Gestational trophoblastic disease by sittichoke

1. Gestational
Trophoblastic Disease
Sittichoke Mahasukontachat, MD

2. Objective study
• Define spectrum of Gestational Trophoblastic
Disease (GTD)
• Review types of hydatidiform molar pregnancies,
diagnosis, treatment, and follow up
• Review types of gestational trophoblastic neoplasia,
diagnosis, classification, treatment, and follow up
• Review expectations for future childbearing

3. Gestational Trophoblastic Disease
• Gestational trophoblastic disease (GTD) is the
term used to describe the heterogeneous group
of interrelated lesions that arise from abnormal
proliferation of placental trophoblasts.
• Benign lesions
– Hydatidiform moles (complete and partial )
• Malignant lesions
– Invasive mole, placental-site trophoblastic
tumor(PSTT), and choriocarcinoma.
Berek JS, editor. Berek and Novak’s Gynecology.
Philadelphia: Lippincott Williams & Wilkins; 2012. pp. 1458.

4. Hydatidiform Mole

5. Epidemiology
• Estimates of the incidence of molar pregnancy vary
dramatically in different regions ofthe world.
• Incidence:
• USA /EU 0.6-1.1 per 1,000 pregnancies
• Japan 1.9 per 1,000 pregnancies
• Thailand 2.8 per 1,000 pregnancies
• Taiwan 8 per 1,000 pregnancies
• Indonesia 11.5 per 1,000 pregnancies
• Geographical Location: highest rates in areas of Asia

6. Epidemiology
• Case control study (ITALY AND USA)
• Rate of complete mole increases
– Diet deficient in animal fat and vitamin A (Asia)
(not for partial moles)
– Maternal age > 40 years ( 5-10 fold)
– Previous molar pregnancy
• Rate of partial mole increases
– OCPs
– Irregular menstruation

7. Pathogenesis and Cytogenetics of HM
Complete Partial
Genetic
Diploid Constitution Triploid/ teraploid
Patho-genesis
4%
Fertilization of
an empty
ovum by two
sperms
“Diandric
dispermy”
90%
Triploid
fertilization of a
normal ovum by
two sperms
“Dispermic
triploidy”
96%
Fertilization of
an empty
ovum by one
sperms that
undergoes
duplication
“Diandric
diploidy”
10%
Tetraploid
fertilization of a
normal ovum by
three sperms
“Dispermi
c triploidy”
46XX Karyotype
69XXX
69YXX
69YYX
46XX
46XY

8. Empty
ovum
Complete mole
Endoreduplication
Empty
ovum
Empty
ovum
23X
23X
23X
23X
23Y
23X
46XX
46XY
46YY
46XX
Heterozygous
Homozygous
Non-viable gamete

9. Partial mole
23X
23X
23Y
23Y
23X
69XXX
23Y
23X
23X
69XXX
23X
69XXX
69YYY
Non-viable gamete

10. Complete VS Partial Mole

11. Complete mole
villous vesicles
Gross villous vesicles are
occasionally seen and tend
to be smaller and less
numerous compared with
complete mole.
•Normal gestational
products may be present.

12. The microscopic of complete
mole:
•Hyperplasia of trophoblastic
cells
•Hydropic swelling of all villi
•Vessels are usually absent
•Partial mole
•Hydropic villi and trophoblastic
hyperplasia are less
conspicuous in partial mole.
•Fetal tissues like erythrocyte
may be found.
•Scalloping of chorionic villi and
trophoblastic stromal inclusions.

13. The changing symptoms of complete
mole

14. Diagnosis of Hydatidiform Mole
• Passage of vesicular tissue
• Serum quant β-hCG elevated
(Can be > 1,000,000 IU/L)
• Enlarged uterus
• Ultrasound: multiple echoes, cystic dilatations
• “snowstorm pattern”
• Fetus vs. No fetus
• Ectopic hydatidiform moles

15. Ultrasonography
• Ultrasonography is a reliable and sensitive
technique for the diagnosis of complete
molar pregnancy. Because the chorionic villi
exhibit diffuse hydropic swelling, complete
moles produce a characteristic vesicular
ultrasonographic pattern as soon as in the
first-trimester

16. Complete Mole
Snow-storm appearance
Or
Vesicular ultrasonoghaphic
pattern

17. Partial mole
• Ultrasonography finding:
– Focal cystic spaces in the placental tissues
and an increase in the transverse diameter of
the gestational sac (Ratio of T A-P : >1.5)
– PPV 90%.

18. Management
Complete history and physical examination
Investigations
Medical and surgical care
1
2
3

19. Complete history 1 and physical examination
• History and physcal examination:
– Should aim to rule out the classic
symptoms and signs that would lead to a
diagnosis of:
• severe anemia
• dehydration
• preeclampsia
• thyrotoxicosis
• The patient should be stabilized
hemodynamically

20. 2 Investigations
• Investigations:
– Laboratory:
Pre-evacuation hCG
Complete blood count
Electrolytes, BUN, creatinine
Liver function tests
Thyroid function tests
– Imaging:
Pelvic ultrasound
Chest x-ray

21. Phantom hCG
• Pseudohypergonadotropinemia is a result of
the presence of heterophilic antibodies in serum
giving rise to a falsely elevated hCG.
•If there is discrepancy with the clinical
presentation, hCG levels should be measured
again with a different immunoassay.
•The other alternative is to measure the urine
hCG level because heterophilic antibodies are
not excreted into the urine.

23. Hook effect
•Can occur with a falsely low serum hCG level.
When the serum hCG level is too high, there
are not enough antibodies in the solution to bind
the hCG molecules.
•Much of them are being washed away without
being measured.
•If very high hCG level is suspected, the
laboratory should be informed and the serum
should be diluted before measurement.

24. If the urine has no hCG the Ab of the - hCG will β move to the end
of the tape lonely as the picture below and a single will be appear
which means that the test is negative.

25. If some hCG exist in the urine tow line will be appeared and the
test result is positive.

26. The home kit tests are not safe from hook effect !, which produce a
false negative result . When the concentration of hormone is very
high the hook effect will happen as the mechanism shown below .

27. 3 Medical and surgical care
• Medical care:
– Correction of:
Anemia
Dehydration
Hyperthyroidism
hypertension

28. Surgical care:
Suction curettage
Hysterectomy
•The method of choice
•Performed with the mole in
situ.
•The ovaries may be
preserved at the time of
surgery
•Large ovarian cysts may
be decompressed by
aspiration.
•Not prevent metastasis

29. Suction Curettage
• 1. Oxytocin infusion—Before the induction of
anesthesia.
• 2. Cervical dilation
• 3. Suction curettage
• The use of a12-mm cannula is strongly advised
to facilitate evacuation.
• Uterus > 14 weeks of gestation, one hand
should be placed on top of the fundus, and the
uterus should be massaged to stimulate uterine
contraction and reduce the risk of perforation.
• 4. Sharp curettage—Remove any residual
molar tissue.

30. Prophylactic Chemotherapy
• Controvery .
• Prevented metastasis
• Reduced the incidence and morbidity of local
uterine invasion
• Single course of actinomycin D at time of
evacuation
• Useful in the management of high-risk
complete mole, especially when hCG
assessments for follow up are unavailable or
unreliable

31. Prophylactic Chemotherapy
• In 1 RCT , a single course of methotrexate and
folinic acid reduced the incidence of post molar
trophoblastic disease from 47.4% to 14.3% (P <.05)
in patients with high-risk moles:
– ), hCG levels greater than 100,000 mIU/mL,
– uterine size greater than gestational age,
– ovarian size greater than 6 cm
– However, the incidence was not reduced in patients
with low-risk moles
– On the other hand, the use or prophylactic chemotherapy
increases the risk of drug resistance

32. Follow up
• 1. Human Chorionic Gonadotropin (hCG)
– Monitored with weekly of hCG levels until
these levels are normal for 3 consecutive
weeks
– Followed by monthly until levels are normal for
6 consecutive months

33. Follow up (2)
2. Contraception
• Patients should be used effective
contraception during the entire interval of
hCG follow up
• Oral contraceptive may be used safely
• IUD should not inserted until the patient
achieves a normal hCG level.

34. Gestational Trophoblastic
Neoplasia (GTN)

35. Diagnosis
• The current FIGO criteria for diagnosis of post-molar
GTD
• a) Four values or more of hCG documenting a
plateau (±10% of hCG value) over at least 3
weeks: days 1, 7, 14, and 21.
• b) A rise of hCG of 10% or greater for 3 values or
longer over at least 2 weeks; days 1,7 and 14.
• c) The presence of histologic choriocarcinoma.
• d) Persistence of hCG 6 months after mole
• evacuation.

36. 36
NONMETASTATIC DISEASE
◎ Locally invasive GTT
: about 15% of patients after molar evacuation and after
other gestations
◎ Symptoms
① irregular vaginal bleeding
② theca lutein cysts
③ uterine subinvolution or asymmetric enlargement
④ persistently elevated serum hCG levels
◎ Histology of persistent GTT
① after molar evacuation ⇒⇒ H-mole or choriocarcinoma
② after nonmolar pregnancy ⇒⇒ always choriocarcinoma

37. METASTATIC DISEASE
•• 4% of patients after evacuation of a complete mole
•• usually associated with choriocarcinoma
•• early vascular invasion with widespread dissemination
•• spontaneous bleeding at meatstatic foci
•• metastatic site
: lung(80%), vagina(30%), pelvis(20%), liver(10%),
and brain(10%)

38. 38
METASTATIC DISEASE
1. Pulmonary
•• lung involvement is visible on chest x-ray of 80% of
patients with metastatic GTT
① ““snowstorm”” pattern
② discrete rounded density
③ pleural effusion
④ an embolic pattern by pulmonary arterial occlusion
•• Sign : chest pain, cough, hemoptysis, dyspnea,
or asymptomatic lesion
2. Vaginal
•• occurs in 30% of patients with metastatic tumor
•• highly vascular, may bleed vigorously if sample is taken
for biopsy
•• Sign : irregular bleeding, purulent discharge

39. METASTATIC DISEASE
3. Hepatic
• 10% of patients
• Sx : epigastric or RUQ pain (if metastases stretch the hepatic
capsule)
• hemorrhagic causing hepatic rupture → & intraperitoneal
bleeding
4. CNS
• 10% of patients
• generally seen in patients with advanced disease
• spontaneous bleeding → acute focal neurologic deficits

40. 40
STAGING
- by FIGO classification
◎ Stage ⅠⅠ
: patients have persistently elevated hCG levels and tumor
confined to the uterine corpus
◎ Stage ⅡⅡ
: patients have metastases to the vagina and pelvis or both
◎ Stage ⅢⅢ
: patients have pulmonary metastases with or without
uterine, vaginal, or pelvic involvement
◎ Stage ⅣⅣ
: patients have advanced disease and involvement of the
brain, liver, kidneys, or gastrointestinal tract

41. 0033--110044 110044--110055 ＞＞
41
PROGNOSTIC SCORING SYSTEM
SSccoorree
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11
22
44
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4400
≥≥
4400
-- --
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pprreeggnnaannccyy
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bboorrttiioonn
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ooff
aanntteecceeddeenntt
pprreeggnnaannccyy aanndd
ssttaarrtt ooff
cchheemmootthheerraappyy
((mmoonntthhss))
＜＜
44
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66
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1122
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ggoonnaaddoottrrooiinn
((IIUU//lliitteerr))
＜＜
110033 11
110055
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iinncclluuddiinngg
uutteerriinnee ((ccmm))
-- 33--
44
≥≥55 --
SSiittee ooff mmeettaassttaasseess
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SS
pplleeeenn,,
kkiiddnneeyy
GGII--ttrraacctt LL
iivveerr BBrraaiinn
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-- 11--
55--88 ＞＞

42. 42
PROGNOSTIC SCORING SYSTEM
◎ to consider other variables
to predict the drug resistance
to assist in selecting appropriate
chemotherapy
◎ higher than 7
: categorized as high risk requires intensive
combination chemotherapy
Ex STAGE III:8

43. 43
DIAGNOSTIC EVALUATION
◎ All patients with persistent GTT should undergo a careful
pretreatment evaluation
① complete history and physical exam
② measurement of serum hCG level
③ hepatic, thyroid, and renal function test
④ determination of baseline peripheral WBC & platelet count
◎ The metastatic workup
① chest radiograph or CT scan
② ultrasonography or CT scan of the abdomen & pelvis
③ CT or MRI scan of the head
◎ When the pelvic exam & chest radiographic findings are
negative, metastatic involvement of other sites is uncommon

44. MANAGEMENT OF PERSISTENT GTT
44
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cchheemmootthheerraappyy
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HHyysstteerreeccttoommyy wwiitthh aaddjjuunnccttiivvee cchheemmootthheerraappyy
LLooccaall rreesseeccttiioonn
PPeellvviicc iinnffuussiioonn
SSttaaggee ⅡⅡ aanndd ⅢⅢ
LLooww rriisskkaa
IInniittiiaall SSiinnggllee--aaggeenntt cchheemmootthheerraappyy
RReessiissttaanntt CCoommbbiinnaattiioonn cchheemmootthheerraappyy
HHiigghh rriisskkaa
IInniittiiaall CCoommbbiinnaattiioonn cchheemmootthheerraappyy
RReessiissttaanntt SSeeccoonndd--lliinnee ccoommbbiinnaattiioonn cchheemmootthheerraappyy

45. MANAGEMENT OF PERSISTENT GTT
45
1. Stage ⅠⅠ
- the selection of Tx is based primarily on whether the
patients desire to retain fertility
A. Hysterectomy plus Chemotherapy
•• If patient does not wish to preserve fertility
⇒⇒ hysterectomy + adjuvant single chemotherapy
•• Reasons of adjuvant chemotherapy
① to reduce disseminating viable tumor cells at surgery
② to maintain a cytotoxic level of chemotherapy in case
viable tumor cells are disseminated at surgery
③ to treat any occult metastases that may already be
present at surgery

46. MANAGEMENT OF PERSISTENT GTT
46
B. Chemotherapy Alone
•• In patients with stage ⅠⅠ who desire to retain fertility
⇒⇒ single-agent chemotherapy
⇒⇒ 92.1% of patients attained complete remission
•• Patients are resistant to single-agent chemotherapy
(desire to retain fertility)
⇒⇒ combination chemotherapy
•• If resistant to both
⇒⇒ local uterine resection may be considered

47. MANAGEMENT OF PERSISTENT GTT
47
2. Stage ⅡⅡ and ⅢⅢ
- low-risk : single agent chemoTx
- high-risk : combination chemoTx
A. Vaginal and Pelvic Metastasis
•• vaginal metastases may bleed profusely
(∵∵ highly vascular and friable)
⇒⇒ controlled by packing or by wide local excision
B. Pulmonary Metastasis
•• persistent viable pulmonary metastasis despite intensive
chemotherapy
⇒⇒ thoracotomy may be attempted to excise the
resistant focus

48. MANAGEMENT OF PERSISTENT GTT
48
C. Hysterectomy
•• may be required in patients with metastases to control
uterine hemorrhage or sepsis
D. Follow-up (Stage ⅠⅠ ~ ⅢⅢ)
① weekly measurement of hCG levels until normal
for 3 consecutive weeks
② monthly measurement of hCG values until normal
for 12 consecutive months
③ effective contraception during the entire interval of
hormonal follow-up

49. MANAGEMENT OF PERSISTENT GTT
49
3. Stage ⅣⅣ
- primary intensive combination chemotherapy and the
selective use of radiation therapy and surgery
A. Hepatic Metastasis
•• resistant to systemic chemotherapy
→→ hepatic arterial infusion of chemotherapy
•• acute bleeding of tumor
→→ hepatic resection

50. MANAGEMENT OF PERSISTENT GTT
B. Cerebral Metastasis
•• If diagnosed, whole-brain irradiation (3,000 cGy in
10
50
fractions) can be instituted promptly
•• conurrent use of combination chemotherapy and
brain
irradiation
→→ spontaneous cerebral hemorrhage ↓↓
C. Follow-up (Stage ⅣⅣ)
① weekly determination of hCG levels until they
are
normal 3 consecutive weeks
② monthly determination of hCG levels until they
are
normal for 24 consecutive months
•• increased risk of late recurrence
→→ prolonged gonadotropin follow-up is required

51. MANAGEMENT OF PERSISTENT GTT
51
GTN
Mole
Evacuation and
weekly hCG titers
Metastatic
work-up
↓ hCG
titers
Choriocarcinoma
↑ or plateaud
hCG titers
Careful follow-up
and contraception
Uterine disease Lung metastasis
Distant metastasis
Stage Ⅰ Stage Ⅱ Stage Ⅲ Stage Ⅳ
Single drug
chemotherapy or
hysterectomy
Pelvic metastasis
Calculate
risk
Combination
chemotherapy
± surgery ± RT
Low High
Follow-up Resistant

52. 52
# Chemotherapy

53. 53
SINGLE-AGENT TREATMENT
◎ Nonmetastatic and low-risk GTT
⇒⇒ actinomycin D (Act-D) or MTX has achieved comparable
and excellent remission rates
◎ Protocols
① Act-D can be given every other week as a 5-day regimen
or in a pulsatile fashion
② use of MTX was the same
◎ Methotrexate with folic acid (MTX-FA)
① the preferred single agent in the Tx of GTT
② remission rates
- 90.2% in stage ⅠⅠ
- 68.2% in low-risk stages ⅡⅡ & ⅢⅢ
③ after Tx with MTX-FA, thrombocytopenia, granulocytopenia
and hepatotoxicity developed in only 1.6%, 5.9% and 14.1%
of patients

54. 54
COMBINATION CHEMOTHERAPY
1. Triple Therapy
◎ etoposide, MTX, Act-D, cyclophosphamide
and vincristine (EMA-CO)
- had complete remission in patients with metastasis and
a
high-risk score (76~94%)
- remission occurred in 13 of 15 patients (86%) with brain
metastasis
◎ EMA-CO regimen
① the preferred primary Tx in patients with metastasis
and a
high-risk prognostic score
② generally well tolerated
③ seldom has to be suspended because of toxicity

55. 55
COMBINATION CHEMOTHERAPY
2. Duration of therapy
◎ Combination chemotherapy should be given as often
as
toxicity permits until the patients achieves three
consecutive normal hCG levels
◎ After normal hCG levels are attained, at least two
additional course are administered to reduce the
risk
of relapse

56. Subsequent Pregnancies
• Patients with hydatidiform moles can
anticipate normal reproduction in the future.
• Patient has had a molar pregnancy, either
partial or complete, increased risk of
having a molar gestation in
subsequent conceptions.
• After one molar pregnancy, the risk of having
molar disease in a future gestation is
about1% to 1.5%.

57. • 1.Perform pelvic ultrasonographic
examination during the first trimester to
confirm normal gestational development.
• 2.Obtain an hCG measurement 6 weeks
after completion of the pregnancy to
exclude occult trophoblastic neoplasia.

58. 58
# Surgery

59. Role of surgery
•Remove resistant or persistent disease in
the uterus or metastatic sites
•Decrease the uterine tumor load in case of
limited metastasis
•Control profuse tumor hemorrhage
•Treat infection
•Relieve symptoms like bowel or urinary
obstruction due to the large tumor bulk.

60. Thank you