Gestational Trophoblastic Disease (GTD) Lecture Notes

Gestational Trophoblastic Disease (GTD) Dr Muhamed Ahmed Al Bellehy Under Supervision of Prof Dr Mohamed Hesham Disease of trophoblast characterized by abnormal trophoblast proliferation  Gestational trophoblastic disease (GTD) comprises a group of disorders...

Gestational Trophoblastic Disease (GTD) Dr Muhamed Ahmed Al Bellehy Under Supervision of Prof Dr Mohamed Hesham Disease of trophoblast characterized by abnormal trophoblast proliferation  Gestational trophoblastic disease (GTD) comprises a group of disorders RCOG, 2020 o premalignant conditions : complete and partial molar pregnancies (known as hydatidiform moles) o malignant conditions (gestational trophoblastic neoplasia (GTN)) of  invasive mole  choriocarcinoma  Very rare  placental site trophoblastic tumour (PSTT) and epithelioid trophoblastic tumour (ETT).  atypical placental site nodules (PSNs)  malignant potential remains unclear  neoplastic transformation of atypical placental site nodules to placental site trophoblastic tumour may occur GTN Persistence of GTD after primary GTN may develop after treatment (defined as a persistent 1. molar pregnancy (50%) elevation of hCG) 2. non-molar pregnancy (50%) (miscarriage, termination of pregnancy or normal pregnancy)  The diagnosis of o GTN does not require histological confirmation (No). o complete mole, partial mole, atypical PSN and PSTT/ETT does require histological confirmation GTD-GTN concept Ultrasound examination is helpful in making a pre-evacuation diagnosis of Hydatiform mole but the definitive diagnosis is made by histological examination of the products of conception. [RCOG] Gestational trophoblastic neoplasia is staged clinically without regard for histological findings (even if available) (FIGO) (2009).  HYDATIFORM MOLE HYDATIDIFORM MOLE—MOLAR PREGNANCY It is a benign disease of the trophoblast characterized by: – Preserved villous pattern – Villous stromal edema (Hydropic villi) – Trophoblast proliferation. – ± aypia Classification: classify them as either complete or partial moles according: Complete Moles Partial Moles RCOG, 2020  Diploid  usually (90%) triploid  10%  tetraploid or mosaic conceptions.  androgenic in origin __ Have a diploid  2 sets of paternal haploid genes and 1 set of maternal haploid chromosomal composition of paternal genes origin  in almost all cases dispermic fertilisation of an ovum.  46,XX (75–80%)  duplication of  a triploid karyotype—69,XXX, 69,XXY—or much less chromosomes of a single sperm following commonly, 69,XYY. These are each composed of: fertilisation of an ‘empty’ ovum. o Two paternal haploid sets of chromosomes contributed by  46,XY or 46,XX (20–25%)  dispermic dispermy and one maternal haploid set. fertilisation (fertilization by two sperm) of o Less frequently, a similar haploid egg may be fertilized an ‘empty’ ovum. by an unreduced diploid 46,XY sperm. Both cases the chromosomes of the ovum are  These triploid zygotes result in some embryonic development, either absent or inactivated however, it ultimately is a lethal condition. Fetuses that reach advanced ages have severe FGR, multiple congenital anomalies  no evidence of fetal tissue  usually  a fetus or fetal red blood cells  NB: Not all triploid or tetraploid pregnancies are partial moles. For Dx of partial mole, there must be histopathological evidence of trophoblast hyperplasia Incidence and Risk Factors GTD  uncommon in the UK, 1/714 live births. RCOG 2020 ethnic variation  Asian  Asian women 1/387 live births women > non-Asian women  non-Asian 1 in 752 women extremes of age  < 15 years 1 in 500 pregnancies  > 50 years 1 in 8 pregnancies GTN may  molar pregnancy develop  non-molar pregnancy After live birth 1/50 000. after 1/50 000  In the UK, cure rate 98–100%, _ chemotherapy rate 0.5–1.0% for GTN after partial molar births pregnancy and 13–16% after complete molar pregnancy.  outcomes for women with GTN /GTD are better with management from GTD centres  failure or delay to treat GTN can be fatal.  Twin Pregnancy Comprised of a Normal Fetus and Coexistent Complete Mole 1 in 22,000 to 100,000 pregnancies  Other  History of prior hydatidiform mole:  1 prior complete mole, the risk of another mole is 1.5%  1 previous partial mole, the rate is 2.7 %.  2 prior molar pregnancies, 23 % of women had a third mole.  Blood group A B AB (controversial)  History of infertility Pathology Macroscopically Uterus: Enlarged – Extremely soft – Full of a mass of clear vesicles. These vary in size and often hang in clusters from thin pedicles. In a partial molar pregnancy there are less advanced hydatidiform changes and contains some fetal tissue. Ovaries show multiple theca lutein cysts Microscopically See below  COMPLETE MOLE PARTIAL MOLE Histological examination of products of conception  definitive Dx (RCOG 2020) Hydropic villi Diffuse, often marked Focal, variable Trophoblastic proliferation Diffuse, variable Focal, slight Trophoblast Atypia Marked Mild Fetus, amnion, fetal RBCs Absent Present Ploidy status and immunohistochemistry staining for p57, a paternally imprinted gene, may help in distinguishing partial from complete molar pregnancies (RCOG 2020) P57 Immune staining Negative Positive Cytogenetic Analysis Diploidy; 46,XX most common Triploidy; 69,XXX most common Paternal origin Paternal and maternal origin Clinical Features “Mole” clinical/ultrasound diagnosis Common Rare Medical complications Common ??Missed Miscarriage _ Rare B-HCG > 100.000 40 years- 3.5% after hysterectomy 75% for theca lutein cysts Up to one third metastatic Non-metastatic Complications GTDs I-Complications of the possible aetiological factor II-Complications of the disease 1-Bleeding: Vaginal -=>Rh isoimm. Of Rh the –ve -If severe => Shoch, ARF, DIC 2-Infection: May occur but it is not a disease of infection. - 3- Increased HCG => Hyperemsis – PET - Thyrotoxicosis Yes 4-DIC Yes 5-Pathological Fate GTN 6-Recurrence next pregnancy Yes III-Complications of Treatment -Medical ttt Yes -Surgical ttt Yes -Blood transfusion Yes  Clinical Presentation – Symptoms Type of patient See Incidence and Risk Factors Of Early Pregnancy Missed period, exaggerated symptoms of early pregnancy Of Complication Hyperemesis (20%)_ collapse, anemia, ecchymotic patches, bleeding gums Obstetric Discharge: Brownish, prune juice, vesicles Symptoms Bleeding: Vaginal bleeding mild – moderate or Severe. 40% present with bleeding/discharge Pain: Dull aching (Distenstion) Asymptomatic 40%– accidentally discovered Mean GA at diagnosis 10 weeks RCOG 2020  The most common presentation  irregular vaginal bleeding (60%) + positive pregnancy test + supporting ultrasonographic evidence  Less common presentations: HEG, excessive uterine enlargement, hyperthyroidism, early-onset pre-eclampsia and abdominal distension due to theca lutein cysts  Very rarely  haemoptysis or seizures d2 metastatic disease affecting the lungs or brain. Examination General - Dehydration – Weight loss in hyperemesis. examination - Signs of PET - Signs of Thyrotoxicosis - Hypovolemic Shock. - Iron deficiency Anemia. - Occasionally a larger CYST may undergo torsion, infarction, and hemorrhage abdominal No tenderness – rigidity or rebound tenderness – uterus may be enlarged hard to feel abdominally examination – No fetal heart – no fetal parts – no fetal movement perceived. Local examination V&V: brownish discharge – Vesicles may be seen Cx: extremely soft, paritally open due to softness, no tender motion Uterus: Extremely soft, more than amenorrhea in 60% of cases, not tender Adnexa: Mass = Theca lutein cysts, no tenderness. DP: Fullness by adnexal cysts, no tenderness  INVESTIGATIONS Serum B- COMPLETE MOLAR PREGNANCY HCG Serum B-hCG levels are commonly elevated above those expected for gestational age. May be of value  hCG > 2 MoM may help Urine HCG may be false- negative: – These high values can lead to erroneous false-negative urine pregnancy test results because of oversaturation of the test assay by excessive B-hCG hormone. In these cases, serum B-hCG determinations with or without sample dilution will clarify the condition. PARTIAL MOLE B-hCG levels may be significantly elevated, but more commonly concentrations fall into ranges expected for gestational age elevated human chorionic gonadotrophin after a possible pregnancy  RCOG: Referral to a GTD centre either after o an ectopic pregnancy has been excluded, o or after two consecutive treatments with methotrexate for a pregnancy of unknown location.  GTN requires more intensive chemotherapy than treatment of a pregnancy of unknown location  Other causes of Low levels of hCG elevation (between 10 IU/l and 200 IU/l) o Very rarely, familial raised hCG  These women have menstrual cycles and can conceive. o Malignant germ cell tumours and any epithelial cancers including bladder, breast, lung, gastric and colorectal cancers. o pituitary hCG o the presence of human anti-mouse antibodies  hCG glyco-protein can be present in many forms, in both serum and urine, o forms including  intact hCG   free hCGb subunit  nicked hCG  hCG b-core fragment. o Molar pregnancies and GTN can produce all these variants of hCG. o Most hCG assays for routine laboratory use do not measure all hCG variants. o UK GTD centres use specialised in-house hCG assays to detect all forms of hCG ULTRASOUND COMPLETE MOLE: Echogenic uterine mass with numerous anechoic cystic spaces but without a fetus or amnionic sac. The appearance is often described as a “snowstorm”. RCOG  make a pre-evacuation Dx by ultrasound to exclude non- viable and molar pregnancies. PARTIAL MOLE Thickened, multicystic placenta along with a fetus or at least fetal tissue. The most common misdiagnosis is *incomplete or missed abortion. DXX a multifetal pregnancy or a uterine leiomyoma with cystic degeneration.  RCOG, RCOG for early Dx Ultrasound features suggestive of 2020  COMPLETE MOLAR PREGNANCY o POLYPOID MASS between 5 - 7 weeks of gestation and thickened cystic appearance of the villous tissue after 8 weeks of gestation with no identifiable gestational sac  PARTIAL MOLAR PREGNANCY o an enlarged placenta or cystic changes within the decidual reaction in association with either an empty sac or a delayed miscarriage Using these criteria, sensitivity for complete mole is 95% and 20% for partial mole soft markers FOR ultrasound diagnosis of a partial molar pregnancy, including cystic spaces in the placenta, and ratio of transverse to anteroposterior dimension of gestational sac > 1:1.5. Using these extra criteria, 41.4% of partial molar pregnancies are correctly diagnosed prior to removal compared  accuracy of pre-evacuation Dx of molar pregnancy o  When pregnancy tissue was routinely examined after surgical removal, the incidence of molar pregnancy and atypical PSNs, unrecognised prior to removal, was 2.7%  The majority of histologically proven complete moles are associated with an ultrasound Dx of delayed miscarriage or anembryonic pregnancy  RCOG,  When to Do Histological examination? 2020 o For suspected mole o of products of conception o For all failed pregnancies_ if no fetal parts are identified at any stage of the pregnancy  As it is difficult to Dx of a molar pregnancy before evacuation. And As GTD can be difficult to recognise at the time of miscarriage  If no tissue has been sent to pathology pregnancy test 3 weeks after the miscarriage. If this is still positive, serum levels should be tracked to ensure that the level is falling and, if not ultrasound to look for further pregnancy tissue. All tissue obtained should be sent to pathology.  no histological examination for products of conception when fetal parts are visible o risk of GTN 1/20 000 o after all repeat evacuations  As persistent trophoblastic neoplasia may develop after any pregnancy.  Rationale The incidence of GTD, unrecognised prior to removal, is 2.7%.--> Failure to Dx of GTD at time of termination leads to a significantly higher risk of life-threatening complications, surgical intervention, including hysterectomy and multi-agent chemotherapy.  MANAGEMENT o Place of care GTD center o Personnel o individualized based on o lines of treatment  medical evacuation  surgical evacuation  Hystrotomy o special groups  2n evacuation  Prophylactic chemotherapy  Theca Lutein cyst  Ectopic GTD o after care  follow up  contraception  when to get pregnant  outcome of pregnancy  1/8  recurrence o 80% the same type of GTD  EVACUATION OF A MOLAR PREGNANCY (RCOG 2020) Suction curettage medical evacuation  the method of choice for removal of  o COMPLETE MOLE suction curettage such as partial mole and twin  irrespective of uterine size pregnancies (normal pregnancy with a molar pregnancy)  as they are not associated  Medical evacuation of complete molar pregnancies should with fetal parts be avoided if possible o partial molar except when the o Risk of developing GTN and requiring chemotherapy size of fetal parts deters the use was 16-fold higher compared with surgical removal of suction curettage and then why?? medical removal can be used  a higher rate of incomplete removal with Ultrasound guidance during Suction medical methods curettage to minimise risk of perforation  Oxytocic agents  and to ensure that as much tissue as may force tissue into venous spaces at the site possible is removed. of the placental bed  disseminate Excessive vaginal bleeding may occur and trophoblastic tissue through the venous system the involvement of an experienced  may lead to clinician is advised  embolic and metastatic disease in the lung  Also  ARDS, similar to AF embolism  following evacuation of moles   Anti-D prophylaxis o Anti-D prophylaxis is required following evacuation of partial moles o anti-D NOT required following evacuation of complete moles  Because of poor vascularisation of chorionic villi and absence of anti-D antigen in complete moles  Confirmation of Dx of complete molar pregnancy may not occur for some time after removal, which could delay administration of anti-D. If Dx of complete mole cannot be established within 72 hours, anti-D prophylaxis can be administered Other data  Evacuation of complete molar pregnancies with mifepristone and misoprostol should be avoided (RCOG 2010) o since it increases the sensitivity of the uterus to prostaglandins.  Preparation of the cervix  Osmotic dilators are preferable than medical means Comment Ripening of the cervix with either Safe _ immediately not associated with an increased risk of physical dilators or prior to evacuation developing GTN prostaglandins Prolonged cervical preparation, should be avoided  risk of embolization of trophoblastic particularly with prostaglandins apy.  oxytocic agents before and during surgical evacuation o prior to completion of the evacuation o If the woman is experiencing significant haemorrhage prior to evacuation  surgical evacuation should be expedited  when a life threatening bleeding  oxytocic infusions may be used.  the need for oxytocin infusion weighed up against risk of tumour embolisation. EVACUATION PRECAUTIONS Intraoperative bleeding can be profuse with molar pregnancy evacuation. Thus with large moles, Adequate anesthesia intravenous access Blood-banking. The cervix is mechanically dilated to allow insertion of a 10- to 14-mm suction curette. As evacuation is begun, oxytocin is infused to limit bleeding. Intraoperative sonography to help ensure that the uterine cavity has been emptied. When the myometrium has contracted, thorough but gentle curettage with a sharp large-loop Sims curette is performed. If bleeding continues AFTER uterine evacuation, other uterotonic agents are given. (Methergin – Carboprost – Misoprostol) In some cases, pelvic arterial embolization or hysterectomy may be necessary EVACUATION COMPLICATIONS 1. ADULT RESPIRATORY DISTRESS SYNDROME: Potential causes – Trophoblastic deportation, – High-output congestive heart failure caused by anemia or hyperthyroidism, preeclampsia, – Iatrogenic fluid overload. Pulmonary complications occurs in 1/4 of patients with uterine size > 16 weeks' gestation. managed with – Ventilator support – central monitoring with a Swan-Ganz catheter to accurately determine fluid status and the need for fluids, blood products, or diuresis. – Chest X ray after evacuation to rule out significant trophoblastic deportation, pulmonary metastasis,  or development of pulmonary edema. 2. UTERINE PERFORATION should rarely occur Most frequently, these will occur in the midline of the uterine fundus If perforation is recognized: – Suction should be immediately discontinued, cannula removed, and rate of oxytocin infusion increased. – Laparoscopy or laparotomy should be performed to access the site of perforation. Surgical management should be individualized based on the site and extent of perforation If hemostasis is adequate and there is no damage to gastrointestinal organs,  CURETTAGE can be completed under laparoscopic visualization. If not so + If uterine perforation is through a focus of deep myometrial penetration by invasive mole some patients will require hysterectomy small series have suggested that individual patients with invasive moles can be treated with segmental resection and repair of the affected myometrium.. Prophylactic Following evacuation (not recommended) chemotherapy  long-term prognosis for hydatidiform mole was not improved Second  second (repeat) uterine evacuation (RCOG 2020) Evacuation If symptomsare persistent, evaluation by hCG level and ultrasound. (RCOG 2020) Consultation with the relevant trophoblastic screening centre prior to second evacuation. Women with persistent heavy vaginal bleeding + evidence of retained pregnancy tissue on ultrasound  may need a repeat surgical removal. second removal for GTN __> 40% of women avoided chemotherapy as a consequence of undergoing second removal with low complication rates Other forms of hysterotomy Evacuation increase blood loss and may increase incidence of persistent trophoblastic disease(ACOG, 2012). Hysterectomy  when with the mole in may be preferable for women who have completed childbearing. situ ± ovarian women aged ≥ 40 preservation – approximately 1/3 will develop GTN, and hysterectomy markedly reduces this likelihood (Williams, 2014).  offers the advantage of: Complete evacuation of hydatidiform mole Simultaneous sterilization for women who no longer wish to bear a child. Decreases risk of malignant sequelae to approximately 3.5% from the 20% anticipated after evacuation with D&C.  adnexa should not be removed unless the patient is perimenopausal or there is obvious adnexal metastasis.  Hysterectomy does not eliminate the potential for malignant sequelae: Women must have their hCG levels monitored after hysterectomy THECA LUTEIN CYSTS Clinically evident theca lutein cysts (> 5–6 cm) of the ovary – with additional smaller cysts often detected by ultrasound alone. detected in approximately 1/4 --1/3 of women with hydatidiform mole Ovarian enlargement correlates with marked elevation of serum hCG levels > 100,000 mIU/ml. Histologically and physiologically these cysts are similar to iatrogenic ovarian hyperstimulation produced by exogenous gonadotropin/hCG administration. Onset Although theca lutein cysts are usually detected before molar evacuation, they often develop within the first week after evacuation. The mean time for disappearance is approximately 8 weeks. – usually regress spontaneously after evacuation – do not need to be drained or removed unless torsion or intraoperative rupture with hemorrhage occurs Complications: – develop overt ovarian hyperstimulation with fluid retention and/or ascites (very rare) – Ovarian torsion or rupture, requiring oophorectomy. – PESRISTANCE: these cysts may persist for several months after hCG level remission 30% will develop secondary enlargement in response to rising hCG levels associated with postmolar sequelae – Theca lutein cysts are associated with an increased incidence of postmolar GTN  75% incidence of postmolar sequelae among women with bilateral theca lutein cysts. Twin pregnancy of a fetus and coexistent molar pregnancy managed? (one viable fetus + the other pregnancy is molar) RCOG 2020  advice from the regional fetal medicine unit & the relevant trophoblastic screening centre  poor Pregnancy Outcome Maternal morbidity outcome for GTN GTG, 2010   perinatal morbidity  incidence of pre-  increased risk  25% a live birth eclampsia, as   early fetal loss (40%) high as 20%.   PTD (36%). in a large higher rate of babies  incidence of pre-  no increased risk UK series, surviving (51%), eclampsia  4%  outcome after chemotherapy was unaffected  no maternal  deaths.  Histological examination of the placenta is recommended  Prenatal invasive testing for fetal karyotype in cases where o unclear if the pregnancy is a complete mole with a coexisting normal twin or a partial mole. o abnormal placenta, such as suspected mesenchymal hyperplasia of the placenta.  Follow-Up RCOG 2020 Baseline initial β-hCG level is obtained within 48 hours after evacuation The median time for such resolution is 7 weeks for partial moles and 9 weeks for complete moles serial estimation of hCG levels (1 week), either in blood or urine specimens hCG has reverted to normal within 56 days of the pregnancy event Yes No ↓↓↓↓↓↓↓↓↓↓↓↓↓↓↓↓↓↓↓↓↓↓↓↓ ↓↓↓↓↓↓↓↓↓↓↓↓↓↓↓↓↓↓↓↓↓↓↓↓ follow up for 6 months from uterine evacuation follow-up for 6 months from normalisation of hCG Follow-up for PARTIAL MOLAR PREGNANCY is concluded once hCG has returned to normal on two samples, at least 4 weeks apart once hCG has normalized the possibility of GTN developing is very low.  at the end of any future pregnancy  Q did the woman received chemotherapy after GTD o No no need to have hCG measured after any subsequent pregnancy event o Yes hCG levels 6-8 weeks after any subsequent pregnancy event to exclude disease recurrence  Diagnostic criteria for GTN Plateau: 3000 – 3200 – 2900 – 2750 Rising: 3000 – 3400 – 3900 Turns +ve after –ve (after 6 months) Histology => Choriocarcinoma Histological examination for Dx GTD/GTN  Histological examination of products of conception  definitive Dx  When to Do Histological examination? o For suspected mole o of products of conception _to exclude trophoblastic neoplasia o For all failed pregnancies_ if no fetal parts are identified at any stage of the pregnancy  incidence of GTD, unrecognised prior to removal, is 2.7%.  no histological examination for products of conception when fetal parts are visible or identified on ultrasound o risk of GTN 1/20 000 o after all repeat evacuations  As persistent trophoblastic neoplasia may develop after any pregnancy.  Rationale - threatening complications, surgical intervention, including hysterectomy and multi-agent chemotherapy.  If no tissue has been sent to pathology, a pregnancy test should be carried out 3 weeks after  the miscarriage. If this is still positive, serum levels should be tracked to ensure that the level is falling and, if not, an ultrasound is arranged to look for further pregnancy tissue. All tissue obtained should be sent to pathology. CONTRACEPTION (RCOG 2010) During  Old (RCOG 2010) Follow- o until hCG levels revert to normal  barrier methods. up o Once hCG level have normalized  combined oral contraceptive pill may be used. o no evidence as to whether single-agent progestogens have any effect on GTN. o If oral contraception has been started before DX of GTD was made  remain on oral contraception  but there is a potential but low increased risk of developing GTN.  until hCG levels revert to normal barrier methods of contraception. – If oral contraception is started before hCG reverts to normal there is a potential but low increased risk of developing GTN.  Once hCG level have normalized combined oral contraceptive pill may be used. single-agent progestogens – no evidence as to whether single-agent progestogens have any effect on GTN. Most recommend either: – Combination hormonal contraception – or injectable medroxyprogesterone acetate. IUD are not recommended because of the risk of uterine perforation if there is an invasive mole, confusion with bleeding patterns and reduced reliability. barrier and other methods are not recommended because of their relatively high failure  rates. after molar Women should be advised not to conceive until their follow-up is complete. pregnancy Women who undergo chemotherapy are advised not to conceive for 1 year after completion of treatment. The risk of a further molar pregnancy is low (1/80) following a molar pregnancy and if pregnancy is normal (98%) there is no increased risk of obstetric complications. If a further molar pregnancy does occur, in 68–80% of cases it will be of the same histological type.  GESTATIONAL TROPHOBLASTIC NEOPLASIA (GTN) The diagnosis of GTN is established when a woman has: – Biochemical: Rising or plateauing hCG levels – Clinical: Develops metastatic disease after evacuation of a hydatidiform mole. – Histological: Dx of invasive mole, placental site tumor, or choriocarcinoma is a histologic criterion for GTN. Preceding lesions – Approximately ½ cases of GTN follow molar pregnancies – Approximately ½ follow term pregnancies, spontaneous abortions, and tubal pregnancies. Background Types of Trophoblast:  Cyto – Syncitio –Intermediate trophoblast. Intermediate trophoblast is a distinct subtype of trophoblastic tissue that arises from the cytotrophoblast. It is sub-categorized by location: 1. Villous at anchoring villi of  (polyhedral and uniform nuclei, prominent cell border; intermediate trophoblastic column abundant eosinophilic to clear cytoplasm cohesive growth) trophoblast 2. Implantation at implantation site  differentiated from VILLOUS INTERMEDIATE TROPHOBLAST PSTT arise from site (or basal plate),  by pleomorphic irregular nuclei, large and hyperchromatic, this type intermediate may multinucleation abundant eosinophilic to amphophilic trophoblast cytoplasm infiltrative growth (splitting muscle, replacing vascular wall...etc) 3. Chorionic-type at chorionic laeve of  round to polyhedral nuclei, may multinucleation abundant Epithelioid intermediate fetal membrane eosinophilic to clear cytoplasm cohesive growth Trohoblastic trophoblast tumour arises from this type. Spread of GTN Local Myometrium – Serosal surface – Parametrium – Vagina..etc. Blood: Spleen – Kidney - Lung – Liver – GIT – Brain – Vagina (Submeatal secondaries).. Etc. Lymphatic (rare and late) DIAGNOSTIC CRITERIA FOR GTN   Women with WHO scores of 0 -6  have low-risk disease ≥ 7  the high-risk group. ≥ 13  a higher risk of – early death (within 4 weeks), often due to bleeding into organs, or – late death due to multi-drug- resistant disease Suspected GTN after pregnancy RCOG 2020 persisting What to Do gynaecological  hCG level and ultrasound examination ± second (repeat) uterine evacuation symptoms after  in the case of acute haemodynamic compromise an evacuation for o surgical management molar pregnancy o balloon tamponade o uterine artery embolisation  to reduce the risk of hysterectomy for women who wish to preserve fertility.  Embolisation will not always stop the bleeding but will permit management of blood loss. o Bleeding from vaginal metastases can be reduced by compression from a vaginal pack Presenting  A urine pregnancy test (when?) symptom for o Persistent or irregular vaginal bleeding > 8 weeks after a pregnancy event . persistent GTN  at risk of having GTN after a non-molar o Other Symptoms  from metastatic disease, such as dyspnoea and haemoptysis, or new pregnancy?__ onset of seizures or paralysis, can occur very rarely investigated for o 3 weeks after medical management of failed pregnancy/ or a miscarriage_ if products of GTN after a non- conception are not sent for histological examination molar pregnancy  Biopsy of secondary deposits in the vagina can cause major haemorrhage and is not recommended.  GTN is staged clinically without regard for histological findings, (even if available) using the system of FIGO, 2009_ + the modification of the WHO (1983) prognostic index score.  Other investigation for GTN o computed tomography of the chest and abdomen, or magnetic resonance imaging of the head and pelvis, all with contrast o serum hCG o Doppler ultrasound of the pelvis.  Treatment Chemotherapy is usually the primary treatment. In specific cases, hysterectomy may be primary or adjuvant treatment. Rarely, women with multi-relapsed disease will require high-dose chemotherapy with stem cell recovery Single- gent chemotherapy protocols Combination chemotherapy is given for:  For Nonmetastatic or low-risk metastatic neoplasia scores ≤ 6  For High-risk disease scores ≥ 7  Rcog 2020 A single-agent intramuscular MTX alternating EMA-CO, includes etoposide, ethotrexate, actinomycin D, daily with folinic acid for 1 week followed by 6 rest days cyclophosphamide, and oncovin (vincristine).  Monotherapy protocols with either methotrexate or intravenous multi-agent chemotherapy actinomycin D are equally effective yet methotrexate is less EMA-CO administered / 2-3 weeks toxic than actinomycin D. Adjuvant surgical and radiotherapy may also be employed. Treatment is continued, in all cases, until hCG level has returned to normal and then for a further 6 consecutive weeks (RCOG 2020)  At least three courses of EMA-CO after the patient achieves undetectable hCG levels as consolidation therapy to reduce the risk of relapse,  Cure rates almost 100%; cure rates approximate 90 percent FOLLOW UP Once serum b-hCG levels are undetectable, SURVEILLANCE is continued for 1 year. – During this time, effective contraception  to avoid any teratogeniceffects of chemotherapy to the fetus as well as to mitigate confusion from rising b-hCG levels caused by superimposed pregnancy.  Low risk GTN High risk GTN: EMA-CO Regimen PSTT and ETT RCOG 2020 the rarest forms of GTN _ 0.2% of all GTD  They tend to (compared to other forms of GTN) o produce less hCG o confined to the uterus for longer, o more often involve lymphatics o more chemoresistant. o Their presentation and behaviour are different and less predictable.  For these reasons, they are not managed according to their FIGO score  PSTTs and ETTs are diagnosed by histological examination of retained pregnancy tissue.  poor prognostic factor for adverse outcome o the most important  interval to presentation from the last known and presumed causative pregnancy  An interval > 48 months  previously has been associated with a 100% death rate regardless of stage.  After more intensive treatments given to PSTT/ETT  over 50% died in this group  women presenting within 48 months are nearly all long-term survivors o Stage IV disease  management of PSTT and ETT o Hysterectomy is curative in localised disease. for stage I disease hysterectomy is the mainstay of management o In women with a long time period since the antecedent pregnancy and/ or with distant and/or extensive metastatic disease  intensive platinum-based combination agent chemotherapy only if the interval > 48 months. o women with multi-relapsed disease  high-dose chemotherapy with stem cell recovery, or treatment with immunotherapy placental site  PSNs have been regarded as a benign finding of little clinical significance. nodule or atypical  There have been reports of PSNs ± atypical features, which have either been admixed with PSTTs or placental site ETTs, or that have subsequently progressed over time to PSTTs or ETTs. nodule be o atypical PSNs  may progress to cancer in 10–15% of women. managed  So [New 2020] o Women with an atypical placental site nodule (PSN) or where the local pathology is uncertain  histology reviewed centrally+ perform staging investigations and to determine further management.  o Women with typical PSN  do not require further investigation or review.  C/P o vaginal bleeding resulting in endometrial biopsy.  TTT o women who have completed their families  consider a hysterectomy in the absence of metastatic disease. o careful counselling and further testing  for Women who desire more children outcome of after GTD RCOG 2020 subsequent  How long should a woman wait after GTD before trying to conceive? Contraception (see below) pregnancies  fertility outcomes after GTN o favourable o Although it is common for periods to stop during treatment, they nearly always restart within a few weeks to months after completing chemotherapy. o Further pregnancies are achieved in 80% of women following treatment for GTN with either methotrexate alone or multi-agent chemotherapy  pregnancy outcomes o more than 98% of women will not have a further molar pregnancy nor are they at increased risk of obstetric complications o after chemotherapy for GTN there is an increased risk of GTD in subsequent pregnancy risk  low (1/80)  68–80% of further molar pregnancy will be of the same histological type  pregnancy following a previous molar pregnancy (post-pregnancy screening)  pregnancy following a previous molar pregnancy+ not required treatment for GTN no post- pregnancy hCG.  Pregnancy following a previous molar pregnancy + required chemotherapy for GTN  hCG levels checked. follow-up can be safely stopped after 10 years long-term  premature menopause for women treated with combination agent chemotherapy outcome of o 13% will have had premature menopause by the age of 40 years and 36% by the age of 45 women treated years for GTN o The age at menopause advanced by  -agent chemotherapy  -agent chemotherapy. o women who receive high-dose chemotherapy are unlikely to regain ovarian function  secondary cancers o for Women who require multi-agent chemotherapy which includes etoposide may be at  very low risk of developing secondary cancers. o If combination chemotherapy is < 6 months  there appears to be no increased risk o in women surviving for more than 25 years  16.6 relative risk (RR) of developing acute myeloid leukaemia.  4.6 RR for developing colon cancer  3.4 RR for melanoma  5.79 RR for breast cancer. Other After a molar pregnancy exogenous estrogens and other fertility drugs for ART may be used once hCG levels hormone replacement therapy after a molar pregnancy have returned to normal. suspected ectopic  Ectopic molar pregnancy is a rare event. molar pregnancy  Symptoms and signs and Dx are the same as any other ectopic pregnancy.  If there is a local tissue diagnosis of ectopic molar pregnancy, the tissue should be sent to a centre with appropriate expertise for pathological review.  The histopathological features can be confused with choriocarcinoma