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11th Postgraduate Course for Training in Reproductive Medicine and Reproductive Biology

Gestational trophoblastic disease

D. Herbert

Definition

Originate from placental tissues

Rare human tumors curable even when metastatic

4 entities :
  • Complete hydatidiform mole
  • Partial hydatidiform mole
  • Placental site trophoblastic tumors
  • Choriocarcinoma

Pathology

· Complete mole

  • Product of an abnormal conception lacking identifiable embryonic or fetal tissue.
  • Chorionic villi with generalized hydropic swelling.
  • Diffuse trophoblastic hyperplasia.
  • Implantation-site trophoblast with diffuse and marked atypia.
Karyotype :
  • 90% : 46 XX
  • 10% : 46 XY
  • Entirely of paternal origin
  • Mitochondrial DNA of maternal origin

· Partial mole

  • Presence of identifiable embryonic or fetal tissues.
  • Variation in size of chorionic villi, focal swelling, cavitation and trophoblastic hyperplasia.
  • Implantation-site trophoblast with focal, mild atypia.
If presence of a fetus :
  • growth retardation and multiple congenital malformations.
  • Karyotype : 90-93% triploid
  • One extra haploid set of paternal origin

· Choriocarcinoma

  • Dimorphic population of cytotophoblast and syncitiotrophoblast without formed chorionic villi plus evidence of myometrial invasion.
  • Hemorragic nodules and often extensive necrosis.
  • Highly metastatic potential.
  • Origin : any type of gestation
Hydatidiform mole 45%
Normal term pregnancy 25%
Spontaneous abortion 25%
Ectopic pregnancy 5%

Karyotype : variable

· Placental site trophoblastic tumor

  • Intermediate trophoblastic cell lineage
  • Recognition difficult : differentiation from cytotrophoblast in continuous serie of stage.
Unpredictable behavior :
  • 90% benign
  • 10% metastatic , killing

Origin : 95% after a term pregnancy
Extremely resistant to chemotherapy
Karyotype : variable

EPIDEMIOLOGY AND RISK FACTORS

· Hydatidiform mole

1/1000 pregnancies USA and most regions of the world
2/1000 pregnancies Japan
Japanese in Hawai incidence> non-Japanese< in Japan
Maternal age > 35 year old : 2x for> 35 yo ; 7,5x for> 40 yo
  < 20 year old
Previous hydatidiform mole 10x
Diet ↓ risk with diets rich in carotene and adequate amounts of fat intake

· Choriocarcinoma

Epidemiology not well understood

USA 1/24000 pregnancies and 1/19920 live births
ASIA 1/6000 to 1/8000 pregnancies
Age over 40 yo ↑risk 8x
Most important risk factor history of previous hydatidiform mole (29 to 83% cases)

CLINICAL PRESENTATION

  • Vaginal bleeding
  • Uterine size palpably larger than gestational age
  • Theca lutein ovarian cysts
  • Preeclampsia
  • Hyperemesis
  • Spontaneous incomplete abortion (partial mole)
  • Hyperthyroidism (rare)
  • Respiratory insufficiency (rare)

METASTATIC DISEASE

  • 4% after complete molar pregnancy.
  • More commonly after nonmolar pregnancy.
  • Often associated with choriocarcinoma, highly vascular and prone to severe haemorrage either spontaneously or during biopsy.

Most common metastatic sites

· Lungs 80%
· Vagina 30%
· Pelvis 20%
· Liver 10%
· Brain 10%

DIAGNOSIS

  • Ultrasound
    • multiple small sonolucencies (3 to 5 mm diameter) = hydropic villae, without embryo (complete mole) .
    • " Snow storm pattern ".
  • β HCG higher than gestational age.
  • In placental site trophoblastic tumors : HPL , not β HCG.

TREATMENT

· Hydatidiform mole (non metastatic)

D&C or hysterectomy if no desire of fertility.

Follow up :
  • weekly β HCG: 3 normal values
  • then 1x/month for 6 months
  • Return to normal values within 9 to 11 weeks

WHO Prognostic Index Score to determine the resistance to chemotherapy

  Score
  0 1 2 4
Prognostic Factors        
Age ≤ 39 > 39 - -
Previous pregnancy Mole Abortion Term -
Interval (months < 4 4-6 7-12 > 12
β hCG (mIU/ml) < 10 3 10 3-10 4 10 4-10 5 > 10 5
ABO groups - O or A B or AB -
Largest tumor, including uterine(cm) - 3-5 > 5 -
Site of metastases Lungs, pelvis, vagina Spleen, Kidney GI tract, Liver Brain
Number of Metastases - 1-3 4-8 > 8
Prior Chemotherapy - - Single Multiple
  • Low risk : 0-4
  • Intermediate risk : 5-7
  • High risk : > 8

Persistent Gestational Trophoblastic Tumor

18-29% of complete moles (USA).

Diagnosis : if plateau of β hCG for 3 consecutive weeks or if β hCG.

Histology may be different (Choriocarcinoma or placental site trophoblastic tumor).

Criteria of severity

  • <β hCG > 100 000 mUI/ml at diagnosis
  • ovarian thecomas> 6cm
  • preeclampsia, hyperthyroidism, tumoral embolism

Risk of persistent trophoblastic disease then 40-50%

Risk diminishes to 10-15% with chemoprophylaxis (Methotrexate or Dactinomycin)

Staging : if pelvic examination and Chest X-Ray(or Chest CT-scan)in order,very low risk of finding metastases elsewhere.

CHEMOTHERAPY

According to WHO prognostic Index Score
  • Score= 7 :low to intermediate risk,so monochemotherapy
  • Score= 7 :high risk and therefore polychemotherapy.

Monochemotherapy

Methotrexate (MTX)→ 90% CR.

If failure with MTX, with further ttt→ 100% CR.

Polychemotherapy

5 drugs : etoposide,MTX,dactinomycin,cyclophophamide (EMA-CO).

83% CR versus 30-45% CR with monochemotherapy in " high risk " situations.

FOLLOW-UP

· β hCG weekly during treatment until 3 normal levels (3 weeks)
· β hCG every 2 weeks for the next 2-3 months.
· β hCG 1x/month for the next 6 months,then every 2 months.
· Follow-up after 1 year for all metastatic patients with b hCG 1x/year.
· Efficient birth control during the whole period of treatment and follow-up.
· Wait a minimum of one year of follow-up before starting a pregnancy.

Pregnancy experience, after GTD · Fertility :
  • 68 % live births after complete mole
  • 74 % live births after partial mole
  • 68 % term live births after persistent GTT.

· Even with chemotherapy

· Risk subsequent molar pregnancy :

  • 1% (after one mole)
  • 15% to 28% after 2 molar pregnancies
  • risk persistent GTT 3x in patients with repeat mole

· Rate of stillbirth higher after persistent GTT than general population (odd ratio 2,9)

· Infertility rate same as in general population (4%)

· Rate of premature deliveries, ectopic gestations , congenital anomalies ,C-section same as general population.

References

  • Berkowitz and Goldstein :NEJM 1996 pp 1740-1748
  • Society of Gynecologic Oncologists clinical Practice Guidelines : Oncology, 1998 pp 455-461
  • Rose : Seminars in Oncology 1995 pp 149-156
  • Semer & Mcfee: Seminars in Oncology 1995 pp 109-113
  • Redline &Abdul-Karim : Seminars in Oncology 1995 pp 96-109
  • Goldstein and Berkowitz :Seminars in Oncology 1995 pp 157-160
  • Loret de Morla & Goldfarb : Seminars in Oncology 1995 pp193-197
  • Berkowitz & al :Seminars in Oncology 2000, pp 678-685