GtD for undergraduate review

1. Gestational Trophoblastic
Disease
22nd June 2018
MBCHB – 6th Year

2. Gestational Trophoblastic Disease (GTD)
• Definition: Is a heterogeneous group of interrelated but distinct
neoplasms derived from the placenta. The lesions may be:
a. Premalignant:
i. Complete hydatidiform mole
ii. Partial Hydatidiform mole
b. Malignant:
i. Invasive mole
ii. Choriocarcinoma
iii. Placental site trophoblastic tumor (PSTT)
iv. Epitheloid trophoblastic tumor (ETT)
Most women with GTD can be cured with their fertility preserved.

3. Epidemiology
• Varies widely throughout the world with higher rates in Asia, Africa
and Latin America
• Choriocarcinoma occurs in about 1:20,000 to 40,000 pregnancies.
• Although less common than hydatidiform mole, choriocarcinoma,
PSTT and ETT can develop after any type of pregnancy

4. Risk Factors
• Age:
• The risk of complete molar pregnancy is highest in women over age 40 and younger than
20.
• Age is less a factor for partial moles.
• all women of childbearing age are at risk for the disease.
• Pregnancy number: Nulliparous women are at more risk.
• Having a molar pregnancy before:
• Once a woman has had a hydatidiform mole, there is about a 1 in 60 chance that she will
have another one.
• It is important to remember that 98% of subsequent pregnancies will be normal.
• Blood type:
• Women with blood type A or AB are at slightly higher risk than those with type B or O.

5. Hydatidiform Mole
• Hydatidiform mole (H. Mole) means that the placenta trophoblastic
cells proliferate abnormally:
a. There is stromal edema ,
b. With formation of vesicules looking like grape on its
appearance.
c. Two types exist:
i. Complete Hydatiform Mole
ii. Partial Hydatiform Mole

6. Risk Factors
• Oral Contraceptive pills:
• Women who take birth control pills are about 50% more likely to get GTD
when they do become pregnant.
• This risk is lower for shorter use of birth control pills and higher for longer use.
• But the risk is still so low that it doesn’t outweigh the benefit of using the pills.
• Lifestyle:
• smoking and drinking alcohol can increase the risk of GTD.
• Number of sexual partners: Having more than 10 sexual partners
increases the risk of GTD.
• Socioeconomic status: Lower socioeconomic status has been
associated with an increased risk.

7. Clinical Manifestation of H. Mole
1. Vaginal bleeding:
• 97% with complete hydatidiform moles
• less often with incomplete (partial) moles.
• Bleeding typically starts during the first trimester, often between the 6th and
the 16th week of pregnancy.
• Women with GTD often pass blood clots or watery brown discharge from
the vagina (Prune juice)
• Sometimes, pieces of the moles resembling a bunch of grapes become
dislodged from the uterus and are discharged through the vagina.
• Women with partial moles are mostly diagnosed after a partial or missed
miscarriage. The molar pregnancy is found when the D & C is done to
remove the products of conception.

8. Clinical Manifestation of H. Mole
2. Anemia
3. Abdominal swelling:
• A uterus larger than the period of amenorrhea is seen with complete hydatiform mole.
3. Vomiting:
• Tedency toward severe emesis gravidarum and sometimes Hyperemesis gravidarum
4. Preeclampsia:
• Preeclampsia develop during the first or second trimester of a complete molar pregnancy.
• It affects about 25% of women with complete moles but only about 4% of women with
partial moles.
5. Hyperthyroidism:
• Hyperthyroidism (overactivity of the thyroid gland) occurs in about 7% of women with
complete hydatidiform moles. Symptoms of hyperthyroidism include rapid heartbeat, warm
skin, and mild tremors (shaking).

9. Complete Vs Partial Hydatiform Mole
• Complete hydatidiform mole
• A sperm has fertilized an “empty”
egg (contains no nucleus or DNA).
• All the genetic material comes
from the father’s sperm.
Therefore, there is no fetal tissue.
• Up to 20% of patients with
complete moles will need
additional surgery or
chemotherapy after their initial
surgery.
• A small percentage of complete
moles may develop into
choriocarcinoma, a malignant
form of GTD.
• Partial hydatidiform mole
• Two sperm fertilize a normal egg.
• These contain some fetal tissue
mixed in with the trophoblastic
tissue.
• No viable fetus is being formed.
• Only a small percentage of
patients with partial moles need
further treatment after initial
surgery.
• Partial moles rarely develop into
malignant GTD.

10. Complete vs. partial mole
Partial
Complete
Feature
Triploid
(69,xxx or 69,
xxy)
Diploid(usually 46,xx
or rarely 46,xy)
Karyotype
focal
diffuse
Swelling of chorionic villi
focal
diffuse
Trophoblastic hyperplasia
Present
absent
Embryonic tissue
usually<
100,000
Often > 100,000
hCG
<5%
15 - 20%
Trophoblastic sequelae
Rare
Up to 25%
Theca lutein cysts
Rare
Up to 25%
Medical complications
Small for dates
50% large for dates
Uterine size

11. Diagnosis
• Complete :
U/S usually very sensitive – generalized swelling (snow-storm )
• partial mole
U/S may detect focal cystic spaces of varying diameter
Diagnosis on histology of curettings

12. Hydatidiform Mole Treatment
• Evaluate for coexisting conditions:
- History and physical
- CBC, coagulation profile, serum chemistry
- thyroid function
- blood type and cross match
- chest radiography
- pelvic ultrasonography
• Evacuation of mole
- Suction curettage - preferred due to soft uterus and
risk of uterine perforation
- Hysterectomy if completed childbearing
• If Rh negative, give Anti D

13. Hydatidiform Mole Treatment
chemotherapy
Hydatidiform Mole is usually not treated with
chemotherapy because it is benign disease.

14. Follow-Up Care – Molar Pregnancy
• 80% of patients cured by evacuation
• Follow B-hCG levels every two weeks until 3 consecutive tests negative
• Then monthly B-hCG every month for 6-12 months
• More than half of patients will have complete regression of hCG to normal
within 2 months of evacuation.
• Avoid pregnancy for at least 12 months after first normal B-hCG (oral
contraceptive pills is preferable)
• Subsequent Pregnancies:
• Send placenta for pathology
• Check B- hCG 6 weeks postpartum

15. Prognosis
• Complete mole has the latent risk of local invasion or
telemetastasis
• The high-risk factors includes
• β-HCG>100000IU/L
• uterine size is > 20 weeks size.
• the luteinizing cyst is >6cm
• If >40 years old,the risk of invasion and metastasis may be 37%, If >50
years old,the risk of invasion and metastasis may be 56%.
• repeated mole: the morbidity of invasion and metastasis increase 3~4
times

16. Gestational Trophoblastic Neoplasia (GTN)
• Persistent/Invasive Mole
• Choriocarcinoma
• Placental-Site Trophoblastic Tumor (PSTT)
• Epitheloid Trophoblastic Tumors
These are malignant tumors

17. Risk Factors for GTN After Mole
• Preevacuation uterine size greater than gestationl age or larger than
20 weeks gestation
• Theca-lutein cysts larger than 6 cm
• Age > 40 years
• Serum hCG levels > 100,000 mIU/mL
• Previous hydatidiform mole

18. GESTATIONAL TROPHOBLASTIC NEOPLASIA
(GTNS)

19. Invasive Mole
• Also known as chorioadenoma destruens, penetrating mole, malignant mole or
molar destruens
• An important complication of H.Mole
• Represent 50% of cases of persistent GTD
• These develop in about 20% of women who have had a complete mole removed
by curettage.
• The risk of developing these in women with complete moles is increased if:
• There is a long time (more than 4 months) between the time periods had
stopped and treatment.
• The uterus has become very large.
• The woman is older than 40 years.
• The woman has had GTD in the past.

20. Invasive Mole
• Invasive moles can be complete or partial,
• Complete moles invade much more often than partial nodes.
• These moles sometimes disappear on their own, but most require treatment with
chemotherapy.
• In about 15% of cases, the tumor spreads through the bloodstream
(metastasizes) to other sites, usually the lungs.
• Pathology:
• Grossly: different size of vesicles in myometrium,there may be or may not be primary focus in uterine
cavity.
• Microscopically: villous structure and trophoblastic cells proliferation
and differentiation

21. Persistent Mole
Definition of persistent molar disease and need for chemotherapy (at
least one of the following):
• B-hCG plateau for ≥ 4 values for ≥ 3 weeks
• B-hCG increase of ≥ 10% for ≥ 3 values for ≥ 2 weeks
• B-hCG persistence 6 months after molar evacuation
• Histopathologic diagnosis of choriocarcinoma
• Presence of metastatic disease

22. Choriocarcinoma
• Most aggressive type of GTN
• Abnormal trophoblastic hyperplasia
• Absence of chorionic villi
• Direct invasion of myometrium
• Most often develops from a complete hydatidiform
mole
• Vascular spread to distant sites:
• Lungs
• Brain
• Liver
• Pelvis and vagina
• Spleen, intestines, and kidney

23. Choriocarcinoma
• May come from any type of pregnancy
- 25% follow abortion or tubal pregnancy
- 25% with term gestation
- 50% from hydatidiform moles
• 2-3% of moles progress to choriocarcinoma
• Incidence 1 in 40,000 pregnancies
• Rarely, choriocarcinomas can develop in other parts of the body in both men and
women. These are not related to pregnancy as ovaries and testicles
• Nongestational choriocarcinoma tends to be less responsive to chemotherapy and has a
less favorable prognosis than the gestational variant

24. Placental-Site Trophoblastic Tumor (PSTT)
• Originate from intermediate cytotrophoblast cells
• Secrete human placental lactogen (hPL)
• B-hCG often normal
• Less vascular invasion, necrosis and hemorrhage than
choriocarcinoma
• Lymphatic spread
• Arise months to years after term pregnancy but can occur after
spontaneous abortion or molar pregnancy

25. Placental-Site Trophoblastic Tumor (PSTT)
• Most common symptom is vaginal bleeding
• Tend to:
- Remain in uterus
- Disseminate late
- Produce low levels of B-hCG compared to other GTN
- Be resistant to chemotherapy (treat with surgery)

26. Signs & Symptoms GTN
• Continued uterine bleeding, uterine perforation, enlarged irregular
uterus, persistent bilateral ovarian enlargement
• From metastatic lesions: abdominal pain, hemoptysis, melena,
increased intracranial pressure (headaches, seizures, hemiplegia),
dyspnea, cough, chest pain

27. Diagnosis of GTN
• Increase or plateau in B-hCG after molar pregnancy
• Pathologic diagnosis by D&C or biopsy of metastatic lesions
• WARNING: biopsy of metastatic lesions can result in massive
hemorrhage
• Metastatic workup: CXR (or CT chest), CT abdomen/pelvis +/- CT/MR
of brain

28. Classification & Staging of GTD
• FIGO Staging
• Describes anatomic distribution of disease
• World Health Organization (WHO) Scoring Index
• Describes prognosis

29. FIGO Staging
Stage Description
I Disease confined to the uterus
II Disease extends outside the uterus but
limited to genital structures (adnexa, vagina,
and broad ligament)
III Disease extends to the lungs with or without
genital tract involvement
IV Disease involves any other metastatic sites

30. WHO Prognostic Score Index
Score
Characteristic 0 1 2 4
Age <40 ≥40 - -
Antecedent preg Mole Abortion Term -
Pregnancy to
treatment
Interval (months)
<4
months
4-6
months
7-12 months >12 months
Pretreatment hCG <103 103- 104 104-105 >105
Largest tumor size
(including uterus)
< 3cm 3-4 cm ≥5cm -
Site of metastases Lung Spleen,
kidney
GI tract Liver, brain
Number of metastases - 1-4 5-8 >8
Previous failed
chemotherapy
- - Single drug ≥2 drugs

31. Therapy for GTN
• Single agent therapy for nonmetastatic (stage I) or
low-risk metastatic (stage II and III) with score <7 
survival rates ~ 100%
• Combination chemotherapy +/- radiation and/or
surgery for high-risk metastatic disease with score ≥7

32. Therapy: Nonmetastatic GTN
• Single-agent with either methotrexate or dactinomycin
• Chemotherapy continued until hCG values normal and then 2-3 cycles
beyond
• Change to alternative single-agent for hCG plateaus above normal or
toxicities
• If significant elevation of hCG or new metastases, switch to
multiagent
• 85-90% cured with initial regimen, <5% will require hysterectomy for
cure

33. Therapy: Low-risk Metastatic GTN
• Low-risk metastatic disease can be treated with single-agent
therapy with 5-day regimens
• Cure rates ~100% but 30-50% will be develop resistance to first
agent
• If resistance to sequential single-agent chemotherapy (5-10% of
patients), switch to multiagent chemotherapy

34. Therapy: High-risk Metastatic GTN
• Stage IV
• Stage II/III with score > 7
• Disease refractory to single-agent chemotherapy
Combination Chemotherapy:
• EMACO:
• Day 1: Etoposide, Methotrexate and Dactinomycin
• Day 8: Cyclophosphamide and Vincristine (Oncovorin)
• Repeat q2 weeks until remission
• Continue for at least 2-3 cycles beyond first normal
hCG
• MAC (Methotrexate, Dactinomycin, Cyclophosphamide)
• EMA/EP – EMA + Etoposide and Cisplatin

35. Metastatic Gestational Trophoblastic Tumors
• Surgery
• It is indicated for tumor resistant to chemotherapy and single metastases
persisting despite chemotherapy.
• RT
• RT, in combination with chemotherapy, is clearly indicated for the primary
management of patients with brain metastases.

36. PSTT Therapy
• Hysterectomy
• Chemotherapy for metastatic disease or nonmetastatic disease with poor
prognosis:
- Interval from index pregnancy > 2 years
- Deep myometrial invasion
- Tumor necrosis
- Mitotic count > 6 per 10 high-power fields
• Survival rates:
• ~100% for nonmetastatic disease
• 50-60% for metastatic disease

37. Follow-up Care
• After completion of chemotherapy, follow serial hCG every 2 weeks
for three months, then monthly for one year
• Physical examinations every 6-12 months and imaging as indicated

38. Reproductive Performance
• Most women resume normal ovarian function
• Women who undergo chemotherapy are advised not to conceive for
one year after completion of treatment
• No increase risk of stillbirths, abortions, congenital anomalies,
prematurity, or major obstetric complications

39. False Positive Serum hCG
• Phantom hCG syndrome/ phantom choriocarcinoma
• 3-4% of healthy individuals have human-antimouse antibodies that
can mimic hCG immunoreactivity
• To verify:
• Urine hCG should be negative
• Should not show parallel decrease with serial dilutions
• Test at national B-hCG reference lab