Gestational Trophoblastic Disease Evidence Base management اعداد الدكتورة الق سعيد عبد الحسين

GTN 1- HM: ( CHM, PHM) 2- Invasive mole: ( chorioadenoma destruens). 3- Choriocarcinoma, PSTT Composed of both syncytiotrophoblast & cytotophoblast cells, Except PSTT ← Intermediate trophoblastic cell

HM The most common form of GTD Benign in nature Incidence vary world wide At a rate of 1/700 live birth , In Asian 1/387 ……non Asian 1/ 752 live birth 1600 cases registered in UK , folic acid and carotene A woman X O man ……..10X more risk of choriocarcinoma > A woman X A man AB women…….. worse prognosis. In Iraq ???? The year before and now, what do u think??

HM ( cont.) Should suspected in any women with: 1- Bleeding in 1st ½ of pregnancy 2- Passage of vesicles. 3- Hyperemesis gravidarum 4- Onset of preeclampsia < 24 wks 5- Absent fetal heart tone 6- Uterus too large for the estimated GA To establish the Dx: 1- U/S 2- Serial B-hCG

Invasive mole In 10- 15 % of patient who had primary HM, Considered benign neoplasm But its locally invasive and may → metastases.

Choriocarcinoma Is rare 2-5 % of all cases of GTN….In US 1/40 000 preg., but in Asia is higher ½ of all cases of Choriocarcinoma , the antecedent gestational event is HM ¼ follow term pregnancy ¼ follow abortion

PSTT Is a rare variant of GTT Arise from HM, or less common from normal term pregnancy Usually confined to the uterus Metastases late in its course Syncytiotropboblastic cell generally absent from this tumour…..→ minimal secretion of HCG

Important note Any women with a recent history of Molar pregnancy, abortion, or normal pregnancy…who presents with vaginal bleeding or a tumour in any organ should had at least one B-HCG essay to ensure that metastatic GTN is not the cause. This important since cure rate of properly treated metastatic GTN approaches 90%.

Clinical Findings: 4- Multiple theca lutein cysts causing enlargement of one or both ovaries …15-30% of Molar preg ( in ½ of these cases both ovaries are enlarged and causing pain, involution of the cysts proceeds over several weeks and is parallels the decline of B-hCG value. Surgical treatment of these cyst only if the cyst ( Rupture, Torsion, or hemorrhage , or the enlarged ov become infected. Some studies shows that patient with theca lutein cyst have more likely to developed malignant squeal of GTN.

Clinical Findings:( cont. ) 5- Preeclampsia in the first trimester or early second trimester ( unusual in normal pregnancy) is said to be pathognomonic for HM , seen in 10-12% of patients. 6- Hyperthyriodism from stimulation of thyrotropin receptors by hCG occ Treatment involve evacuation of the mole. Occasional ly may need brief antithyroid therapy.

Clinical Findings:( cont. ) Because of the earlier diagnosis of molar pregnancy , the classical S&S of gestational trophoblastic disase now less prevalent. In one center survey….the incidence of excessive uterine enlargement ( 28%), hyper emesis (8%), PEtrophoblastic disease remained static… for that surveilance of postmolar B-hCG is important.

Clinical Findings:( cont.) Lab. Findings: 1- The characteristic feature of GTN…. Is production of B-hCG. It may be detected in serum or urine of all patients with HM or malignant GTD and its level correlate well with the number of viable tumor cells present. 2- Monitoring of B-hCG is necessary tool for the diagnosis, treatment and follow up

Clinical Findings:( cont.) Today, sensitive and specific immunoassays are available to differentiate B-hCG from LH by measuring the beta chain of hCG. Seriel B-hCG are best monitored in the same Lab, using the same immunoassay technique. The rate of decline in B-hCG titer also important , using the serum B-hCG radioimmunoassay , a normal postmolar pregnancy hCG regression curve highlight the weekly hCG levels in patients undergoing spontaneous remission New test: immunostaining with p57KIP2 in special center for diagnosis of CHM

Clinical Findings:( cont.) This provide a reference for the comparison of serial values. Mostly B-hCG regress progressivly declined to nondetectable levels within 14 weeks following evacuation of a molar pregnancy If hCG titer rises or plateaus ←viable tumor continues to persist

Clinical Findings:( cont.) C. Ultrasonographic Findings: Simple, safe , reliable so it’s the method of choice for patients with suspected molar pregnancy. In CHM, …multiple hypo echoic areas correspondiIn partial mole …focal area of trophoblastic changes and fetal tissues may be noted Chorioca …U/S …enlarge uterus with necrotic and hemorrhagic pattern PTSS …show intrauterine mass

Clinical Findings:( cont.) U/S is mandatory in any patient with bleeding in the 1st half of pregnancy + a uterus greater than 12 weeks GA, even if the uterus is appropriate for GA. Early CHM, have U/S picture of delayed miscarriage or anembryonic pregnancy, also may associated with suggestive U/S changes of both cystic spaces in the placenta and a ratio of transverse / AP dimension of GS > 1.5 needed to reliably dx PHM (RCOG guidelines)

Clinical Findings:( cont.) In case of twin pregnancy, with one viable and the other molar pregnancy…. Can proceed with preg. If the mother wish that after appropriate counselling … Probability of achieving viable pregnancy is 40% + risk of complication such as pulmonary embolism and PET No risk of developing Persistent GTD after that + outcome after chemotherapy is un affected ( RCOG guidelines )

Differential Diagnosis GTD must be distinguished from : 1- Normal pregnancy 2- Ectopic pregnancy U/S is useful and quantitative B-hCG levels improve the accuracy of the diagnosis. Tissue obtained for histopathology is invaluable.

Treatment: HM: 1- Evacuation : after confirm the dx, CBC, clotting function study, LFT, RFT, CXR done preevacuation. Suction curettage is the method of choice, its safe, rapid and effective in nearly all cases. IV oxytocin started after moderate amount of tissue removed and may continuou for 24hs postevacuation if necessary ( but if no sever bleeing preferably at the end of evacuation … RCOG recommendation) Suction curettage with the largest curette possible should be followed by gentle sharp curettage, and tissue from the decidua bassalis should be submitted separately for pathological study.

Treatment :( cont.) Suction curettage can be done even if the uterus size 28 weeks Blood lose usually is moderate, but precaution should be taken for the possibility of a transfusion. When large HM ( > 12 weeks hemorrhage occurs. It’s the method of choice in CHM because of lack of fetal parts , catheter up to 12 mm usually enough

If there is sever Hge before evacuation, they can be used accordingly. Treatment :( cont.) Theoretical risk of using potent oxytocic drugs because of the potential to embolise and disseminate trophoblastic tissues through the venous system But this is know to occur in a normal pregnancy especially when uterine activity is increase, ex, in accidental Hge, the myometrial contraction will force the tissue into the venous space at the placental bed>>>> to embolic and metsastaic disease in the lung But significant Hge may occur after evacuation of large ut,. So recommended that medical Rx start after complete the evacuation, If there is sever Hge before evacuation, they can be used accordingly.

Oxytocin is usually the drug which is used Treatment :( cont.) Oxytocin is usually the drug which is used PG2 should be reserved for cases which is ineffective In PHM with large fetal parts, suction curettage cant be used, may need medical termination>>>>may have increase risk for the need of Rx for persistence GTD, although the % of PHM who need chemotherapy is low ( 0.5 %). Use of mifepristone should be avoided , evacuation of CHM with this agent should be avoided since it increase the sensitivity of the uterus to PG2 (RCOG guidelines)

Histological ex. Of the products of conception: Treatment :( cont.) Histological ex. Of the products of conception: All products of conceptions obtained after evacuation of termination of any pregnancy whether medical or surgical should be submitted for HP ex. That is because of the difficulties in the diagnosis of molar pregnancy ( pre evacuation ), especially in case of therapeutic termination of pregnancy, when there is no evidence of fetal tissue or in case of repeated evacuation Ploidy status may help to differentiate PHM from CHM

Persistent GTN after nonmolar pregnancy : Treatment ( cont.) Persistent GTN after nonmolar pregnancy : If persistent bleeding after nonmolar pegnancy ….should do PT to exclude persistent GTN Vaginal bleeding is common but symptoms from metastases as dyspnoea or abnormal neurological finding Persistent GTN should be suspected in any cases of acute respiratory or neurological symptoms after any pregnancy Prognosis for women with persistent GTN after nonmolar pregnancy is worse ( 21% mortality after life birth , 6% after nonomolar miscarriage, partly because of delay diagnosis)

Treatment :( cont.) Hysterectomy: Before use of suction curettage, hysterectomy was frequently use for patient with uterus >12-14 weeks size. Now its good option for patient not desirous of future pregnancy and for older women ( who are more likely to develop malignant sequelae) Don’t removed the theca lutean cyst….regression to normal size as the hCG titer diminished. Still there is need for hCG follow up Likelihood of metastatic disease following hysterectomy for GTD 20%....→3.5%

2- Complications: Treatment :( cont.) The maternal- fetal barrier contains leaks large enough to permit passage of cellular and tissue elements, so that migration of trophoblastic tissue to the lung are frequent. Spontaneous regression of these ectopic trophoblastic tissue will occur, but rarely …syndrome of acute pulmonary insufficiency may occur …( presented as dyspnoea and cyanosis within 4-6 hours after evacuation of molar pregnancy as result of massive deportation of trophoblasts to pulmonary vasculature … and subsequent formation of pulmonary emboli Excessive fluid administartion, A., infection, coagulopathy PET, hyperthyriodism …→Pulmonary oedema, …→high output congestive heart failure

Complications ( cont.) Medical complications of HM are observed in approximately 25% of patients with uterine enlargemnt of > 14-16 wks gestational size and less frequently among patient with lesser degrees of uterine enlargemnt The mole should be evacuated as soon as possible after stabilization of any medical complications.

Treatment (cont.) 3- Prophylactic chemotherapy: ??? If to give prophylactic chemotherapy ( methotrexate, dactinomycine )after CHM, should be offered to patient considered at high risk for persistent GTD ( >35, previous molar pregnancy, trophoblastic hyperplasia, B-hCG> 100 000 mIu/L, uterine size more than gestational age, ovarian size more than 6cm), or in whom poor follow up is expected. Several studies ….→→incidence of postmolar GTD may be ↓ with prophylactic chemotherapy but the incidence not reduced in p. with low risk Other study shows that p. who use prophylactic chemotherapy and develop postmolar GTD will need more chemotherapy for the follow up In addition to fatalities that could occur with the chemotherapy while its not eliminate the need for more surveillance Further studies needed to justify the use in comparison with SE.

Treatment (cont.) 4- surveillance following molar pregnancy: Because of 20-30 % risk of malignant dis. So regardless the method of termination, close monitoring with serial B-hCG is essential for every patient. After evacuation by 48hs start serial B-hCG… then weekly interval …till serum B- hCG declines to non detectable level on 3 successive essay If titer remission occur spontaneously within 14 wks without plateau…then repeat b-hCG titer monthly at least one year.

In case of PHM, at least 6-12 months . Treatment (cont.) In case of PHM, at least 6-12 months . Then the patient enter into regular gyn. Care program. Despite earlier Dx of Molar pregnancy…incidence of persistent GTD has not decreasd ¾ of p. with malignant non metastatic GTD…& ½ with malignant metastatic disease develop these tumor as sequelae to HM, the remainder followed term pregnancy, abortion or ectopic pregnancy. Most malignant squally usually within the 1st 6 months after evacuation

B/ Malignant GTN: may be diagnosed as: Treatment (cont.) B/ Malignant GTN: may be diagnosed as: Invasive mole, choriocarcinoma, PSTT 1- Plateauing or Rising postmolar B-hCG( plateau of 4 values ± 10% over a period of 3 weeks. 2- Rise in B-hCG of > 10% of 3 values over a period of 2 weeks. 3- persistence of detectable B-hCG > 6 months after evacuation.

Looks for the site of metastasis esp. in the lower genital tract Treatment (cont.) If malignant disease is dx, …next good history and exam ( may see enlarge ut. + ovarian enlargment caused by theca lutein cyst) Looks for the site of metastasis esp. in the lower genital tract CXR may see lung metastases Liver metastases dx by U/S or CT Brian metastases dx by CT or MRI Ratio of S B-hCG values to the concentration of B-hCG in CSF ( normal >60: 1) may help Baseline, hematological count , coagulation study, LFT, RFT to assess the risk for drug toxicity.

Treatment (cont.) After all site of metastases identified…next Patient desire to preserve fertility or not Specific therapy should be initiated.

Single agent chemotherapy. Treatment (cont.) 1- Non metastatic GTD: Trophoblastic disease confined to the uterus is the most common malignant lesion seen in GTD Dx usually during the follow up period after evacuation of molar pregnancy Single agent chemotherapy. Combined chemotherapy and hysterectomy with surgery done on the 3rd day of drug therapy if the patient dose not wish to preserve reproductive function and the disease confined to the uterus.

Treatment ( cont.) The change in the diagnosis from premalignant molar pregnancy to malignant form which need chemotherapy usually made clinically. This made on clinical assessment, especially the pattern of changes of B- can bleed heavily

Treatment (cont.) Chemotherapy regimens for non metastatic or low risk GTD: Drug doses: Methotrexate 30-60mg/ m2 IM once a week ( for non metastatic dis only) Methotrexate 0.4 mg / Kg /d IV or IM for 5 days, repeat every 14 days.. The therapeutic efficacy of the two drugs is apparently equivalent But no RCT to compare the effect of each

The regimen of choice has not been establish yet . Treatment (cont.) The regimen of choice has not been establish yet . But Weekly IM methotrexate injection provide a convenient and cost effective alternative to the more intense 5 days regimens with methotrexate or dactinomycin and with minimal SE Treatment failure: ( indicated by rising B-hCG or presence of new metastases) or intolerable SE should resucourse and the first day of the next.

Treatment (cont.) The first cycle of treatment to be given as inpatient, but subsequent cycles as outpatient but close to the hospital

Chemotherapy regimens for non metastatic or low risk GTD: Treatment (cont.) Chemotherapy regimens for non metastatic or low risk GTD: Follow up: B-hCG titer weekly. Switch to alternative drug if B-hCG rises 10 folds or more , titer plateaus at elevated levels, or new metastases appear. Dialy or weekly Lab as indicated, hold chemotherapy for WBC < 3000 ( absolute neutrophlie <1500). Platelet < 100000, significantly elevated BUN, Cr, AST ,ALT, bilirubin, or significant SE (Sever stomatitis, GI ulceration, or febrile coarse).

Treatment (cont.) OCCP or other birth control, continuo for at least 1 year following remission Chemotherapy continued for I course after negative B-hCG ( the number of treament cycles necessary to induce remission is proportionate to the magnitude of B-hCG conc at the start of therapy. , at least 3-4 courses of single. And CXR monthly until remission is induced, at 3 months intervals for 1 year thereafter, then at 6-month interval indefinitely.

Treatment ( cont.) CCP if taken while the hCG still high ….may increase the need for treatment Other type of hormonal contraception don’t link to the need for more treatment The small potential risk of using emergency CC in woman with ↑ B-hCG outweighed the potential risk of pregnancy to the woman HRT may be used safely once hCG return to normal level

Using single agent chemotherapy, or multiple agent. Treatment (cont.) 2- Metastatic GTD: Using single agent chemotherapy, or multiple agent. Multiple agent in case of resistant to single agent

3- clinical classification of malignant GTD Treatment (cont.) 3- clinical classification of malignant GTD National Cancer institute (NCI): use in the US to determine the prognosis of the p. in response to single agent chemotherapy. World Health Organization ( WHO): this scoring system is based on individual’s risk factors. As age,

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