Gestational Trophoblastic Disease ASSOCIATE PROFESSOR IOLANDA BLIDARU MD, PhD

Gestational Trophoblastic Disease Complete / Partial vesicular mole Invasive mole (chorioadenoma destruens ) Placental-site trophoblastic tumor Choriocarcinoma

HYDATIDIFORM MOLE

A benign tumor of the chorionic villi, characterized by: Definition A benign tumor of the chorionic villi, characterized by: Marked proliferation of the trophoplast, (both the syncytium & cytotrophoplast). Oedema or hydropic degeneration of the connective tissue stroma of the villi → distension → formation of vesicles. Avascularity of the villi: the blood vessels disappear from villi (early death of the embryo)

Incidence 1:2000 pregnancies in US and Europe 10 times more in South-East Asia, West Africa and Mexico = 1/120-1/240 pregnancies choriocarcinoma ► 1/15,000 pregnancies → 1/500 to 1/1000 pregnancies

RISK FACTORS race deficiency of protein or carotene higher incidence toward the beginning and (more) the end of the childbearing period. age: 10 times more in women over 45 years old consanguinity blood type: the malignant form ► more frequent in group A viral infections the ovarian theca-lutein cysts

1. placental vascular deficiency 2. genetic hypothesis PATHOGENESIS 1. placental vascular deficiency 2. genetic hypothesis 3. immunological theory .

Pathology The uterus is distended by thin walled, translucent, grape-like vesicles of different sizes. These are degenerated chorionic villi filled with fluid. No vasculature in the chorionic villi → early death + absorption of the embryo.

Pathology Trophoblastic proliferation ↑ secretion of hCG, thyroxine and P. E production is low (absence of the fetal supply of precursors).

Pathology High hCG → multiple theca lutein cysts in the ovaries (about 50% of cases) exaggeration of the normal early pregnancy symptoms and signs

Histologic section of a complete hydatidiform mole Villi of different sizes The large villous in the center exhibits marked edema Marked proliferation of the trophoblasts

Types: Complete mole Partial mole

1. Complete mole The whole conceptus a mass of vesicles. No embryo. Result of fertilization of enucleated ovum (no chromosomes) with a sperm which will duplicate giving rise to 46 chromosomes of paternal origin only.

1. Complete mole

2. Partial mole - A part of trophoblastic tissue only shows molar changes. - There is a fetus or at least an amniotic sac. - Result of fertilization of 1 ovum by 2 sperms - the chromosomal number is 69 chromosomes

2. Partial mole

DIFFERENTIATION BETWEEN COMPLETE AND PARTIAL MOLE Complete Mole Feature Present Absent Embryonic or fetal tissue Focal Diffuse Swelling of the villi Trophoblastic hyperplasia Paternal and maternal 69 XXY or 69 XYY Paternal 46 XX (96%) or 46 XY (4%) Karyotype Rare 5-10% Malignant Changes

Diagnosis

(A) Symptoms Amenorrhoea: short period (2-3 months). Exaggerated symptoms of pregnancy especially vomiting. 3.Preeclampsia (headache + oedema)

(A) Symptoms 4. Vaginal bleeding separation of vesicles from uterine wall brown blood - retained in the uterine cavity. 5. Enlargment & tenderness of the uterus (concealed blood). 6. Passage of vesicles is diagnostic. 7. Abdominal pain - dull-aching (rapid distension of the uterus) - colicky (expulsion) - sudden and severe (perforating mole) - ovarian pain torsion or stretching cystic ovary

(B) Signs

General examination Pre-eclampsia (20-30% of cases), Hypertension + proteinuria. Pallor (anemia). Hyperthyroidism (3-10% of cases) due to chorionic thyrotropin & HCG. Breast signs of pregnancy.

Abdominal examination The uterus is larger than the amenorrhea (50%). The uterus is doughy in consistency (absence of amniotic fluid + distension with vesicles). Fetal parts and heart sound cannot be detected (except in partial mole). Absence of external ballottement.

Local examination Passage of vesicles (sure sign). Bilateral ovarian cysts in 50% of cases. No vaginal ballottement.

(C) Investigations 3. X-ray to the abdomen: no fetal skeleton. Serum b -hCG level is highly elevated (> 100.000 mIU/m1). 2. Ultrasonography characteristic intrauterine "snow storm" appearance no identifiable fetus bilateral ovarian cysts 3. X-ray to the abdomen: no fetal skeleton. 4. X-ray of the chest.

A real-time ultrasound of a hydatidiform mole. The dark circles of varying sizes at the top center are the edematous villi.

Differential diagnosis The increased uterine size multiple fetuses single macrosomic fetus hydramnios uterine myomas. The uterine bleeding spontaneous abortion noncomplicated ectopic pregnancy uterine fibroids cancer of the uterine corpus

Complications Haemorrhage. Infection. Perforation of the uterus (spontaneously or during evacuation). Pregnancy induced hypertension. Hyperthyroidism. Subsequent choriocarcinoma in about 5% of cases and invasive mole in about 10% of cases. Recurrent mole (1-2%).

Treatment As soon as the diagnosis of vesicular mole is established the uterus should be evacuated. The selected method depends on: the size of the uterus whether partial expulsion has already occur the patient's age and fertility desire. 3.Cross - matched blood should be available before starting.

1. Evacuation Suction - dilatation of the cervix + Suction Curettage - D&C Hysterotomy - large mole - under i.v. oxytocin in saline solution; - - The material removed is sent for histological examination.

4. Hysterectomy It should be considered in women over 40 years who have completed their family to prevent developing choriocarcinoma.

Follow up ß-hCG is measured every week till the test becomes negative for 3 successive weeks, then every month for one year. Pregnancy is allowed if the test remains negative for one year.

Follow up Persistent high level remnants of molar tissues which necessitate: a. chemotherapy (methotrexate) b. hysterectomy, if women had enough children. Rising hCG level after disappearance means developing of choriocarcinoma or a new pregnancy.

Contraception during follow up The combined pill - when the beta-HCG becomes negative. Till this happens, the condom can be used.

Invasive Mole or Chorioadenoma Destruens a trophoblastic tumor with penetration of the myometrium by the chorionic villi; locally malignant; rarely metastasizes; may lead to perforation of uterus.

Gestational Choriocarcinoma Choriocarcinoma is evident in the fundus of the hysterectomy specimen Hemorrhagic lesions 40

Gestational Choriocarcinoma Sheets of anaplastic CT and ST cells with hemorrhage & necrosis. Myometrial & blood vessels invasion and early metastases No Villus formation Syncytiotrophoblast Cytotrophoblast 41

Metastatic Disease 1- Pulmonary (80 %) 2- Vaginal metastases (30 %) In 4% of patients after molar evacuation but is seen more commonly after other GTDs Sites of metastases 1- Pulmonary (80 %) 2- Vaginal metastases (30 %) 3- Hepatic (10 %) 4- Central nervous system (10 %) 42

Metastatic Disease If the pelvic examination & chest X-ray are negative, it is very uncommon to have metastatic involvement of other sites 43

Chest X ray: widespread metastatic lesions.

GTN Vaginal Metastasis

Cranial MRI scan: Large metastasis on the left (black arrows) Brain MRI of a patient with a solitary brain metastasis in remission

CT Scan: Liver metastsis Autopsy specimen Multiple hemorrhagic hepatic metastasis CT Scan: Liver metastsis

FIGO Anatomic Staging Of GTN Disease confined to the uterus Stage I GTN extends outside of the uterus but is limited to the genital structures (adnexa, vagina, broad ligament) Stage II GTN extends to the lungs, with or without known genital tract involvement Stage III All other metastatic sites (brain, liver) Stage IV FIGO Anatomic Staging The FIGO GTN Description = FIGO stage: FIGO Score FIGO Oncology Committee, 2002

Hysterectomy plus Chemotherapy is indicated: WMethotrexate (MTX) is the first line of choice Hysterectomy plus Chemotherapy is indicated: If the patient does not wish to preserve fertility or There is a resistance to chemotherapies Methotrexate is less toxic than actinomycin D Methotrexate or actinomycin D alone equally effective compared with a combination of the two.