1. Gestational Trophoblastic Disease
Yi-Chun Lee, MD
Division of Gynecologic Oncology
Department of Obstetrics & Gynecology
State University of New York
Downstate Medical Center

2. Introduction
A continuum of tumors arising in the fetal chorion during pregnancy
Unique diseases
the elaboration of beta-hCG
the sensitivity to chemotherapy
the immunobiological relationship between the disease and its host

3. Introduction (cont.) Histologically, GTD is classified as:
Hydatidiform mole (complete & partial mole)
Invasive mole (chorioadenoma destruens)
Choriocarcinoma
Placental site trophoblastic tumor
Clinically, GTD is classified as:
Benign trophoblastic neoplasia
Malignant trophoblastic neoplasia
non-metastatic
metastatic
good prognosis (low risk)
poor prognosis (high risk)

4. Gestational Trophoblastic Disease

5. Hydatidiform Mole Incidence
7 to 10 times higher frequency of molar pregnancy in Asian countries than in North America or Europe
In the US: 1 in 1,500 live births
Ireland study from 1st & 2nd trimester abortions:
Incidence of complete mole: 1 : 1,945
Incidence of partial mole: 1 : 695
in Mexico: 1 in 200 pregnancies
in Taiwan: 1 in 125 pregnancies
? due to reporting differences rather than true incidence differences
hospital-based vs. population-based data

6. Hydatidiform Mole Risk factors Socioeconomic & nutritional factors:
Low dietary carotene and animal fat
Vitamin A deficiency
Advanced maternal age: 5 to 10 folds greater risk when older than 40
Not associated with partial mole
History of prior SAB and infertility
Relative risk of 3.1 for complete mole & 1.9 for partial mole among women with 2 or more prior miscarriages comparing to women with no SAB
Infertility: odds ratio of 2.4 for complete & 3.2 for partial mole
Repeat hydatidiform moles occur in 1.2 to 1.4% of patients
a subsequent greater risk of invasive mole or choriocarcinoma
No significant association with gravidity

7. Hydatidiform Mole Etiology
Remains unclear
Appears to be due to abnormal gametogenesis and fertilization
The karyotype in 87% of hydatidiform mole is 46, XX
Most appear to arise from an anuclear empty ovum fertilized by a haploid sperm (23X), which then duplicates its own chromosomes
Up to 13% have 46, XY chromosomal composition
The result of two spermatozoa (23X+23Y) fertilizing an anuclear empty ovum
Whereas chromosomes in the complete mole are entirely of paternal origin, the mitochondrial DNA is of maternal origin

8. Hydatidiform Mole

9. Hydatidiform Mole

10. Diagnosis of Hydatidiform Mole
Primarily diagnosed in the 2nd trimester during the 1960s and 1970s, currently mostly diagnosed in the first trimester
Histologically
proliferation of the trophoblasts (both cytotrophoblast and syncytiotrophoblast) with varying degrees of hyperplasia and dysplasia
the chorionic villi are fluid-filled and distended (hydropic degeneration)
fetal blood vessels are absent
Clinically
signs and symptoms of pregnancy
the most frequent presenting symptom: abnormal uterine bleeding (89-97%)
the uterine size larger than the EGA in 38 to 51% of the cases
from chorionic tissues and retained blood expanding the cavity
passage of the typical hydatid vesicles per vagina

11. Diagnosis of Hydatidiform Mole (cont.)
may present with pre-eclampsia early in pregnancy (12-27%) or prolonged hyperemesis gravidarum (20-26%)
both associated with distended uterus and high beta-HCG levels
ovarian theca lutein cysts
generally 6 to 12 cm in diameter, may enlarge to more than 20 cm
found in 46% of the patients by ultrasound; 26% by clinical exam
usually detected at presentation, may develop after D&E
directly correlated with the serum levels of beta-hCG
may be aspirated in symptomatic patients
The clinical diagnosis is made by:
an elevated serum beta-hCG
absence of fetal heart tones
snowstorm pattern on ultrasound in the absence of a fetus
if a fetus is present, and/or fetal blood vessels or fetal parts on histologic exam, associated with trophoblastic proliferation and hydropic degeneration, a diagnosis of partial mole is made

13. Partial Hydatidiform Mole
The incidence is 1 in 10,000 to 1 in 100,000 pregnancies
The risk appears to be associated with reproductive history rather than dietary factors
Prior history of SAB and infertility
Use of OCP
Hsitory of irregular menstruation
Not associated with advanced maternal age and dietary carotene deficiency
Pathologic features
Varying-sized chorionic villi with focal swelling and focal trophoblastic hyperplasia
Focal mild atypia of implantation-site trophoblasts
Marked villous scalloping and prominent stromal trophoblastic inclusions
Identifiable fetal or embryonic tissues

14. Partial Hydatidiform Mole

15. Partial Hydatidiform Mole

16. Partial Hydatidiform Mole

17. Partial Hydatidiform Mole
The most common karyotype (90-93 %) is triploidy 69, XXY
results from fertilization of an apparently normal ovum by two sperms
other chromosomal abnormalities including trisomics, double trisomics, and tetraploidy have been identified
normal 46, XX or 46, XY also have been reported
when fetuses are identified with partial moles, they generally have stigmata of triploidy including growth retardation and multiple congenital anomalies
phenotypically normal infants have been delivered of mothers with a co-existing molar pregnancy
Clinical presentation
8-11% excessive uterine enlargement; 4% preeclampsia
None reported with ovarian theca lutein cysts, hyperthyroidism or hyperemesis
A malignant potential of 2 to 4%
Clinical follow-up similar to that of complete mole

18. Comparison of partial vs complete hydatidiform mole
Partial Complete
Cytogenetic analysis Triploid Diploid
most common 69, XXY 46, XX
origin paternal & maternal paternal
Pathology
hydropic villi focal, variable diffuse, marked
trophoblastic proliferation focal, slight diffuse, variable
fetus, amnion, fetal RBCs present absent
scalloping of chorionic villi present absent
stromal trophoblast inclusions present absent
Clinical
“mole” clinical/US Dx rare common
uterus large for dates rare 25 to 50%
theca lutein cysts rare 25 to 35%
malignant sequelae < 5% 6 to 32%
metastatic disease < 1% up to 25%

19. Management of Molar Pregnancy
CXR, LFTs, CBC, serum beta-hCG, type & screen (Rh status)
Suction and sharp curettage
may consider hysterectomy if completed childbearing
Patients are followed with weekly serum beta-hCG until three negative titers are obtained, thereafter, monthly serum beta-hCG for 6 to 12 months
85 to 90% of the patients will have their serum beta-hCG return to normal in 8 to 12 weeks after evacuation
NETDC experience: 37% did not complete follow-up; 4% lost to follow-up even before undetectable hCG levels
Mandatory contraception during the period of follow-up
If pregnancy is suspected during the period of follow-up, an early ultrasound is required

20. Management of Molar Pregnancy (cont.)
The molar tissues produce a number of hormones
human chorionic gonadotropin
human placental lactogen
human molar thyrotropin (?)
responsible for some patients developing hyperthyroidism
thyroid storm is a possible complication of GTN, especially at the time of molar evacuation

21. Gestational Trophoblastic Tumors
Malignant hydatidiform mole
Invasive mole
Choriocarcinoma
The risk seems to be related to hormonal factors
History of light menstrual flow
Menarche after age of 12
Prior use of OCP

22. Invasive Mole

23. Choriocarcinoma

24. Malignant Hydatidiform Mole
Approximately 18 to 29% of the patients will have plateau or rising serum beta-hCG levels during the post-evacuation follow-up
postmolar GTTs: the presence of a re-elevation or persistent plateau in hCG for at least 3 consecutive weeks (in US)
considered to have malignant hydatidiform mole
risk factors for developing invasion and metastasis
serum beta-hCG > 100,000 mIU/ml
uterine size greater than gestational age
theca lutein cyst > 6 cm
advanced maternal age
repetitive molar pregnancy ( 3-fold increased risk)

25. Malignant Hydatidiform Mole (cont.)
Should have a complete metastatic evaluation
complete medical history and physical examination
CXR, CT or MRI of the abdomen, pelvis and head
CBC, electrolytes, TFTs, and LFTs
transvaginal pelvic ultrasound with color flow Doppler can accurately detect uterine disease and help selecting hysterectomy candidate
If no metastases detected
single agent chemotherapy (methotrexate or actinomycin D)
in patients not interested in future fertility, hysterectomy would reduce the chemotherapy cycles by about 50%
weekly serum beta-hCG during the treatment
continue chemotherapy until one cycle past a negative serum beta-hCG titer
serum beta-hCG follow-up: weekly until 3 negative titers, then monthly for one year

26. Invasive Mole Incidence Histologically Management
the overall incidence: 1 per 15,000 pregnancies
approximately 10 to 17% of hydatidiform moles will result in uterine invasion and 4% distant metastasis following molar evacuation
Histologically
the same features as a hydatidiform mole
invasion and destruction of myometrium
Management
similar to that of malignant hydatidiform mole

27. Choriocarcinoma Incidence reported to occur in 1 in 40,000 pregnancies
comprise approximately 20% of malignant GTN
about 2 to 3% of hydatidiform moles progress to choriocarcinoma
association with the antecedent pregnancy:
50% hydatidiform moles
25% normal term gestation
22% abortion
3% ectopic pregnancy

28. Choriocarcinoma (cont.)
Histologically
consists of sheets of trophoblasts (both cytotrophoblasts and syncitiotrophoblasts)
no chorionic villi
extensive hemorrhage and necrosis of the invaded tissues
In the absence of metastases
could be treated with single agent chemotherapy
follow-up also similar to malignant hydatidiform mole and invasive mole

29. Staging of Malignant GTN
The metastatic evaluation should be thorough since the prognosis and treatment will be different if metastases are present
the most frequent sites in descending order: lung (80%), lower genital tract (vagina, 30%), brain (10%), liver (10%), kidney, and GI tract
metastases are often hemorrhagic
Three systems
FIGO staging system
Prognostic group clinical classification
WHO prognostic scoring system
Modified WHO prognostic scoring system adapted by FIGO

30. FIGO Staging for GTTs
A system based on anatomic criteria and conforming to the staging systems used for all other gynecologic cancers
Adopted by the International Federation of Gynecologists and Obstetricians (FIGO) Cancer Committee in 1982
Modified in 1992
Most treatment centers in the US and Europe determine therapy and report results using prognostic factor systems rather than an anatomic system alone
When reporting, the following factors should be noted:
prior chemotherapy given for known GTT
placental site tumors should be reported separately
histologic verification of disease is not required

31. FIGO Staging for GTTs Stage I: disease confined to uterus
Stage II: GTT extending outside uterus but limited to genital structures
Stage III: GTT extending to lungs with or without known genital tract involvement
Stage IV: all other metastatic sites
A: with no risk factors
B: with one risk factor
C: with two risk factors
Risk factors:
serum beta-hCG > 100,000 mIU/ml
duration of disease > 6 months from termination of antecedent pregnancy

32. Prognostic Group Clinical Classification
Used by most major US centers to determine treatment and report results
GTT patients are divided into 3 groups:
nonmetastatic
low risk metastatic
high risk metastatic
patients who are not likely to be cured by single-agent chemotherapy
at the highest risk for treatment failure
based on the presence of one or more of the 5 factors

33. Prognostic Group Clinical Classification
I. Nonmetastatic gestational trophoblastic tumor
II. Metastatic gestational trophoblastic tumor
A. Low risk
1. hCG < 100,000 IU/24-hour urine or < 40,000 mIU/ml serum
2. Less than 4 months from antecedent pregnancy event or onset of symptoms to treatment
3. No brain or liver metastases
4. No prior chemotherapy
5. Pregnancy event is not term delivery (mole, ectopic, or SAB etc.)
B. High risk
1. hCG > 100,000 IU/24-hour urine or > 40,000 mIU/ml serum
2. Greater than 4 months from antecedent pregnancy event or onset of symptoms to treatment
3. Brain or liver metastases
4. Prior chemotherapy failure
5. Antecedent term pregnancy

34. World Health Organization Prognostic Scoring System
In 1983, the WHO adopted a modified prognostic scoring system
based on patients’ age, parity, type of antecedent pregnancy, time interval between antecedent pregnancy and GTT event, hCG level, paternal and maternal blood type, number and site of metastases, largest tumor mass, and previous chemotherapy
a weighted score was applied to each factor
each factor was assumed to act as an independent variable
the effects of all factors were assumed to be additive
a score of 4 or less: low risk; 5 to 7: intermediate risk; 8 or more: high risk

35. WHO Prognostic Scoring System
Score
Risk factors
Age (years) < 39 >39
Antecedent pregnancy H. mole Abortion Term
Pregnancy event to treatment
interval (months) < > 12
hCG (IU/ml) < > 105
ABO blood groups
(female x male) O x A B
A x O AB
No. of metastases > 8
Site of metastases Spleen GI tract Brain
Kidney Liver
Largest tumor mass,
including uterine (cm) > 5
Prior chemotherapy Single Two or
agent more drugs

36. Modified WHO Prognostic Scoring System as adapted by FIGO
Score
Risk factors
Age (years) < 39 >39
Antecedent pregnancy H. mole Abortion Term
Interval months from
index pregnancy < > 12
hCG (IU/ml) < > 105
No. of metastases > 8
Site of metastases Lung Spleen GI Brain
Kidney Liver
Largest tumor mass,
including uterine (cm) > 5
Prior chemotherapy Single Two or
agent more drugs
Example: Stage IV:9 or Stage II:4

37. Treatment of Non-Metastatic GTTs
Single-agent chemotherapy (methotrexate or actinomycin D)
Hysterectomy
advisable as initial treatment who no longer wish to preserve fertility
could reduce the required cycles and shorter duration of chemotherapy
Weekly serum beta-hCG titers during the treatment period
Continue chemotherapy until one cycle past a negative serum beta-hCG titer
Chemotherapy is changed to the alternate agent if the beta-hCG level plateaus or toxicity occurs
Combination chemotherapy for patients failing both methotrexate or actinomycin D
Serum beta-hCG follow-up: weekly until 3 negative titers, then monthly for one year

38. Treatment of Low-Risk Metastatic GTTs
Also treated with single-agent chemotherapy similar to that of non-metastatic GTTs
Combination chemotherapy for patients failing single-agent regimen
Hysterectomy
adjuvant treatment as in non-metastatic GTT
may be necessary for persistent or chemotherapy-resistant uterine disease

39. Chemotherapy for non-metastatic and low-risk metastatic GTTs
Methotrexate 0.4 mg/kg IV or IM daily x 5 days; 2-week cycle
Methotrexate mg/kg IM days 1, 3, 5, 7;
folinic acid mg/kg IM days 2, 4, 6, 8; every days
Methotrexate mg/m2 IM weekly
Actinomycin-D ug/kg IV daily x 5 days; 2-week cycle
Actinomycin-D 1.25 mg/m2 IV; 2-week cycle
Recommended only for treatment of persistent, non-metastatic postmolar GTTs

40. Treatment of High-Risk Metastatic GTTs
Require intensive chemotherapy
The standard chemotherapeutic regimen
MAC (methotrexate, actinomycin-D, and cyclophosphamide)
excellent results with minimal toxicity
Patients with WHO score greater than 8 are frequently treated with a more aggressive regimen
EMA-CO (etoposide, methotrexate, actinomycin-D, cyclophosphamide, and vincristine)
Patients with brain metastases
require whole-brain XRT (3000 cGy) in combination with the chemotherapy
systemic corticosteroids are given to reduce brain edema
craniotomy to control bleeding or provide acute decompression or resection of chemotherapy-resistant disease

41. EMA-CO regimen for high-risk metastatic GTTs
Day 1 Etoposide 100 mg/m2 IV over 30 minutes
Methotrexate 100 mg/m2 IV push; then 200 mg/m2 IV over hours
Actinomycin-D 0.5 mg IV push
Day 2 Etoposide 100 mg/m2 IV over 30 minutes
Folinic acid 15 mg IM q 12 hours for 4 doses beginning hours after starting methotrexate
Day 8 Vincristine 1.0 mg/ m2 IV push
Cyclophosphamide 600 mg/ m2 IV
Repeat cycle every 2 weeks

42. Treatment of High-Risk Metastatic GTTs (cont.)
Patients with liver metastases
reported complete remission rate of 62.5 to 90% with combination chemotherapy alone
may require whole-liver XRT (2000 cGy) in combination with the chemotherapy
both chemotherapeutic agents and XRT are hepatotoxic
an alternative is to embolize the hepatic arteries if bleeding occurs
may consider hepatic resection in selected cases
Serum beta-hCG follow-up: weekly until 3 negative titers, then monthly for 24 months (due to an increased risk of late recurrence)

43. Treatment Outcome Remission rate:
Stage I / non-metastatic GTN: 100%
Single-agent chemotherapy: 92%
metastatic GTN
Stage II: 100%
low risk: 100% (single-agent chemotherapy: 87.1%)
high risk: 100% (single-agent chemotherapy: 25%)
Stage III: 99.3%
low risk: 100% (single-agent chemotherapy: 81.7%)
high risk: 97.8% (single-agent chemotherapy: 26.5%)
thoracotomy has a limited role
Stage IV: 78.9%
multimodal therapy: combination chemotherapy, RT, and surgery
Recurrence rate after initial remission:
Non-metastatic GTTs: 2%
Good-prognosis metastatic GTTs: 4%
Poor-prognosis metastatic GTTs: 13%
The incidence of late recurrences is less than 1%

44. Treatment Outcome The pregnancy rate after chemotherapy is high
Pregnancies after hydatidiform mole:
68.6% full-term live births; 7.4% premature deliveries
0.9% ectopic pregnancies; 0.5% stillbirths; 17.3% SAB
4.1% infants with major and minor congenital malformations
Pregnancies after partial mole:
75.3% full-term live births; 1.6% premature deliveries
0.4% ectopic pregnancies; 0.4% stillbirths; 15.1% SAB
1.5% infants with major and minor congenital malformations
Pregnancies after GTT:
67.6% full-term live births; 6.0% premature deliveries
1.2% ectopic pregnancies; 1.5% stillbirths; 15.8% SAB
2.3% infants with major and minor congenital malformations
In a recent report of 9 patients received EMA-CO, 4 achieved pregnancy, and all resumed normal menstrual cycles
No difference in either the conception rate or pregnancy outcome between women receiving single-agent and combination chemotherapy

45. Placental-Site Trophoblastic Tumor
An uncommon type of choriocarcinoma
Histologically
infiltration of the myometrium by mononuclear intermediate trophoblasts without hemorrhage or necrosis
the intermediate trophoblasts stain positive for human placental lactogen (with immunoperoxidase)
Tumor markers
serum beta-hCG titers are only slightly elevated
serum human placental lactogen is usually not detectable
The most important prognostic factor: a long interval from the antecedent pregnancy (> 4 years)
Treatment
primary surgery: total abdominal hysterectomy
recurrence or metastatic disease:
chemotherapy, but with uniformly poor results
radiation therapy may provide local control

46. Placental-Site Trophoblastic Tumor

47. Summary GTN is a curable disease However, a cure requires:
4/23/2017
Summary
GTN is a curable disease
However, a cure requires:
a thorough understanding of the pathology, clinical presentation, prognostic factors, and clinical management by the physicians
patients’ understanding of the disease, importance of follow-up (including contraception), and compliance