Definition

:
It is a pathologic condition characterized by aggressive invasion of the endometrium and myometrium by trophoblastic cells.

Incidence: 1:5000 pregnancies in the Far East and 1:50,000 pregnancies in U.K. Pathology:
 Origin: GTN arises following conception as follows:  About 50% of cases follow hydatidiform mole.  25% follow abortion.  23% follow normal pregnancy.  2% follow ectopic pregnancy.  In rare cases, the tumor arises as a teratoma in the ovary or testicles. Many of the reported nonmolar cases actually may represent disease due to an unrecognized early molar pregnancy.  Macroscopic Appearance:  The uterus: o The tumor starts in the endometrium: as a soft friable dark red hemorrhagic mass projecting into the cavity of the uterus, sometimes forming a polyp. o In some cases, the tumor arises deep in the myometrium (intramural): so it will not give rise to uterine bleeding except late in the disease and curettage of the uterus will not show the tumor.  The ovaries: The tumor secretes human chorionic gonadotropin (HCG) which causes cystic changes in the ovaries in about 30% of cases. The cysts are lined by theca lutein cells. The tumor also secretes human placental lactogen and chorionic thyrotropin.  Microscopic Appearance: The tumor microscopically consists of:  Cells: sheets of cytotrophoblasts (Langhans cells) and syncytium showing malignant characteristics.  Blood vessels: The blood vessels are eroded by the tumor and this causes the hemorrhagic naked-eye appearance.  Villi: No chorionic villi are seen and this differentiates choriocarcinoma from invasive mole.  Mode of spread:  Direct spread: to other pelvic organs as the tubes, ovaries, and parametrium.  Bloodstream: the tumor disseminates early by the blood stream to reach distant organs as the liver, lungs, brain, and bones. Retrograde venous spread may give rise to secondaries in the vulva and vagina. Secondaries of choriocarcinoma:

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o Appear as dark red hemorrhagic nodules. disseminate late. 20. necrosis. It develops from neoplastic transformation of chorionic-type intermediate trophoblast. this tumor resembles placental site trophoblastic tumor. These tissues penetrate deep into the myometrium. epithelioid trophoblastic tumor grows in a nodular fashion rather than the infiltrative pattern of placental site trophoblastic tumor.25% of patients will present with metastatic disease. 2|Page Tumor . Grossly. Gestational Placental Site Trophoblastic Tumor The preceding pregnancy may be remote. Histologic Classification Origin Almost exclusively from complete or partial molar gestations. adjacent parametrium. or cannot be confirmed. sometimes involving the peritoneum. It can follow any type of pregnancy but develop more commonly following a normal pregnancy Choriocarcinoma Gestational choriocarcinomas initially invade the endometrium and myometrium but tend to develop early blood-borne systemic metastases. Invasive Mole Most cases develop following molar pregnancy. Sheets of anaplastic cytotrophoblast and syncytiotrophoblast cells with prominent hemorrhage.000). It tends to infiltrate only within the uterus. the pattern mirrors that of choriocarcinoma. o Produce large amounts of human chorionic gonadotropin. Histologic characters Whole chorionic villi with excessive trophoblastic overgrowth and invasion. but the cells are smaller and display less nuclear pleomorphism. Chorionic villi are absent. o In rare cases the secondaries disappear after removal of the primary tumor. and vascular invasion. When this tumor spread. 50% of all reported cases were fatal. vagina (30%). It is supposed that the body forms antibodies aqamst chorionic tissue and these antibodies will overcome the secondaries after removal of the primary growth. brain (10%) and liver (10%). Epithelioid Trophoblastic Microscopically. or vaginal vault. and produce low levels of β-hCG relative to their mass. less commonly follow a nonmolar pregnancy (1:30. This tumor consists predominantly of intermediate trophoblasts at the placental site Behavior Locally invasive but lack the pronounced tendency to develop widespread metastases typical of choriocarcinoma. Classification: I. o The common sites of metastases are the lungs (80%).

 Alternatively. 3|Page . O Vagina or lungs No Diagnosis: I.000 mIU/ml > 100.HCG Blood group Metastasis Prior chemotherapy High risk group Term pregnancy > 4 months > 40.  Amenorrhoea: due to continuous production of β-HCG.000 mIU/ml < 100. vaginal hemorrhage can follow tumor erosion into uterine vessels.  Manifestations:  Locally invasive trophoblastic tumors may perforate through the myometrium and lead to intraperitoneal bleeding. B Liver or brain Failed Molar pregnancy or abortion < 4 months < 40. Clinical Classification  Non-metastatic Disease:  Types:  Invasive moles arising from complete molar gestations comprise most cases of nonmetastatic GTN (15-20% of complete moles develop locally invasive disease after evacuation.000 IU/ml A.  Rupture of the liver. or necrotic tumor may involve the uterine wall and serve as a nidus for infection. but rarely after 2 years of abortion.  Abdominal swelling: may be present.  Onset: Bleeding occurs immediately or after several weeks or months.  Prognosis: the prognosis is excellent for all types despite these possible manifestations. or evacuation of a molar pregnancy.  Offensive blood stained vaginal discharge: due to ulceration and infection of the tumor.000 IU/ml AB.  Metastatic Disease: Low risk group Antecedent pregnancy Duration of the disease Serum β. labour.  Acute abdominal pain: Due to:  Perforation of the uterus by the growth and intraperitoneal haemorrhage.  Placental site trophoblastic tumors and epithelioid trophoblastic tumors are other rarer causes of nonmetastatic GTN.  Rupture or torsion of a theca lutein cyst. 2-4% of partial moles). Clinical presentation  Symptoms: History of recent abortion.HCG Urinary β.II. delivery or evacuation of a vesicular mole followed by:  Persistent or irregular vaginal bleeding:  Incidence: Vaginal bleeding is the commonest symptom.

 PV examination: haemorrhagic secondaries may be found in the vagina. and 21).  β-hCG remains elevated for 6 months or more.  Dyspnoea and haemoptysis (lung metastases). phantom β-hCG can be demonstrated by a negative urine pregnancy test.  Rise of β-hCG of 3 weekly consecutive measurements or longer.  Hyperthyroidism: It is present in about 10% of cases because: o The HCG has the capacity to stimulate the thyroid gland. 7. This "phantom" β-hCG reading results from the presence in serum of heterophilic antibodies that interfere with the β-hCG immunoassay and cause a false-positive result. and 14).  Examination:  General examination:  Cachexia and severe anaemia: which is out of proportion to the amount of blood loss due to toxic absorption from the necrotic tumor and secondary infection.  Fever: is common due to necrosis and infection. 4|Page .  Neurological symptoms e. Patients with persistent mild elevation of β-HCG should be investigated for the following possibilities:  Phantom β-HCG: Occasionally. no true β-hCG or trophoblastic disease is present.HCG every week until it becomes negative then every month for one year. patient should be followed by serial serum β. Criteria for the Diagnosis of GTN (FIGO Oncology Committee. II. o The ovaries may be enlarged and cystic.g.  Bimanual examination: o The uterus may be of normal sized or enlarged and soft. only if the patient's serum β-hCG level is significantly higher than the detection threshold of the urine test. 14. 7. Symptoms suggesting metastasis: May be the first manifestation of the disease:  Vaginal swellings (vaginal metastasis). There are several ways to clarify the diagnosis:  First. Investigations I. in reality.  Jaundice (liver metastases). o Trophoblasts secrete chorionic thyrotrophin.  Local examination:  Inspection: haemorrhagic secondaries may be seen in the vulva. headache (brain metastases).  Histologic diagnosis of choriocarcinoma. For early detection Following evacuation of a molar pregnancy. over a period of 2 weeks or more (days 1. persistent mild elevations of serum β-hCG are detected when. 2002)  Plateau of β-hCG lasts for 4 measurements over a period of 3 weeks or longer (days 1.  Differential diagnosis: with other causes of secondary postpartum hemorrhage.

the ratio is less than 60:1. Lumbar puncture with simultaneous estimation of β.Second. Hormonal contraception may be helpful in lowering titers to an undetectable level.  Evaluation of liver metastasis: CT & MRI are done. if phantom β-hCG is suspected.  Other values of ultrasonography include: detecting the tumor itself.  Chemotherapy and surgery usually have no effect. and most of these are detected by routine chest x-ray which reveals "cannonballs" or "snowstorm" appearance.  Third. labour or evacuation of a mole. 5|Page .  Lastly.  Uterine curettage: This should be done in every case of severe or persistent uterine bleeding occurring after abortion. an intramural tumor will not be detected by curettage. However. III.  CT & MRI: when chest x-ray is negative. a different β-hCG assay performed using an alternate method may accurately demonstrate the absence of true β-hCG. sp. performing serial dilutions of the serum sample results in a proportional decrease in the βhCG level if β-hCG is truly present. To confirm the diagnosis  Trans-vaginal sonography:  Confirming serologic diagnosis: when serologic criteria are met for GTN. some specialized laboratories may be able to block the heterophilic antibodies.  II. liver metastases and possible Doppler ultrasound to diagnose intramural tumor.  Quiescent Gestational Trophoblastic Disease:  Patients with persistent mild elevations (usually in the range of 50 mIU/mL or less) of true β-hCG may have a dormant premalignant condition if no tumor is identified by physical examination or imaging studies.HCG in serum and CSF should be done if brain scan is negative:  In absence of brain metastases the concentration of β. but patients should be monitored closely because metastatic GTN may develop eventually. phantom β-hCG measurements will be unchanged.  Evaluation of brain metastasis: CT & MRI. For staging (detect spread)  Evaluation of pelvic metastasis:  Pelvic CT scan: to determine the extent of the disease. when:  There has been a long delay in monitoring of serial β-hCG levels or  Noncompliance with contraception or  Both. the cysts in the ovaries. The low β-hCG titers may persist for months or years before disappearing. computed tomography (CT) or magnetic resonance imaging (MRI) is performed.HCG in the spinal fluid is low and serum/CSF ratio is greater than 60:1. a new intrauterine pregnancy should be excluded using β-hCG levels correlated with sonographic findings.  Excisional biopsy: from possible metastases in the vulva or vagina.  Evaluation of lung metastasis:  Chest x-ray: About 80% of patients with choriocarcinoma have pulmonary metastases.  With brain metastasis.

followed by monthly titers until the level is undetectable for 12 months. β-hCG is so essential for diagnosis. broad ligament) GTN extends to the lungs. V. electrolytes. Explanation is unknown. liver function and renal function tests. prognosis is bad in women with group A or AB. Blood grouping. II. Electrocardiogram. Women with stage IV disease are followed for 24 months because of the greater risk of late relapse. determine prognosis and follow up treatment. high risk = WHO score of > 7. or III GTN consists of weekly β-hCG measurements until the level is undetectable for 3 weeks. To prepare for surgery     Complete blood count and platelet count. vagina. To follow up treatment Monitoring of patients with stage I. Assessment of the patient for treatment planning I.IV. High) Modified WHO Prognostic Scoring System as Adapted by FIGO Scores 0 1 2 Age (yr) Antecedent pregnancy Interval months from index pregnancy Pretreatment serum β-hCG (mIU/mL) Largest tumor size (including uterus) Site of metastases Number of metastases Previous failed chemotherapy drugs Blood Group < 40 Mole <4 < 1000 — Lung — — 4 — — ≥ 40 Abortion 4–6 1000-10000 3–5 cm Spleen. Patient risk group (Low vs. kidney 1–4 — O or A — Term 7–12 10000-100000 ≥ 13 ≥ 100000 — Liver. Thyroid function tests to diagnose the rare patient with secondary hyperthyroidism. 6|Page . brain >8 ≥ 5 cm Gastro-intestinal 5–8 1 AB or B ≥2 Low risk = WHO score of 0 to 7. with or without known genital tract involvement All other metastatic sites (brain. Treatment: I. liver) Stage I Stage II Stage III Stage IV II. Stage (FIGO anatomic staging) Clinical staging (FIGO anatomical staging) Disease confined to the uterus GTN extends outside of the uterus but is limited to the genital structures (adnexa.

000 cGy) with concurrent use of combination chemotherapy (intensive intravenous combination chemotherapy and intrathecal methotrexate)  Craniotomy to manage complications (acute decompression) Liver Resistant Resection to manage complications. Metastatic  Aggressive combination chemotherapy: EMA/EP regimen is the most effective treatment (it has a poorer prgnosis). Second-line combination chemotherapy / Hepatic arterial infusion of chemotherapy. Epithelioid Trophoblastic Tumor Hysterectomy is the primary treatment. If no further need for fertility: Hysterectomy with adjunctive chemotherapy.II. Rare types of GTN Placental site trophoblastic tumor Non-Metastatic If fertility can be sacrificed: Hysterectomy is the primary method of treatment due to its relative insensitivity to chemotherapy. here are too few cases to evaluate the efficacy of chemotherapy 7|Page . Adjuvant chemotherapy is administered for three reasons:  To reduce the likelihood of disseminating viable tumor cells at surgery  To maintain a cytotoxic level of chemotherapy in the bloodstream and tissues in case viable tumor cells are disseminated at surgery  To treat any occult metastases that may already be present at the time of surgery Resistant If the patient wants to preserve fertility Combination chemotherapy Local resection (when local resection is planned. or arteriography may help to define the site of the resistant tumor) If no further need for fertility Hysterectomy with adjunctive chemotherapy Stage II and III Low risk (local resection is optional) Initial Resistant Initial Resistant Initial Brain Single-agent chemotherapy Combination chemotherapy High risk (local resection is optional) Combination chemotherapy Second-line combination chemotherapy Stage IV Combination chemotherapy  Whole-brain irradiation (3. If patient wants to preserve fertility: combination of operative hysteroscopic resection followed by chemotherapy. Treatment according to patient risk Stage I Initial If the patient wants to preserve fertility: Single-agent chemotherapy.  Radiation may have a role in some situations. MRI. a preoperative ultrasonography. Local resection is optional.

This is given for patients who become refractory to or relapse from EMA/CO.  Actinomycin-D: in the presence of renal or hepatic impairment we start with or shift to actinomycin-D which is less toxic. and 7 and oral folinic acid 7. Drugs used Course of therapy  Methotrexate:  Weekly regimen: 30 mg/m2 with minimal toxicity (up to 81% CR rate).  EMA/EP protocol: replacing cyclophosphamide and vincristine component with etoposide and cisplatin. toxic symptoms recover in 10 days" (up to 67 CR rate).12 µg/kg each day. 3. 5-year survival rate is 97% Results 5-year survival rate is 70% 8|Page .  The Modified Bagshawe Protocol (MBP): or EMA/CO protocol (Etoposide.  5-day regimen: 0.  5-day regimen: 5-day course of dactinomycin.4 mg/kg/day for 5 consecutive days on alternating weeks (up to 60 CR rate). methotrexate.I. Treatment is repeated every 2 weeks "not < 7 days. 5. and Actinomycin-D alternating with cyclophosphamide and oncovin "vincristine") This is now used as a primary treatment. at least two additional courses of chemotherapy are administered to reduce the risk of relapse.25 mg/m2 IV bolus every 2 weeks. not > 14 days. 6. It is given for resistant GTN. Chemotherapy Chemotherapy is given according to the risk group identifies: Low risk group therapy A single cytotoxic drug is given:  Methotrexate: usually the drug to start with. 4. After normal hCG levels are attained.5 mg orally on days 2. Combination chemotherapy should be given as often as toxicity permits until the patient achieves three consecutive normal hCG levels. β-hCG is followed up once or twice weekly until it is undetectable then one more course is given.  Alternating Regimen: 50 mg on days 1. Actinomycin-D & Cyclophosphamide. and 8.  Actinomycin-D:  Pulse regimen: 1. High risk group therapy Multiple agents are used:  The MAC triple therapy of Li: Methotrexate.

So:  Brain metastases should receive radiation.  If further children are not desired hysterectomy may be done during the first course of chemotherapy.  The ovaries are left to avoid menopausal symptoms (ovarian metastasis is very rare). o Perforation of the uterus with intra-Peritoneal haemorrhage. Post-treatment surveillance  All patients with stage I through stage III disease should receive follow-up with:  Weekly measurement of β-hCG levels until they are normal for 3 consecutive weeks  Monthly measurement of β-hCG values until levels are normal for 12 consecutive months  Effective contraception during the entire interval of hormonal follow-up  Patients with stage IV disease should receive follow-up with:  Weekly determination of β-hCG levels until they are normal for 3 consecutive weeks  Monthly determination of β-hCG levels until they are normal for 24 consecutive months  Subsequent Pregnancy Outcome: Patients may expect a normal reproductive outcome after achieving remission from gestational trophoblastic disease. Surgery  Hysterectomy:  Indications:  Drug resistance or toxicity.  Surgical excision of localized metastases: in the vagina. lung or brain may be indicated:  If these lesions persist after chemotherapy (resistant cases). 2000-3000 rads "cGy" in combination with chemotherapy. This shortens the period of treatment with chemotherapy.II. Radiotherapy Liver and brain metastases may bleed as a result of necrosis during the course of chemotherapy. of tumor emboli.  Liver metastases receive radiation.  Preparation:  The operation should be done during a course of chemotherapy to minimize dissemination. from the bowel.  In massive haemorrhage e. Women having a pregnancy affected by a histologically confirmed complete or partial mole may be counseled that the risk of a repeat mole in a subsequent pregnancy is 1 to 2 percent. 9|Page . 2000 Rads only if they are extensive or subcapsular. Most will be of the same type of mole as the preceding pregnancy. III. III.g. Pregnancy after combination EMA/CO chemotherapy for GTN also has a high probability of success and a favorable outcome.  Complications as: o Severe uterine bleeding. o Rupture or torsion of a theca lutein cyst.

and breast cancer up to 25 years after treatment for GTN. colon cancer. melanoma. Secondary Tumors: Etoposide-based combination chemotherapy has been associated with an increased risk of leukemia. Algorithm for the management of persistent gestational trophoblastic tumor 10 | P a g e .