Gestational Trophoblastic Disease (GTD) By Ahmed Refaat Abd ELzaher Assistant Lecturer of Medical Oncology South Egypt Cancer Institute 2015

GTD Overview Heterogeneous group of related lesions Arise from abnormal proliferation of trophoblast of the placenta Can follow any gestational event – abortion, miscarriage, ectopic, normal pregnancy Unique because the maternal lesions arise from fetal (not maternal) tissue Most GTD lesions produce (B-hCG) Can be cured even in the presence of widespread metastases

Overview Hydatidiform Mole: Complete Partial ** Benign Gestational Trophoblastic Neoplasia (GTN): Persistent/Invasive Mole Choriocarcinoma Placental-Site Trophoblastic Tumor (PSTT) ** Malignant

Relationship of HM. IM. CH hydatidiform therapeutic or mole spontaneous abortion term pregnancy ectopic invasion mole choriocarcinoma.

Hydatidiform mole

Hydatidiform Mole North America: per 1000 pregnancies Asia: 2-10 per 1000 (3x Western countries) Difference possibly related low dietary intake of carotene (vitamin A deficiency) and animal fat More common at reproductive extremes in age (>35y or <20y)

Hydatidiform Mole Risk Factors: History of previous GTD –If one previous mole, 1% chance of recurrence (vs. 0.1% in general population) –If 2 previous moles, risk of recurrence increases to 16-28% Smoking Vitamin A deficiency Blood type: –A or AB are at slightly higher risk than those with type B or O

Hydatidiform mole 1.Complete mole 23X spermempty egg 23X 46,XX 23X spermempty egg 23Y 23X 46,XY 23Y sperm

Hydatidiform mole 2.Partial mole 23X spermnormal egg 23Y 23X 69,XXY 23Y sperm 23X spermNormal egg 23X 69,XXX 23X sperm 23X

Hydatidiform Mole Clinical Manifestations: Vaginal bleeding (97%) /anemia Enlarged uterus (size > dates) Pelvic pain Theca lutein cysts Hyperemesis gravidarum Hyperthyroidism Preeclampsia <20 weeks gestation Vaginal passage of hydropic vesicles Partial mole usually presented as incomplete or missed abortion

Diagnosis Complete : U/S usually very sensitive – generalized swelling (snow-storm ) partial mole U/S may detect focal cystic spaces of varying diameter Diagnosis on histology of curettings

Complete vs. partial mole PartialCompleteFeature Triploid (69,xxx or 69, xxy) Diploid(usually 46,xx or rarely 46,xy) Karyotype focaldiffuseSwelling of chorionic villi focaldiffuseTrophoblastic hyperplasia PresentabsentEmbryonic tissue usually< 100,000 Often > 100,000hCG <5% %Trophoblastic sequelae RareUp to 25%Theca lutein cysts RareUp to 25%Medical complications Small for dates50% large for datesUterine size

Hydatidiform Mole Treatment Evaluate for coexisting conditions: - History and physical - CBC, coagulation profile, serum chemistry - thyroid function - blood type and cross match - chest radiography - pelvic ultrasonography Evacuation of mole - Suction curettage - Hysterectomy if completed childbearing If Rh negative, give rhogham

Hydatidiform Mole Treatment chemotherapy HM don’t need usually chemotherapy because HM is benign disease.

Follow-Up Care – Molar Pregnancy 80% of patients cured by evacuation Follow B-hCG levels every two weeks until 3 consecutive tests negative Then monthly B-hCG every month for 6-12 months More than half of patients will have complete regression of hCG to normal within 2 months of evacuation. Avoid pregnancy for at least 6 months after first normal B-hCG (oral contraceptive pills is preferable) Subsequent Pregnancies: –Send placenta for pathology –Check B- hCG 6 weeks postpartum

Prognosis Complete mole has the latent risk of local invasion or telemetastasis The high-risk factors includes –β-HCG>100000IU/L –uterine size is > 20 weeks size. –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

Gestational Trophoblastic Neoplasia (GTN) Persistent/Invasive Mole Choriocarcinoma Placental-Site Trophoblastic Tumor (PSTT) ** Malignant

Risk Factors for GTN After Mole Preevacuation uterine size greater than gestationl age or larger than 20 weeks gestation Theca-lutein cysts larger than 6 cm Age > 40 years Serum hCG levels > 100,000 mIU/mL Previous hydatidiform mole

Invasive Mole Myometrial invasion by hydatidiform mole Formerly known as chorioadenoma destruens 1 in 15,000 pregnancies 10-17% of hydatidiform moles will progress to invasive moles

Persistent Mole Definition of persistent molar disease and need for chemotherapy (at least one of the following): –B-hCG plateau for ≥ 4 values for ≥ 3 weeks –B-hCG increase of ≥ 10% for ≥ 3 values for ≥ 2 weeks –B-hCG persistence 6 months after molar evacuation –Histopathologic diagnosis of choriocarcinoma –Presence of metastatic disease

Choriocarcinoma Most aggressive type of GTN Abnormal trophoblastic hyperplasia Absence of chorionic villi Direct invasion of myometrium Most often develops from a complete hydatidiform mole Vascular spread to distant sites: –Lungs –Brain –Liver –Pelvis and vagina –Spleen, intestines, and kidney

Choriocarcinoma May come from any type of pregnancy - 25% follow abortion or tubal pregnancy - 25% with term gestation - 50% from hydatidiform moles 2-3% of moles progress to choriocarcinoma Incidence 1 in 40,000 pregnancies –Rarely, choriocarcinomas can develop in other parts of the body in both men and women. These are not related to pregnancy as ovaries and testicles Nongestational choriocarcinoma tends to be less responsive to chemotherapy and has a less favorable prognosis than the gestational variant

Placental-Site Trophoblastic Tumor (PSTT) Originate from intermediate cytotrophoblast cells Secrete human placental lactogen (hPL) B-hCG often normal Less vascular invasion, necrosis and hemorrhage than choriocarcinoma Lymphatic spread Arise months to years after term pregnancy but can occur after spontaneous abortion or molar pregnancy

Placental-Site Trophoblastic Tumor (PSTT) Most common symptom is vaginal bleeding Tend to: - Remain in uterus - Disseminate late - Produce low levels of B-hCG compared to other GTN - Be resistant to chemotherapy (treat with surgery)

Signs & Symptoms GTN Continued uterine bleeding, uterine perforation, enlarged irregular uterus, persistent bilateral ovarian enlargement From metastatic lesions: abdominal pain, hemoptysis, melena, increased intracranial pressure (headaches, seizures, hemiplegia), dyspnea, cough, chest pain

Diagnosis of GTN Increase or plateau in B-hCG after molar pregnancy Pathologic diagnosis by D&C or biopsy of metastatic lesions WARNING: biopsy of metastatic lesions can result in massive hemorrhage Metastatic workup: CXR (or CT chest), CT abdomen/pelvis +/- CT/MR of brain

Classification & Staging of GTD FIGO Staging –Describes anatomic distribution of disease World Health Organization (WHO) Scoring Index –Describes prognosis

FIGO Staging StageDescription I Disease confined to the uterus II Disease extends outside the uterus but limited to genital structures (adnexa, vagina, and broad ligament) III Disease extends to the lungs with or without genital tract involvement IV Disease involves any other metastatic sites

The World Health Organization (WHO) scoring system for GTD

WHO Prognostic Score Index Score Characteristic0124 Age<40≥40-- Antecedent pregMoleAbortionTerm- Pregnancy to treatment Interval (months) <4 months 4-6 months 7-12 months>12 months Pretreatment hCG< >10 5 Largest tumor size (including uterus) < 3cm3-4 cm≥5cm- Site of metastasesLungSpleen, kidney GI tractLiver, brain Number of metastases >8 Previous failed chemotherapy --Single drug≥2 drugs

Therapy for GTN Single agent therapy for nonmetastatic (stage I) or low-risk metastatic (stage II and III) with score <7  survival rates ~ 100% Combination chemotherapy +/- radiation and/or surgery for high-risk metastatic disease with score ≥7

Therapy: Nonmetastatic GTN Single-agent with either methotrexate or dactinomycin Chemotherapy continued until hCG values normal and then 2-3 cycles beyond Change to alternative single-agent for hCG plateaus above normal or toxicities If significant elevation of hCG or new metastases, switch to multiagent 85-90% cured with initial regimen, <5% will require hysterectomy for cure

Therapy: Low-risk Metastatic GTN Low-risk metastatic disease can be treated with single-agent therapy with 5-day regimens Cure rates ~100% but 30-50% will be develop resistance to first agent If resistance to sequential single-agent chemotherapy (5-10% of patients), switch to multiagent chemotherapy

Therapy: High-risk Metastatic GTN Stage IV Stage II/III with score > 7 Disease refractory to single-agent chemotherapy Combination Chemotherapy: EMACO: –Day 1: Etoposide, Methotrexate and Dactinomycin –Day 8: Cyclophosphamide and Vincristine (Oncovorin) –Repeat q2 weeks until remission –Continue for at least 2-3 cycles beyond first normal hCG MAC (Methotrexate, Dactinomycin, Cyclophosphamide) EMA/EP – EMA + Etoposide and Cisplatin

Metastatic Gestational Trophoblastic Tumors Surgery –It is indicated for tumor resistant to chemotherapy and single metastases persisting despite chemotherapy. RT –RT, in combination with chemotherapy, is clearly indicated for the primary management of patients with brain metastases.

PSTT Therapy Hysterectomy Chemotherapy for metastatic disease or nonmetastatic disease with poor prognosis: - Interval from index pregnancy > 2 years - Deep myometrial invasion - Tumor necrosis - Mitotic count > 6 per 10 high-power fields Survival rates: –~100% for nonmetastatic disease –50-60% for metastatic disease

Follow-up Care After completion of chemotherapy, follow serial hCG every 2 weeks for three months, then monthly for one year Physical examinations every 6-12 months and imaging as indicated

Reproductive Performance Most women resume normal ovarian function Women who undergo chemotherapy are advised not to conceive for one year after completion of treatment No increase risk of stillbirths, abortions, congenital anomalies, prematurity, or major obstetric complications

False Positive Serum hCG Phantom hCG syndrome/ phantom choriocarcinoma 3-4% of healthy individuals have human-antimouse antibodies that can mimic hCG immunoreactivity To verify: –Urine hCG should be negative –Should not show parallel decrease with serial dilutions –Test at national B-hCG reference lab

Summary Hydatidiform mole is a benign condition, 80% cured with suction D&C Malignant GTN: –Persistent or invasive mole –Choriocarcinoma –PSTT WHO score > 7 represents high-risk disease GTN very sensitive to chemotherapy

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