A. Normal Trophoblastic Layers

1. Cytotrophoblast: germinative layer, gives rise to other types. Discrete cells
2. Intermediate Trophoblast: appears latest in development; function is late invasion
3. Syncytiotrophoblast: produces hormones (hCG, others) and responsible for early invasion

B. Overview of Gestational Trophoblastic Disease

1. Complete and Partial Hydatidiform Mole
2. Placental-Site / Epithelioid Trophoblastic Tumors
3. Choriocarcinoma

C. Complete Hydatiform Mole

1. Gross Appearance
   1. Abnormal placenta with grossly swollen chorionic villi
   2. Resembles bunches of grapes
2. Results from fertilization of ovum with lost or inactivated maternal chromosomes
   1. Ovum is fertilized by a 23X sperm and then 23X is duplicated (to 46,XX)
   2. Thus, ~90% of complete moles are homozygous 46,XX of paternal origin
   3. About 10% of complete moles have 46,XY karyotype (probably due to dispermy)
   4. Embryo dies at a very early stage in complete mole
3. Histology
   1. Mole tissue consists of visible swollen villi
   2. All trophoblast types are present, with considerable cytologic atypia
   3. Varying degrees of trophoblastic proliferation without an embryo
   4. Placental circulation has not developed by death of embryo, so villi have no blood
4. Risk factors
   1. Age: Women <15 years and Women >40 years have >5 fold increased risk
   2. Oriental women have about a 3X increased risk compared with Caucasians
   3. Women with previous hydatidiform mole have ~20X risk of developing second one
   4. Low dietary intake of Vitamin A and fat are is associated with molar pregnancy
   5. Overall, Europe and North America rate is about 1 per 1000 pregnancies
5. Symptoms and Diagnosis
   1. Presentation or diagnosis usually between 11th and 15th weeks of pregnancy
   2. Excessive uterine enlargement and abnormal vaginal bleeding
   3. First trimester hypertension
   4. Marked increase in serum hCG is characteristic
   5. Typically diagnosed with hCG levels and corresponding ultrasound parameters
   6. Over two fold increases in serum leptin levels found in molar pregnancies [2]
   7. Chest radiography or CT scan to evaluate for pulmonary metastases
6. Treatment
   1. Suction curettage of uterus in patients who wish to remain fertile
   2. Sharp curettage is performed after suction to remove any residual tissue
   3. RhD-negative patients should receive Rh immune globulin at time of evacuation
   4. For patients who do not wish future pregnancies, a simple histerectomy may be done
   5. Follow up by monitoring hCG levels carefully
   6. About 20% of patients require adjunctive chemotherapy (hCG levels do not fall)
7. Complications
   1. These should be evaluated at time of diagnosis
   2. Preeclampsia
   3. Hyperthyroidism
   4. Electrolyte abnormalities
   5. Anemia
   6. Persistant gestational trophoblastic tumors (~20% of complete molar pregnancies)
8. Cancer Risk
   1. Persistent gestational trophoblastic tumors: most are histologically molar tissue
   2. True choriocarcinoma occurs in 4% of patients after removal of complete mole
   3. However, complete hydatidiform moles account for 50% of all choriocarcinomas

D. Partial Hydatiform Mole

1. No association with age or diet; main association with abnormal menses
2. Usually results from fertilization of an ovum by two paternal sets of chromosomes
   1. Thus, the embryo is triploid (69 chromosomes): two haploid sets are paternal
   2. Contrast with complete mole, which is haploid
   3. Partial mole has very low rate (0.5-2%) of associated choriocarcinoma [4]
3. Fetus is often found in association with partial mole
   1. Almost always with growth retardation and multiple congenital malformations
   2. Triploidy is always fatal, however
4. Partial moles have two populations of chorionic villi
   1. One set is normal
   2. One set shows hydropic swelling, with focal trophoblastic proliferation
5. Presentation
   1. Present with signs and symptoms of incomplete or missed spontaneous abortion
   2. Vaginal bleeding is main problem
   3. Excessive uterine enlargement ~5%
   4. Preeclampsia ~2%
   5. Increased serum hCG levels, but not as in complete molar pregnancy
   6. Diagnosis by clinical history combined with specific ultrasound findings
6. Locally Invasive Hydatiform Mole
   1. Hydropic villous trophoblast has invaded myometrium or its blood vessel
   2. Usual invasion occurs in dilated venous channels occur in ~20% of complete moles
   3. Less hydropic change than complete moles
   4. Trophoblastic proliferation usually prominent

F. Placental Site Trophoblastic Tumor

1. Trophoblastic tumor, ill defined myometrial mass
2. Morphology of tumor
   1. Appears to represent tumor of monomorphic intermediate trophoblast
   2. Chorionic villi usually not present
   3. Cells stain positive for hPL (human placental lactogen), variable for hCG
3. Relatively insensitive to chemotherapy

F. Choriocarcinoma [3]

1. Malignant tumor derived from trophoblast
   1. Also thought of as tumor "allograft" from fetus
   2. Occurs in 1:30,000 pregnancies
   3. Consider diagnosis when exceedingly high levels of hCG (often >100,000 IU/L) found
2. Etiology
   1. 25% from term deliveries
   2. 25% from spontaneous abortions or partial moles
   3. 50% from complete hydatidiform moles
3. Tumor appears as hemorrhagic nodule, with central necrosis
   1. Yellow-brown due to organization of hemorrhage
   2. Lacks intrinsic vasculature, so viable cells usually only at rim of tumor
   3. Dimorphic population of cyto- and syncytiotrophoblast
   4. Strong staining for hCG
   5. Invasion primarily through vascular sinuses
   6. May present with shortness of breath, pulmonary hypertension
4. Disease Stages
   1. Stage I: Disease confined to uterus
   2. Stage II: Disease extending outside of uterus, limited to genital structures
   3. Stage III: Disease extending to lung (regardless of genital tract involvement)
   4. Stage IV: Disease involving other metastatic sites
5. Metastases are common:
   1. Lung 80%
   2. Vagina 30%
   3. Pelvis 20%
   4. Brain 10%
   5. Liver 10%
6. Lung and liver disease usually in patients without molar pregnancy; diagnosis delayed
7. Treatment
   1. Surgery and chemotherapy together
   2. Stage I - histerectomy with single agent chemotherapy (~100% effective)
   3. Stage II/III - single or multiple agent chemotherapy
   4. Stage IV - primary intensitve chemotherapy; surgery and radiation as needed
   5. Whole brain irradiation is used for patients with cerebral metastases
   6. Methotrexate is the agent of choice for single and multiple chemotherapies [5]
   7. Etoposide, vincristine, cyclophosphamide are also used in combination regimens [5]
   8. Intrathecal methotrexate may be included
8. Cure rate depends on risk factors present at each disease stage
9. In general, these tumors are are treatable even when widely disseminated
10. Very sensitive to chemotherapy due to high level of cellular activity

References

1. Berkowitz RS and Goldstein DP. 1996. NEJM. 335(23):1740
2. Sagawa N, Mori T, Masuzaki H, et al. 1997. NEJM. 350(9090):1518
3. Savage P, Roddie M, Seckl MJ. 1998. Lancet. 352(9121):30 (Case Report)
4. Seckl MJ, Fisher RA, Salerno G, et al. 2000. Lancet. 356(9223):36
5. Drugs of Choice for Cancer Chemotherapy. 2000. Med Let. 42(1087):83