡@
- In the presence of an elevated serum HCG titer, the absence of a fetus,
and the characteristic sonographic appearance ("snowstorm pattern"), a
hydatidiform mole is diagnosed.
- The ultrasound helps identify the fluid-filled vesicles within the
uterine cavity (see
Image 2).
- Ovarian theca lutein cysts are observed in 20% of patients with
hydatidiform mole.
- Chest x-ray: This test is recommended because the lung is the most
frequent site of metastasis.
- CT scan of the head, abdomen, and pelvis with contrast
- This is recommended if the patient has malignant GTN (hydatidiform mole
with metastasis to the lungs, choriocarcinoma, or persistent hydatidiform
mole).
- The lungs, lower genital tract, brain, liver, kidney, and
gastrointestinal tract are frequent sites of metastases.
Procedures:
¡@
- Evacuation of the uterus is performed with suction and sharp curettage.
- The tissue is sent for histopathologic examination.
- This exhibits a hydatidiform mole (complete or partial) or a
choriocarcinoma.
- Rarely is a histopathologic diagnosis of an invasive mole made on a
dilation and curettage (D&C) specimen because this requires the identification
of destructive invasion of the myometrium by the trophoblasts. Scant or no
myometrium is recovered on a D&C specimen.
Histologic Findings: Complete hydatidiform moles have
edematous placental villi, hyperplasia of the trophoblasts, and lack or scarcity
of fetal blood vessels.
In the incomplete or partial hydatidiform mole, scalloping of the villi and
trophoblastic inclusions occur within the villi. Fetal blood vessels are
present.
In a hydropic degeneration of a normal pregnancy, edema of the villi is
present, but no trophoblastic hyperplasia. Ghost villi may be observed.
The invasive mole has the same appearance as the hydatidiform mole, but the
myometrium is invaded with the presence of hemorrhage and tissue necrosis.
Although the choriocarcinoma has no chorionic villi, it has sheets of
trophoblasts, hemorrhage, and necrosis. In the PSTT, intermediate trophoblasts
are found between myometrial fibers, without tissue necrosis.
|
|
TREATMENT |
¡@ |
Medical Care:
- Emergency department care involves starting intravenous (IV) fluids
(crystalloids) and sending blood for type and antibody screen. Rh-negative
patients should receive anti¡VRhD immune globulin, such as RhoGAM, if not
already immunized.
- Patients with benign GTN do not require medical therapy. Because 20% of
patients with hydatidiform mole develop malignant disease, such as persistent
hydatidiform mole with or without metastasis, some have suggested the use of a
prophylactic dose of methotrexate (MTX) in noncompliant patients. However,
observing patients with weekly serum HCG titers is preferable, and only
patients with rising or plateauing titers, as occurs in patients with
malignant GTN, should be treated with chemotherapy.
- Patients with malignant nonmetastatic GTN or metastatic low-risk GTN are
treated with single-agent chemotherapy. Many in the United States prefer MTX.
However, actinomycin D can be used in patients with poor liver function.
During treatment, the serum HCG titers are monitored every week. One
additional course of chemotherapy is administered after a normal serum HCG
titer. After 3-4 normal serum HCG titers, the titers are followed once per
month for 1 year. A switch from MTX to actinomycin D is made if the patient
receiving MTX for nonmetastatic or metastatic low-risk GTN develops rising or
plateauing serum HCG titers.
- Patients with high-risk metastatic GTN are subdivided into 2 groups: those
with a WHO score of less than 8 and those with a score of 8 or higher and a
high risk of therapy failure.
- In patients with a WHO score of less than 8, a combination of MTX,
actinomycin D, and cyclophosphamide can be used. This is known as the MAC
regimen. This chemotherapeutic regimen is administered every 21 days until
the serum HCG titers normalize. In patients with a low WHO score, one
additional course of MAC is administered after a normal serum HCG titer.
Some prefer to treat these patients with single-agent chemotherapy (MTX or
actinomycin) because their chances of achieving a cure are high.
- Patients with WHO scores of 8 or higher are treated with a combination
of etoposide, MTX, and actinomycin D administered in the first week of a
2-week cycle and cyclophosphamide and vincristine (Oncovin) administered in
the second week. This is known as the EMA-CO regimen. Some substitute
cisplatin and etoposide for cyclophosphamide and vincristine during the
second week. This is known as the EMA-CE regimen. Some reserve the EMA-CE
regimen for patients in whom EMA-CO fails. Two additional courses of EMA-CO
or EMA-CE are administered after a normal serum HCG titer in very high-risk
patients. Patients with metastasis to the brain receive whole brain
irradiation (3000 cGy) in combination with chemotherapy. Corticosteroids (Decadron)
with systemic effect are administered to reduce brain edema. Patients with
liver metastasis are considered for liver irradiation (2000 cGy).
Surgical Care:
- The treatment of a hydatidiform mole is evacuation of the uterus by
suction and sharp curettage.
- To avoid excessive bleeding, oxytocin is administered intravenously at
the initiation of the suctioning of the uterine contents.
- The largest possible suction curet is used, usually a number 10 or 12F.
Consultations: An obstetrist and gynecologist may be
consulted.
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|
MEDICATION |
¡@ |
The goals of pharmacotherapy are to reduce
morbidity and eradicate the neoplasm.
¡@
Drug Category: Antineoplastics -- Gestational
trophoblastic tumors are sensitive to many antineoplastic agents, especially
those that act in the S phase or the M phase of the cell cycle.
Drug Name
¡@ |
Methotrexate (Folex PFS, Rheumatrex) --
Used both as single agent and in multiagent regimens for the treatment of
malignant GTN. |
| Adult Dose |
0.4 mg/kg IV/IM qd for 5 d when used as
single agent (not to exceed 30 mg)
0.3 mg/kg IV/IM qd for 5 d when used in MAC regimen (not to exceed 15 mg);
may repeat 14-16 d after last dose
50 mg/m2 IV/IM every week is alternative single-agent regimen
100 mg/m2 IV as 12-h infusion on day 1 of EMA-CO regimen
|
| Pediatric Dose |
Children: Not established
Adolescents: Administer as in adults
|
| Contraindications |
Documented hypersensitivity; hepatic
insufficiency |
| Interactions |
Salicylates, procarbazine,
sulfonamides, and NSAIDs may increase effects and toxicity; folic acid and
its derivatives contained in some vitamins may decrease response to MTX; may
increase plasma levels of thiopurines; coadministration with etretinate may
increase hepatotoxicity of MTX |
| Pregnancy |
D - Unsafe in pregnancy |
| Precautions |
Monitor liver enzymes and CBC; most
common adverse effects are hematologic and gastrointestinal; may cause oral
mucositis and hepatic toxicity; liver irradiation can increase
hepatotoxicity |
Drug Name
¡@ |
Actinomycin D (Dactinomycin) --
Intercalates between guanine and cytosine base pairs, inhibiting DNA and RNA
synthesis and protein synthesis. Use as single agent or as part of
multiagent regimen for treatment of malignant GTN. |
| Adult Dose |
0.01 mg/kg IV qd for 5 d as part of MAC
regimen or as single agent (not to exceed 0.5 mg); repeat 14-16 d after last
dose
Alternatively, 0.5 mg IV on days 1 and 2 in EMA-CO regimen
|
| Pediatric Dose |
<6 months: Not recommended
>6 months: Administer as in adults
|
| Contraindications |
Documented hypersensitivity; herpes
zoster; chickenpox |
| Interactions |
Concurrent use with liver irradiation
or MTX increases risk of developing hepatic toxicity |
| Pregnancy |
C - Safety for use during pregnancy has
not been established. |
| Precautions |
Infusion must be IV because it is a
vesicant; monitor CBC and liver enzymes (can cause bone marrow depression
and hepatotoxicity); premedicate against nausea; unsafe to use in normal
pregnancies, especially in first trimester; use as antineoplastic in second
and third trimester of pregnancy should be under the supervision of a
qualified oncologist and qualified obstetrician after proper patient
counseling |
Drug Name
¡@ |
Cyclophosphamide (Cytoxan, Neosar) --
Chemically related to nitrogen mustards. As alkylating agent, mechanism of
action of active metabolites may involve cross-linking of DNA, which may
interfere with growth of normal and neoplastic cells. Part of multiagent
chemotherapy regimens used to treat high-risk metastatic GTN. |
| Adult Dose |
5 mg/kg qd for 5 d as part of MAC
regimen (not to exceed 250 mg)
Course is repeated 14-16 d after last dose
600 mg/m2 IV on day 8 of EMA-CO regimen
|
| Pediatric Dose |
Administer as in adults |
| Contraindications |
Documented hypersensitivity; severely
depressed bone marrow function |
| Interactions |
Allopurinol may increase risk of
bleeding or infection and enhance myelosuppressive effects of
cyclophosphamide; may reduce digoxin serum levels and antimicrobial effects
of quinolones; may increase effect of anticoagulants; coadministration with
high doses of phenobarbital may increase rate of metabolism and leukopenic
activity of cyclophosphamide; thiazide diuretics may prolong
cyclophosphamide-induced leukopenia; potentiates effect of succinylcholine
|
| Pregnancy |
D - Unsafe in pregnancy |
| Precautions |
Preinfusion and postinfusion hydration
prevents hemorrhagic cystitis; monitor CBC; premedicate against nausea;
regularly examine hematologic profile (particularly neutrophils and
platelets) to monitor for hematopoietic suppression; regularly examine urine
for RBCs, which may precede hemorrhagic cystitis |
Drug Name
¡@ |
Etoposide (Toposar, VePesid) --
Inhibits topoisomerase II and causes DNA strand breakage, causing cell
proliferation to arrest in late S or early G2 portion of cell
cycle. One of the drugs in multiagent chemotherapy regimens used to treat
patients with high-risk metastatic GTN. |
| Adult Dose |
100 mg/m2 on days 1 and 2 of
EMA-CO regimen and on day 8 of EMA-CE regimen |
| Pediatric Dose |
Children: Not established
Adolescents: Administer as in adults
|
| Contraindications |
Documented hypersensitivity;
intrathecal administration may cause death |
| Interactions |
May prolong effects of warfarin and
increase clearance of MTX |
| Pregnancy |
D - Unsafe in pregnancy |
| Precautions |
Mix in 250-500 mL of isotonic sodium
chloride solution and infuse over 1 h to prevent hypotension; monitor CBC
(can cause severe myelosuppression); premedicate against nausea |
Drug Name
¡@ |
Vincristine (Oncovin, Vincasar PFS) --
Blocks mitosis; one of the drugs included in multiagent chemotherapy
regimens used to treat patients with high-risk metastatic GTN. |
| Adult Dose |
1 mg/m2 IV on day 8 of EMA-CO
regimen (not to exceed 2 mg) |
| Pediatric Dose |
Children: Not established
Adolescents: Administer as in adults
|
| Contraindications |
Documented hypersensitivity; patients
with demyelinating form of Charcot-Marie-Tooth syndrome |
| Interactions |
Concurrent use with itraconazole can
cause earlier onset and/or increase severity of adverse neuromuscular
effects; acute pulmonary reaction may occur when administered concurrently
with mitomycin-C |
| Pregnancy |
D - Unsafe in pregnancy |
| Precautions |
Caution with severe cardiopulmonary or
hepatic impairment and preexisting neuromuscular disease; administration
must be IV |
Drug Name
¡@ |
Cisplatin (Platinol) -- Inhibits DNA
synthesis and, thus, cell proliferation, by causing DNA cross-links and
denaturation of double helix. Effective antineoplastic used in patients with
chemotherapy-resistant malignant GTN. |
| Adult Dose |
75-80 mg/m2 on day 8 of EMA-CE
regimen |
| Pediatric Dose |
Children: Not established
Adolescents: Administer as in adults
|
| Contraindications |
Documented hypersensitivity;
preexisting renal insufficiency |
| Interactions |
May cause decrease in plasma levels of
anticonvulsants |
| Pregnancy |
D - Unsafe in pregnancy |
| Precautions |
Can cause nephrotoxicity and
neurotoxicity; monitor serum creatinine and electrolytes; administer
prechemotherapy and postchemotherapy hydration; potent emetic; premedicate
with combination of antiemetics; hydroxylated cisplatinum is more
nephrotoxic than chlorinated cisplatinum; should be mixed in isotonic sodium
chloride solution or hypertonic saline for infusion |
Drug Category: Vitamins -- May be used to
alleviate toxic adverse effects of MTX. MTX blocks conversion of uridine to
thymidine, one of the building blocks of DNA. Folinic acid provides a methyl
group to uridine monophosphate, thus forming thymidine monophosphate, overcoming
effects of MTX on tetrahydrofolic acid reductase.
Drug Name
¡@ |
Leucovorin; folinic acid (Wellcovorin)
-- Used to prevent toxicity from high doses of MTX. |
| Adult Dose |
15 mg PO/IM q12h for 4 doses starting
24 h after administration of MTX as part of EMA-CO and EMA-CE regimens |
| Pediatric Dose |
Administer as in adults |
| Contraindications |
Documented hypersensitivity |
| Interactions |
At high doses, may counteract effect of
some anticonvulsants (phenobarbital, phenytoin, primidone); increases
5-fluorouracil toxicity |
| Pregnancy |
C - Safety for use during pregnancy has
not been established. |
| Precautions |
Do not administer intrathecally or
intraventricularly; not to be used for treatment of megaloblastic anemia
secondary to vitamin B-12 deficiency |
|
|
FOLLOW-UP |
¡@ |
Further Outpatient Care:
- In patients with benign GTN, such as those not requiring chemotherapy,
obtain follow-up serum HCG titers once per week until 3-4 normal values are
obtained. Then, obtain them once per month for 6 months. Have patients use
reliable contraception, such as oral contraceptives or depot progesterone
injections, during the period of follow-up care.
- Patients with malignant GTN should have follow-up serum HCG titers once
per week until 4 normal values are obtained. Then, obtain them once per month
for 1 year. Have patients use a reliable method of contraception.
In/Out Patient Meds:
¡@
- During the period of follow-up care, patients with GTN should use a
reliable method of contraception, such as oral contraceptives or depot
progesterone.
- The serum HCG titers are critical in monitoring the status of the disease,
and a normal intrauterine pregnancy interferes with this critical monitoring
tool.
Complications:
¡@
- Plateauing or rising serum HCG titers during the period of follow-up care
may indicate a normal intrauterine pregnancy or persistent GTN with or without
metastasis.
Prognosis:
¡@
- Nonmetastatic GTN has a cure rate with chemotherapy of close to 100%.
- Metastatic low-risk GTN has a cure rate with chemotherapy of close to
100%.
- Metastatic high-risk GTN has a cure rate with chemotherapy of
approximately 75%.
- After 12 months of normal HCG titers, less than 1% of patients with
malignant GTN have recurrences.
Patient Education:
¡@
- The rate of occurrence of a repeat molar pregnancy is approximately 1%.
- The rate of occurrence of a repeat molar pregnancy in a patient with a
history of 2 previous hydatidiform moles is approximately 20%.
- The pregnancy rate after chemotherapy with MTX and cyclophosphamide is
80%. Of women treated with EMA-CO, 46% have had at least 1 live birth after
chemotherapy.
- Patients who become pregnant after treatment for GTN should have a pelvic
ultrasound early during the pregnancy to confirm that the pregnancy is normal.
|
|
PICTURES |
¡@ |
|
|
BIBLIOGRAPHY |
Section 10 of 10 
|
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