Gestational trophoblastic disease Jolanta Zegarska MD,PhD Department of Obstetrics, Gynecology and Gynecological Oncology. Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun

Definition Gestational Trophoblastic Disease (GTD) Represents a spectrum of diseases characterized by active abnormal proliferation of trophoblastic cells Includes a unique spectrum of interrelated diseases: Benign hydatiform mole Invasive mole (Chorioadenoma destruens) Choriocarcinoma Placental site trophoblastictumor (very rare)

Epidemiology and Etiology The incidence of molar pregnancy is about 1 in every 1500 to 2000 pregnancies (white woman) Higher incidence among women in Asia (for example in Taiwan: 1 in every 125 to 200 pregnancies) The cause of GTD is unknown Most patients (80-90%) follow a benign course The risk for the development of a second molar pregnancy is 1 to 3 % (40 times greater than the risk for developing the first molar pregnancy) GTD occur more frequently in women younger than 20 years and older than 40 years

Relationship Abortion, delivery, ectopic pregnancy Hydatidiform mole choriocarcinoma Invasive mole Abortion, delivery, ectopic pregnancy

Hydatidiform mole

Hydatidiform mole/definition the placental trophoblastic cells proliferate abnormally It is a neoplastic proliferation of the trophoblast in which the terminal villi are transformed into vesicles filled with clear viscid material there is stromal edema forms vesicula which is like grape on its appearance

Hydatidiform mole/classification Hydatidiform mole is divided into Complete mole Incomplete/partial mole Based on clinical, patomorphological and genetic features

Complete mole Most hydatidiform moles are complete Have a 46 xx karyotype Both of the x chromosomes are paternally derived It results from the fertilization of an „empty egg” by haploid sperm 23x which then duplicates to restore the diploid chromosomal complement Only a small percentage are 46 XY Complete molar pregnancy is only rarely associated with a fetus, and this may represent a form of twinning

Complete mole/Genetic

Complete mole Histopathologic findings associated with a complete molar pregnancy Hydropic villi Absence of fetal blood vessels Hyperplasia of trophoblastic tissue Invasive mole differs from hydadtidiform mole only in its propensity to invade locally and to metastasize

Complete mole/symptoms Bleeding in the first half of pregnancy Irregular bleeding Heavy vaginal bleeding Lower abdominal pain Excessive nausea/ hyperemesis gravidarum Preeclampsia Irritability Dizziness Photophobia Hyperthyroidism Nervousness Anorexia Tremors

Complete mole/signs Tachycardia Tachypnea Hypertension Absent fetal heart tones (and fetal parts) Grape-like vesicles of the mole may be detected in the vagina Enlarged uterus 50% patients with molar pregnancies 25% have size compatible and 25% have size smaller than gestational age Ovarian enlargement by theca-lutein cyst Occurs in about 1/3of women with molar pregnancies

Complete mole/diagnosis Serum β-human chorionic gonadotropin (β-hcg) higher than normal pregnancy values Ultrasonography Reveals a „snowstorm” pattern Chest film Case courtesy of Dr Andrew Dixon, Radiopaedia.org

Complete mole / prognosis Complete mole has the latent risk of local invasion or telemetastasis The high-risk factors includes β-HCG > 100000 IU/L Uterine size is obviously larger than that with the same gestational time. 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

Incomplete mole 10% of moles are incomplete Is not associated with age Karyotype is usually a triploid Often 69 XXY (80%) These lesions often present with a coexistent fetus The fetus usually has a triploid karyotype and is defective A partial mole has some hydropic villi, whereas other villi are essentially normal Fetal vessels are seen in a partial mole The trophoblastic tissue exhibits less striking hyperplasia

Incomplete mole Patients display most of the pathologic and clinical features of patients with complete mole, although usually in less severe form Partial moles are usually diagnosed later than are complete moles Partial moles generally present as spontaneous or missed abortion Usually is not detected before the spontaneous termination of pregnancy No luteinizing cyst

Incomplete mole Ultrasonography performed for other indications may indicate possible molar degeneration of the placenta associated with the developing fetus An amniocentesis should be performed to determine whether karyotype of the coexisting fetus is normal Uterine size is usually normal or small for dates Preeclampsia usually occurs between 17 and 22 weeks (about 1 month later than with complete mole) Partial moles rarely metastasize, and only rarely is there a need for chemotherapy

Pathologic features Complete mole incomplete mole Embryotic or fetal tissue - + Villus stromal edema diffuseed localized Trophoblastic hyperplasia diffuseed localized Villus outline regular irregular Villus stromal blood vessel - + Karyotype diploid triploid or tetraploid

Hydatidiform mole / treatment Evacuation Suction evacuation followed by sharp curettage of the uterine cavity Regardless of the duration of pregnancy Intravenous oxytocin To help stimulate uterine contractions and reduce blood loss Most patient have an uncomplicated course in the postoperative period Some require blood, fresh frozen plasma or platelet transfusion Rarely a patient can experience acute respiratory distress from trophoblastic embolization or fluid overload

Hydatidiform mole / follow up Weekly serum analysis of β-hcg The levels should steadily decline to undetectable levels Usually within 12 – 16 weeks Chemotherapy Prophylactic chemotherapy is not indicated, because 90% have spontaneus remissions. If the β-hcg levels plateau or rise at any time, chemotherapy should be initiated

Invasive mole

Invasive mole Usually a locally invasive tumor It constitutes about 5 – 10 % of all molar pregnancies Most of those with persistent β-hcg levels after molar evacuation The lesion may: Penetrate the entire myometrium Rupture through the uterus Result in hemorrhage into the broad ligament or peritoneal cavity Rarely is associated with metastases Vagina, lungs Brain (rarely)

Invasive mole / Clinical manifestation irregular vaginal bleeding uterine subinvolution theca lutein cyst does not disappear after emptying uterus abdominal pain metastatic focus manifestation

Invasive mole / Diagnosis history and clinical manifestation successive measurement of HCG ultrasound examination X-ray and CT histologic diagnosis

Invasive mole Histologic confirmation of invasive mole is almost always made at the time of hysterectomy Hysterectomy is usually performed in patients with persistent β-hcg levels following evacuation of molar pregnancy In patients with persistent titers of β-hcg despite chemotherapy who have no evidence of metastatic disease Hysterectomy is usually curative

choriocarcinoma

Choriocarcinoma The frankly malignant form of gestational trophoblastic disease Genetic analysis of choriocarcinomas usually reveals aneuploidy or polyploidy Typical for anaplastic carcinomas Appears grossly as a vascular-appearing, irregular and „beefy” tumor Often growing through the uterine wall Metastatic lesions appear hemorrhagic and have consistency of currant jelly Histological consist of sheets of malignant cytotrophoblast and syncytiotrophoblast with no identifiable villi

Choriocarcinoma 50%gestational choriocarcinoma result from hydatidiform mole Trophoblastic disease following a normal pregnancy is always choriocarcinoma The tumor has a tendency to disseminate hematogenously, particularly to the lungs, vagina, brain, liver, kidneys and gastrointestinal tract FIGO staging of gestational trophoblastic neoplasia

Choriocarcinoma / symptoms Symptoms of metastatic disease Vaginal bleeding Uterine choriocarcinoma Vaginal metastasis Hemoptysis, cough, dyspnea Result of lung metastasis Headache, dizzy spells Central nervous system metastases Rectal bleeding, dark stools Metastasis to gastrointestinal tract

Choriocarcinoma / signs Uterine enlargement Blood seen on examination with a speculum Mass in vagina (metastatic tumor) Acute abdomen Rupture of uterus Abdominal pain Theca-lutein cyst Neurologic signs Partial weakness, paralysis, aphasia etc

Choriocarcinoma / diagnosis Great imitator of the other diseases !!!! May not be suspected Unless it follows molar pregnancy Screen for choriocarcinoma: β-hcg Computer tomography (CT) Pelvis Abdomen head Cerebrospinal fluid β-hcg level Ratio of serum to cerebrospinal fluid hcg levels of less than 40:1 suggest central nervous system involvement β subunit does not cross the blood-brain barrier readily

Clinical features / poor prognosis Urinary β-hcg level > 100 000 IU/24 hr Serum β-hcg level > 40 000 IU Disease presents more than 4 months from the antecedent pregnancy Metastasis to the brain or liver Regardless of β-hcg titer or duration of disease Prior failure to respond to single-agent chemotherapy Choriocarcinoma after a full-term delivery

Choriocarcinoma / treatment Chemotherapy Methotrexate Actinomycin D Cyclophosphamide Modified Bagshave regimen (EMA-CO) Surgery Hysterectomy Pulmonary resection Radiotherapy (in conjunction with chemotherapy) Brain liver

Choriocarcinoma / prognosis 95 -100% of patients with GTN with good prognosis are cured 50 – 70 % patients with poor diagnosis are cured Most patient who die have brain or liver metastases Causes of death: Vaginal bleeding. Haemoptysis. Intraperitoneal hemorrhage. Peritonitis. Metastasis to the vital organs e.g, brain. Pulmonary complications

Prognostic scoring/FIGO/WHO Scores 1 2 4 Age <40 ≥40 — Antecedent pregnancy Mole Abortion Term Interval months from index pregnancy <4 4–6 7–12 >12 Pretreatment serum β-hCG (iu/1) <103 103–104 104–105 >105 Largest tumor size (including uterus) <3 3–4 cm ≥5 cm Site of metastases Lung Spleen, kidney Gastrointestinal Liver, brain Number of metastases 1–4 5–8 >8 Previous failed chemotherapy Single drug ≥2 drugs Low-risk: individuals with a score ≤6

Choriocarcinoma / follow up serum hcg levels should be measured once per week until 4 normal values are obtained. once per month for 1 year. Patients with poor prognosis should be checked monthly for 2 years after 3-4 consecutive weekly normal serum hcg levels. Levels should be checked every 3 months until 5 years Patients should use a reliable method of contraception. Advise not to be pregnant within 12 months after molar evacuation

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