Novak 2003

 Hydatidiform Mole  Persistent Gestational Trophoblastic Tumor  Chemotherapy

 Epidemiology  Complete versus partial mole  Clinical picture  Natural history  Diagnosis  Treatment  Follow up

GTD is among the rare tumors that can be cured even if metastasized Types:  Complete mole  Partial mole  Placental site mole  Choriocarcinoma Persistent GTT: Most commonly follow molar pregnancy May also follow: abortion, ectopic or term pregnancy

% varies in different sites: Japan = 2 : 1000 pregnancies USA = 0.6 – 1.1 : 1000 pregnancies In pathological studies: Complete mole 1 : 945 Partial mole 1 : 695

Risk factors in complete mole: 1 – nutritional: ↓ carotene ↓ vit A 2 – Age: > 35 years = X 2 > 40 years = X 7.5 Risk factors in partial mole: 1 - OCCP 2 - H/O irregular menstruation

Complete mole Pathology:  No fetal or embryonic tissue  Villi show: Diffuse hydropic swelling Diffuse trophoblastic hyperplasia Chromosome: 90% 46XX 10% 46XY

Chromosomes are entirely paternal Mitochondria DNA is maternal in origin 1 - Absent or inactivated ovum nucleus + 1 haploid sperm  endoredublication  homozygous mole 2– Absent or inactivated ovum nucleus + 2 haploid sperms  heterozygous mole

Partial mole Villi vary in size and show:  Focal hydropic swelling  Focal trophoblastic hyperplasia  Focal cavitation  Stromal trophoblastic inclusion  Scalloping Fetal or embryonic tissues

Chromosomes: Absent or inactivated ovum nucleus + 3 haploid sperms  triploid in 90% = 69XXX, 69XXY, 69XYY The fetus shows triploidy stigmata:  GR  Multiple congenital anomalies as: Syndactyly - Hydrocephalus

Complete Partial Fetus absent present Karyotype 46XX(90%) 69XXX 46XY (90%) Hydropic swelling diffuse focal Trophoblastic diffuse focal hyperpleasia Scalloping no present Stromal inclusions no present

Complete Partial past now Vaginal bleeding 97% 84% 74% Anemia 50% 5% Excessive uterine size 50% 28% 4% Preeclampsia 50% 1.5% Hyperemesis 27% 8% Hyperthyroidism 7% 0% Trophoblastic embolism 2% 0% Theca lutein cysts 50% HCG > 100,000mIU/mL 6%

Excessive uterine size: = ↑ trophoblastic tissue  ↑ hCG  ↑ preeclampsia  ↑ hyperthyroidism  ↑ hyperemesis gravidarum  ↑ trophoblastic embolization  ↑ theca lutein cyst size

Preeclampsia: Early preeclampsia = hydatidiform mole Hyperthyroidism: Due to ↑ free T 3, T 4 C/P:  tachycardia  warm skin  tremor

Thyroid storms: Give β–blockers before anesthesia to avoid thyroid storms C/P: ↑ pulse, ↑ temp, ↑ COP + delirium + convulsions may  HF

Trophoblastic embolization: C/P:  dyspnea  cough  tachypnea  ↑ P  chest pain  asymptomatic

Chest examination  diffuse rales Chest X ray  bilateral infiltrates Causes of respiratory distress:  Trophoblastion embolization  Complications of: preeclampsia thyroid storm excessive fluid intake

Theca lutein ovarian cysts  Due to ovarian overstimulation by ↑ hCG  May not be felt with oversized uterus  May  pressure symptoms  treated by decompression by laparoscopic or U/S guided aspiration  If ruptured or torsion occur  acute pain  laparoscope

Complete mole  Invasive = 15%  Metastatic = 4% Risk factors:  hCG > 100,000 mIU/mL  Excessive uterine size  Theca lutein cysts = 6 cm

Low risk = 60%  3.4% persistent mole 0.6% metastatic High risk = 40%  31% persistent mole 9% metastatic Age: > 40 years = 37% > 50 years = 56%

Complete mole U/S  vesicular pattern Partial mole U/S  focal cystic spaces in placenta + ↑ transverse diameter of GS Both together  90% +ve predictive value

I – Hystrectomy + aspiration of CL cyst + follow up as usual 2 - Suction evacuation Preferred ttt for hydatidiform mole Give oxytocine before anesthesia Use 12 canula If > 14 weeks  support the fundus + do fundal massage

Dilatation  ↑ bleeding Suction evacuation  ↓ bleeding If RH –ve  give Anti RH Ig 3 - Prophylactic chemotherapy ↓ invasive mole to 4% after 1 st course ↓ “””””””””””””””””” 0% after 2 nd course Controversial : Why to expose all patients to chemotherapy while only 20% will need it?

Useful if follow up is: Unreliable Unavailable Study: Prophylactic chemotherapy in high risk patients ↓ persistent mole from 47% to 14%

1 - HCG Average time needed to return to normal values = 9 weeks Measure hCG/week  3 consecutive normal results  /month  6 consecutive normal R 2 - Contraception: OCCP or barrier methods IUD is C/I  perforation

 Nonmetastatic disease  Placental-site TT  Metastatic D  Staging  Prognostic scoring systems  Diagnostic evaluation  Management

Invasive mole = 15% after evacuation C/P:  Irregular vaginal bleeding  Uterine subinvolution  Theca lutein cysts  ↑hCG  Perforation of myometrium  internal Hg  Perforation of uterine vessels  vaginal Hg  Infection  acute pain purulent discharge

Histology:  After molar pregnancy  hydatidiform mole or choriocarcinoma  After nonmolar pregnancy  choriocarcinoma = sheets of anaplastic cytotrophoblast and syncytiotrophoblast + no villi

Uncommon Variant of choriocarcinoma Consists of intermediate trophoblast Produce small amounts of hCG & hPL Tends to be confined to the uterus Metastasize late Resistant to chemotherapy

= 4% after molar pregnancy More often after nonmolar pregnancy Usually associated with choriocarcinoma Highly vascular  spontaneous bleeding Early vascular spreading Sites: Pulmonary 80% Hepatic 10% Vaginal 30% Brain 10% Pelvic 20%

1 – Pulmonary metastases: Symptoms: dyspnea cough hemoptysis chest pain asymptomatic May be acute of chronic

Chest X ray:  Snowstorm pattern  Discrete rounded densities  Pleural effusion  Pulmonary artery embolism May be misdiagnosed as 1 ry pulmonary disease and only recognized as GTD after thoracotomy

Pulmonary embolism may  pulmonary HTN Early RF + intubation = bad prognosis 2 – Vaginal metastasis highly vascular biopsy may  excessive bleeding Symptoms: Vaginal bleeding Purulent discharge Site: fornices/suburethral

3 – Hepatic metastasis Usually in advanced cases Symptoms: Epigastric or upper RT ¼ pain due to stretching subcapsular hematoma Rupture  internal Hg 4 – Brain metastasis Usually in advanced cases Spontaneous bleeding  acute focal neurological defects

Stage I confined to uterus Stage II confined to genital structures Stage III pulmonary metastasis Stage IV other metastasis At any stage: A = no risk factors B = 1 risk factor C = 2 risk factors

Age ≤39 >39 Pregnancy mole abortion term Duration 12 hCG Largest size 5 Site of met 0 kidney/spleen GIT/liver brain Number 8 ABO group 0 A/O B/AB Chemotherapy 1 ≥2

 H/O  Examination  hCG  Liver function tests  Kidney function tests  Thyroid function tests  WBCs  Platelet count

Chest  X-ray -- CT Abd & pelvis  U/S -- CT Brain  MRI -- CT If no pulmonary or vaginal metastasis  metastasis are rare Chest CT  for micrometastasis Liver CT  for abnormal LFTs Brain CT  for asymptomatic lesions

If brain CT is normal  measure CSF hCG If serum hCG/CSF hCG = < 60% then there is brain metastasis Pelvic U/S for:  Extent of uterine lesion  Localization of resistant lesions  Identifying patients who will benefit from hystrectomy

 Stage I  Stage II & III  Stage IV

If the patient does not wish to preserve fertility  Hystrectomy + Chemotherapy to:  ↓ dissemination of GTD  Treat dissemination of GTD  Treat occult metastasis  ↓ bleeding  ↓ sepsis

If the patient wish to preserve fertility: Low risk  Single agent High risk  Combined chemotherapy Resistant  Local uterine resection after localization of resistant sites by U/S, MRI, or arteriography

Placental site GTD: - Only curative ttt for nonmetastatic cases is hystrectomy - Resistant to chemotherapy  few metastatic cases reported complete remission after chemotherapy

Pulmonary metastasis Low risk  single agent  82% CR High risk  combined chemotherapy Resistant  thoracotomy after localization of and exclusion of other resistant sites

Vaginal metastasis Low risk  single agent  84% CR High risk  combined chemotherapy Resistant  wide local excision Vaginal bleeding:  Packing of the vagina  Wide local excision  Embolization of hypogastric arteries

Hystrectomy - In metastatic disease  - to control Hg - to control sepsis - In extensive uterine disease  - to ↓ GTT burden - to ↓ chemotherapy courses

Follow up of stage I, II, III: hCG/week  3 consecutive normal results hCG/month  12 consecutive normal results + effective contraception

Should be referred to specialized centers May be unresponsive or rapidly progress All should receive intensive combined chemotherapy ± irradiation / surgery Hepatic metastasis: Resistant cases  intrahepatic infusion of chemotherapy Hemorrhage  local excision or arterial embolization

Brain metastasis: All cases receive:  Whole brain irradiation by 3000 cGy in 10 fractions  Combined chemotherapy + intrathecal MTX  86% CR Resistant  local excision Hemorrhage  craniotomy  50%CR No residual neurologic deficits

Used in nonmetastatic and low risk mm MTX&Act-D are used/other week X5days 1964: MTX-FA  well tolerated  ↓ toxicity MTX-FA  the preferred ttt for GTD MTX-FA  88% CR 81% by single course 90% CR in stage I 68% CR in stage II

Complications:  Thrombocytopenia 1.6%  Agranulocytopenia 6%  Hepatotoxicity 14% Resistant cases:  Choriocarcinoma  Metastasis  Initial hCG > 50,000 mIU/mL

Technique:  Measure hCG after each course  Draw a curve  Stop MTX if the curve is progressively ↓  Do not give MTX at any predetermined or fixed interval  Give another course if:  hCG is ↑ or plateaus for > 3 weeks  hCG ↓ < 1 log at day 18 post ttt

 If the response to the 1 st course is adequate  give the same dose  If the response to the 1 st course is inadequate  ↑ the dose to 1.5 mg/Kg body weight/day X 4 days  Adequate response = ↓ hCG by 1 log  If the response to the 2 nd & 3 rd courses is inadequate  give ACT-D  If the response to ACT-D is inadequate  give combined chemotherapy

 Triple therapy ( MTX + ACT-D + cyclophosphamide ) is inadequate in ttt of high risk cases  50% CR only  Etoposide  95% CR in nonmetastatic and low risk metastatic cases  1984: triple therapy + Etoposide + Vincristine ( EMA-CO )   83% CR in high risk patients

 EMA-CO is well tolerated and is the preferred 1ry ttt for patients with metastasis and high risk score  76% CR when used as 1ry ttt  86% CR in brain metastasis  If resistant to EMA-CO  give EMA-EP (cisplatin) on day 8  76% CR in resistant patients

Duration of Therapy:  Give combined chemotherapy  3 consecutive normal results  Add at least 2 additional courses to ↓ risk of relapse

Complete/Partial mole Persistent GTT Term 70% 70% PTL 7% 6% Ectopic 1% 1% SB ½% 1 1/2 % Recurrence 1 1/2 % 1% 1 st T abortion 16% 15% 2 nd T abortion 1.6% 1.5% Congenital anom 4% 2.5% CS 16% 19%

Recurrence rate: 1 mole = 1% 2 mole = 20% In the next pregnancy:  Do U/S < 14 weeks  Measure hCG 6 weeks after termination/labour  Send placenta or product of conception to pathology