Gestational Trophoblastic Disease (GTD)

Types of GTD
Benign
•    Hydatidiform mole/molar pregnancy (complete or incomplete)
malignant
•    Invasive mole
•    Choriocarcinoma (chorioepithelioma)
•    Placental site trophoblastic tumor



    The term Gestational Trophoblastic Tumors  has been applied the latter three conditions
    Arise from the trophoblastic elements
    Retain the invasive tendencies of the normal placenta or  metastasis
    Keep secretion of the human chorionic gonadotropin (hCG)


Hydatidiform Mole
 (molar pregnancy)

Definition and Etiology
     Hydatidiform mole is a pregnancy characterized by vesicular swelling of placental villi and usually the absence of an intact fetus.
     The etiology of hydatidiform mole remains unclear, but it appears to be due to abnormal gametogenesis and fertilization
    In a ‘complete mole’ the mass of tissue is completely made up of abnormal cells
    There is no fetus and nothing can be found at the time of the first scan.

    In a ‘partial mole’, the mass may contain both these abnormal cells and often a fetus that has severe defects.
    In this case the fetus will be consumed ( destroyed) by the growing abnormal mass very quickly.  (shrink)



Incidence
•    1 out of 1500-2000 pregnancies in the U.S. and Europe
•    1 out of 500-600 (another report 1%) pregnancies in  some Asian countries.
•    Complete > incomplete
    Repeat hydatidiform moles occure in 0.5-2.6% of patients, and these patiens have a subsequent greater risk of developing invasive mole or choriocarcinoma
    There is an increased risk of molar pregnancy for women over the age 40

    Approximately 10-17% of hydatidiform moles will result in invasive mole
    Approximately 2-3% of hydatidiform moles progress to choriocarcinoma ( most of them are curable)





Clinical risk factors for molar pregnancy

Age (extremes of reproductive years)
                <15
                >40
           Reproductive history
                prior hydatidiform mole
                prior spontaneous abortion
           Diet
                Vitamin A deficiency
           Birthplace
                Outside North America( occasionally has this disease)




Cytogenetics
Complete molar pregnancy
Chromosomes are paternal , diploid
    46,XX in 90% cases
    46,XY in a small part

Partial molar pregnancy
Chromosomes are paternal and maternal, triploid.
    69,XXY   80%
    69,XXX or 69,XYY  10-20%





Comparative Pathologic Features of Complete and Partial Hydatidiform Mole

Feature                                                Complete Mole    Partial Mole
Karyotype                                  Usually diploid 46XX    Usually triploidy 69XXX most common. 
Villi                 All villi hydropin; no normal adjacent villi    Normal adjacent villi may be present
vessels             present they contain no fetal blood cells    blood cells
Fetal tissue                                             None present    Usually present
Trophoblast      Hyperplasia usually present to variable degrees    Hyperplasia mild and focal





Signs and Symptoms of Complete Hydatidiform Mole
•    Vaginal bleeding
•    Hyperemesis ( severe vomit)
•    Size inconsistent with gestational age( with no fetal heart beating and fetal movement)
•    Preeclampsia
•    Theca lutein ovarian cysts
Signs and Symptoms of Partial Hydatidiform Mole
•    Vaginal bleeding
•    Absence of fetal heart tones
•    Uterine enlargement and preeclampsia is reported in only 3% of patients.
•    Theca lutein cysts, hyperemesis is rare.


Diagnosis of hydatidiform mole
Quantitative beta-HCG
Ultrasound is the criterion standard for identifying both complete and partial molar pregnancies. The classic image is of a “snowstorm” pattern
    The most common symptom of a mole is vaginal bleeding during the first trimester
    however very often no signs of a problem appear and the mole can only be diagnosed by use of ultrasound scanning. (rutting check)
    Occasionally, a uterus that is too large for the stage of the pregnancy can be an indication.  
    NOTE:  Vaginal bleeding does not always indicate a problem!



Differential diagnosis
•    Abortion
•    Multiple pregnancy
•    Polyhydramnios




Treatment

 Suction dilation and curettage :to remove benign hydatidiform moles
   When the diagnosis of hydatidiform mole is established, the molar pregnancy should be evacuated.
    An oxytocic agent should be infused intravenously  after the start of evacuation and continued for several hours to enhance uterine contractility
•   
•    Removal of the uterus (hysterectomy) : used rarely to treat hydatidiform moles if future pregnancy is no longer desired. 

Chemotherapy with a single-agent drug
     Prophylactic (for prevention) chemotherapy at the time of or immediately following molar evacuation may be considered for the high-risk patients( to prevent spread of disease )



High-risk postmolar trophoblastic tumor
    Pre-evacuation uterine size larger than expected for gestational duration
    Bilateral ovarian enlargement (> 9 cm theca lutein cysts)
    Age greater than 40 years
    Very high hCG levels(>100,000 m IU/ml)
    Medical complications of molar pregnancy such as toxemia, hyperthyrodism and trophoblastic embolization (villi come out of placenta )
     repeat hydatidiform mole


Follow-up
    Patients with hudatidiform mole are curative over 80% by treatment of evacuation.
    The follow-up after evacuation is key necessary
    uterine involution, ovarian cyst regression and cessation of bleeding

    Quantitative serum hCG levels should be obtained every 1-2 weeks until negative for three consecutive determinations,
    Followed by every 3 months for 1 years.
    Contraception should be practiced during this follow-up period


Invasive mole
Definition
        This term is applied to a molar pregnancy in which molar villi grow into the myometrium or its blood vessels, and may extend into the broad ligament and metastasize to the lungs, the vagina or the vulva.








Common Sites for Metastatic
Gestational Trophoblastic Tumors


Site     Per cent
Lung     60-95
Vagina     40-50
Vulva/cervix    10-15
Brain     5-15
Liver     5-15
Kidney     0-5
Spleen     0-5
Gastrointestinal     0-5




Choriocarcinoma



Definition
        A malignant form of GTD which can develop from a hydatidiform mole or from placental trophoblast cells associated with a healthy fetus ,an abortion or an ectopic pregnancy.

    Characterized by abnormal trophoblastic hyperplasia and anaplasia , absence of chorionic villi





Symptoms and signs
•    Bleeding
•    Infection
•    Abdominal swelling
•    Vaginal mass
•    Lung symptoms
•    Symptoms from other metastases





FIGO Staging System for Gestational Trophoblastic Tumors
Stage    Description
Ⅰ    Limited to uterine corpus
Ⅱ    Extends to the adnexae, outside the uterus, but limited to the genital structures
Ⅲ    Extends to the lungs with or without genital tract
Ⅳ    All other metastatic sites

    Substages assigned for each stage as follows:
    A:  No risk factors present
    B:   One risk factor
    C:  Both risk factors
    Risk factors used to assign substages:
    1.   Pretherapy serum hCG > 100,000 mlU/ml
    2.   Duration of disease >6 months





Diagnosis and evaluation
    Gestational trophoblastic tumor is diagnosed by rising hCG following evacuation of a molar pregnancy or any pregnancy event
    Once the diagnosis established the further examinations should be done to determine the extent of disease ( X-ray, CT,  MRI)


Treatment
    Nonmetastatic GTD
    Low-Risk Metastatic GTD
    High-Risk Metastatic GTD


Treatment of Nonmetastatic GTD

    Hysterectomy is advisable as initial treatment in patients with nonmetastatic GTD who no longer wish to preserve fertility
    This choice can reduce the number of course and shorter duration of chemotherapy.
    Adjusted single-agent chemotherapy at the time of operation is indicated to eradicate any occult metastases and reduce  tumor dissemination.

    Single-agent chemotherapy is the treatment of choice for patients wishing to preserve their fertility.
    Methotrexate(MTX) and Actinomycin-D are generally chemotherapy agents
    Treatment is continued until  three consecutive normal hCG levels have been obtained and two courses have been given after the first normal hCG level.



Treatment of Low-Risk Metastatic GTD

    Single-agent chemotherapy with MTX or actinomycin-D is the treatment for patients in this category
    If resistance to sequential single-agent chemotherapy develops, combination chemotherapy would be taken
    Approximately 10-15% of patients treated with single-agent chemotherapy will require combination chemotherapy with or without surgery to achieve remission


Treatment of High-Risk Metastatic GTD

    Multiagent chemotherapy with or without adjuvant radiotherapy or surgery should be the initial treatment for patients with high-rist metastatic GTD
    EMA-CO regimen formula is good choice for high-rist metastatic GTD
    Adjusted surgeries such as removing foci of chemotherapy-resistant disease, controlling hemorrhage may be the one of treatment regimen






EMA-CO Chemotherapy for poor Prognostic  Disease

Etoposide(VP-16)    100mg/M2    IV daily×2 days (over 30-45 minutes)
Methotrexate    100mg/M2    IV losding dose, then 200mg/M2 over 12 hours day 1
Actinomycin D    0.5mg    IV daily×2 days
Folinic acid    15mg IM or p.o. q 12 hours×4 starting 24 hours after starting methotrexate
Cyclophosphamide     600mg/M2    IV on day8
Oncovin (vincristine)    1mg/M2    IV on day8
(Repeat every 15 days as toxicity permits)



Prognosis
    Cure rates should approach 100% in nonmetastatic and low-risk metastatic GTD
    Intensive multimodality therapy has resulted in cure rates of 80-90% in patients with high-risk metastatic GTD


Follow-up After Successful Treatment
    Quantitative serum hCG levels should be obtained monthly for 6 months, every two months for remainder of the first year, every 3 months during the second year
    Contraception should be maintained for at least 1 year after the completion of chemotherapy. Condom is the choice.


Placenta Site Trophoblastic
Tumor (PSTT)
Definition
    Placenta Site Trophoblastic Tumor is an extremely rare tumor that arised from the placental implantation site
    Tumor cells infiltrate the myometrium and grow between smooth-muscle cells


Dignosis and treatment 
    Surum hCG levels are relatively low compared to those seen with choriocarcinoma.
    Several reports have noted a benign behavior of this disease. They are relatively chemotherapy-resistant, and deaths from metastasis have occurred.
    Surgery has been the mainstay of treatment