Gestational Trophoblastic Disease - Assiut University

Gestational Trophoblastic Disease - Assiut University

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: 0.6-1.1 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 1628% 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 sperm 23Y

23X empty egg 23X sperm sperm 46,XX 23Y empty egg 23X 23X

46,XY Hydatidiform mole 2. Partial mole 23Y 23X 23X 23X 23X 23Y

sperm sperm 23X 23X normal egg 69,XXY 23X 23X 23X sperm sperm

23X Normal egg 69,XXX 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 Feature Complete

Partial Diploid(usually 46,xx or rarely 46,xy) Triploid (69,xxx or 69, xxy) Swelling of chorionic villi diffuse focal

Trophoblastic hyperplasia diffuse focal Embryonic tissue absent Present Often > 100,000 usually< 100,000

15 - 20% <5% Theca lutein cysts Up to 25% Rare Medical complications Up to 25% Rare

Karyotype hCG Trophoblastic sequelae Uterine size 50% large for dates Small for dates 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 dont 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 -HCG>100000IU/LHCG>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 Stage Description 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 Characteristic 0 1 2 4

<40 40 - - Antecedent preg Mole Abortion Term

- Pregnancy to treatment Interval (months) <4 months 4-6 months Pretreatment hCG <103

103- 104 104-105 >105 Largest tumor size (including uterus) < 3cm 3-4 cm 5cm

- Site of metastases Lung Spleen, kidney GI tract Liver, brain Number of metastases -

1-4 5-8 >8 Previous failed chemotherapy - - Single drug

2 drugs Age 7-12 months >12 months 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

Thank You For Your Time

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