23. gestational trophoblastic diseases

GESTATIONAL TROPHOBLASTIC

DISEASES

ATANAZIO CHIFUINRO MGUNDAMBBS 5College of medicine malawi(Mw)

OUTLINE Definition embryology Epidemiology Classification Risk factors Clinical features Diagnosis Staging and management Prognosis and follow-up Complications

DEFINITION Spectrum of abnormal proliferation of trophoblasts, ranging from benign to malignant

The trophoblast layer develops into the placenta. Early in normal development, the cells of the trophoblast form tiny, finger-like projections known as villi.

EMBRYOLOGY 30hours:fertilization•Zygote mitotically divides into 2 cells-blastomere

3days: morula formation• 12-16 blastomeres

4days: blastocyst formation within morulablastocyst: • Inner cell mass called embryoblast•Outer cell mass called trophoblast

Day 6:Implantation•Blastocyst attaches to endometrial lining, trophoblasts invade

TROPHOBLAST. By eighth day post fertilization the trophoblast differentiates into:

1. Syncytiotrophoblast• outer layer• Invades endometrial blood vessels • 2nd week end• early utero-placental circulation that surrounds conceptus• the primitive primary secretory component within the placenta

2. Cytotrophoblasts• inner layer• 2-3week surrounded by syncytioblast • forms papillary projections called villi• Villi functional units of placenta• transport of oxygen and nutrients• Cytotrophoblasts are the germinal cells

EPIDEMIOLOGY Incidence of GTDs 1 to 2 per 1,000 deliveries (South Africa, United States and Europe, Turkey) higher incidence rates in Asia 40 per 1000 Although recent studies have found 2 per 1000 Reason: population-based vs hospital-based data collection

RISK FACTORS FOR GTDS Maternal Age Teenagers 7.5 fold higher in > 40years Premature and post mature ova higher rates of abnormal fertilization Older Paternal age implicated

Race Hispanics and Native Americans living in USA Influence from environment or other factors

RISK FACTORS Obstetric history In previous molar pregnancy, 10-fold risk

Complete moles 20% Partial mole 2.9-9.9%

Double risk in previous spontaneous abortion

Blood group Blood group B associated with recurrent molar No evidence against rhesus negative group

Smoking combination oral contraceptive Vitamin A deficiency

WORLD HEALTH ORGANISATION (WHO) CLASSIFICATION OF TROPHOBLASTIC DISEASE Benign Hydatidiform mole

Complete Partial

Malignant gestational trophoblastic neoplasia Invasive hydatidiform mole Choriocarcinoma Placental site trophoblastic tumour Trophoblastic tumour, miscellaneous

Exaggerated placental site Placental site nodule or plaque

Unclassified trophoblastic lesions

BENIGN Hyatidiform mole(vesicular) The most common form of GTD It is made up of villi that are enlarged, edematous and vesicular

The swollen villi grow in clusters that look like bunches of grapes

Partial and complete differ in morphology, clinico-pathology and cytogenic features

COMPLETE HYATIDIFORM MOLE

Mole without fetus or embryo Most often develops when either 1 or 2 sperm cells fertilize an egg cell that contains no nucleus or DNA All the genetic material are paternal. Therefore, there is no fetal tissue. Usually diploid, with a 46,XX karyotype, and all molar chromosomes are paternal in origin. About 10% have a 46,XY karyotype, which arises from fertilization by two spermatozoa.

COMPLETE MOLE, PATHOGENESIS

Duplication 46XX

Empty ovum

23X

Diandric diploidyAndrogenesis

Paternal chromosomes only

COMPLETE MOLE, PATHOGENESIS

46XX

Empty ovum

23X

Dispermic diploidy

Paternal chromosomes only

23X 23X

23X

FEATURES Edematous chorionic villi in clusters “grape like” Different sizes Average size of 1.5cm in diameterMicroscopic features some enlarged villi show fluid filled space “Central cistern pattern” High hCG production

COMPLETE MOLAR PREGNANCY

PARTIAL HYDATIDIFORM MOLE Develops when 2 sperm fertilize a normal egg. Dispermy, fertilization of an intact ovum by two spermatozoa 69XXX, 69XXY

Fetus growth restricted and has multiple congenital malformations often mixed in with the trophoblastic tissue.

Often associated with severe hypertension Few enlarged villi and fewer masses of grape like villi.

PARTIAL MOLE, PATHOGENESIS

69XXY

Normal ovum

23X

Dispermic triploidy

Paternal extra set

23Y 23X23Y 23X23X

PARTIAL HYDATIDIFORM MOLE

DIFFERENCES BETWEEN COMPLETE AND PARTIAL

DIAGNOSISSymptoms Amenorrhea usually of short period (2-3 months).

Vaginal bleeding due separation of vesicles from uterine wall Prune juice discharge may occur. The blood may be concealed causing enlargement & tenderness of the

uterus Passage of vesicles is diagnostic.

pre-eclampsia symptoms headache, and edema

DIAGNOSISSymptoms cont, Abdominal pain dull-aching- Colicky or Sudden Hyperemesis gravidarumPersistent & excessive nausea & vomitingDue to abnormally hCG levels

DIAGNOSIS Signs Pallor Pre-eclampsia (20-30% of cases) usually before 20 weeks’ gestation Eclamptic Convulsions are rare.

Hyperthyroidism(3-10% of cases) Persistent tachycardia tremors. hCG is a glycoprotein similar to TSH with weak thyroid stimulating hormone

Breast signs of pregnancy Breast tenderness large areolae

DIAGNOSIS CONT

Signs Per-abdomen Uterine enlargement more than gestational age(50%) Absent fetal parts

The uterus has a doughy feel Absent FH

Very rarely a mole & fetus will co-exist Partial moles can have a fetal heart

Bilateral ovarian cysts in 50% of cases-theca lutein cystVaginal examinationPassage of vesicles (sure sign).

INVESTIGATIONSBlood related

Quantitative serum ᵦhCG Serum b -hCG level is highly elevated ( > 100.000 mIU/m1)

FBC, Blood group & x-match U&Es & LFTs & TFTsImaging Chest radiograph -metastasis

cannon ball pleural effusion and consolidation

Ultrasound snow storm appearance no identifiable fetus

Doppler color flow of uterus CT-scan and MRI-metastasis Histopathology(if curettage done)






Doppler color flow of uterus-rule out invasive mole CT-scan and MRI-metastasis Histopathology(if curettage done)

PARTIAL MOLE: COMPLEX MASS WITH MANY CYSTIC AREAS (B/T ARROWHEADS) AND AN EMBRYO (ARROW) IN A PATIENT WITH A Β-HCG OF 280,000 MIU/ML

COMPLETE MOLE

Complete mole: “snowstorm” appearance with multiple cystic areas, no fetal tissue present

Corresponding T1 weighted MRI (MRI can be helpful in determining extent of trophoblastic disease)

TREATMENT Mainstay is resuscitation and surgeryResuscitation Correction of fluid loss Blood transfusion for anaemia Correction of coagulopathy Carbimazole/ propanol for hyperthyroidismSurgery Suction and curettage for a non- invasive mole No D&C in known invasive mole due to risk of life threatening Haemorrhage

Hysterectomy Patients with Hyatidiform moles who do not want children any more Uncontrolled bleeding after evacuation

SUCTION, DILATATION AND CURETTAGE Oxytocin infused in IV fluids after the start of

evacuation continued for several hours to enhance uterine contractility Prostaglandins reserved if oxytocin ineffective Products of conception taken for histological examination

COMPLICATIONS OF HYDATIDIFORM MOLE. Those related to the increased trophoblastic tissue volume: Theca-lutein cysts Pregnancy-induced hypertension, hyperthyroidism, Respiratory distress Hyperemesis

Those related to its management: Uterine perforation Infection Haemorrhage

choriocarcinoma in about 5% of cases invasive mole in about 10% of cases. Recurrent mole may occur(1-2%).

Large bilateral theca lutein cysts resembling ovarian germ cell tumors. With resolution of the human chorionic gonadotropin(HCG) stimulation, they return to normal-appearing ovaries.

Large bilateral theca lutein cysts resembling ovarian germ cell tumors. With resolution of the human chorionic gonadotropin(HCG) stimulation, they return to normal-appearing ovaries.

THECA LUTEIN CYSTS They are hormone dependent.

Disappear spontaneously after evacuation of the mole.

So, they are not removed surgically unless complication occur as torsion or rupture

ACCORDING TO MALAWIAN GUIDELINES(2015) If asymptomatic, then schedule D&E under anesthesia with oxytocin infusion

misoprostol ready due to high risk of Haemorrhage. If actively aborting, send patient to theatre immediately & do D&E, with oxytocin and misoprostol ready.

Give Antibiotics (Doxycycline 100 mg BD x 3 days or Metronidazole 400 mg BD x 5 days) for prophylaxis

If at high risk for choriocarcinoma, consult medical oncology

THAT’S A MONKEY, NOTHING TO DO WITH GTDS, DON’T THINK TOO MUCH

CLASSIFICATION OF GESTATIONAL TROPHOBLASTIC DISEASE

WHO Classification

Malignant neoplasms of various types of trophoblast

Malformations of the chorionic villi that are predisposed to develop trophoblastic malignancies

Choriocarcinoma

Complete

Hydatidiform moles

Epithilioid trophoblastic tumors

Placental site trophoblastic tumor

Partial

Invasive

MALIGNANT-GTDS AKA GTN1. Invasive mole (chorioadenoma destruens) A Hyatidiform mole that has grown into the muscle layer of the uterus. Invasive moles can either be complete or partial Complete moles become invasive much more often than partial moles. Invasive moles develop in a little less than 1 out of 5 women who have had a complete mole removed.

MALIGNANT GTDS

2. Choriocarcinoma Invades myometrium and local vasculature to disseminate haematogenously to the lung (57-80%), vagina (30%), pelvis (20%), brain (17%), and liver (10%)

Half of all choriocarcinomas start off as molar pregnancies.

About one-quarter develop in women who have a miscarriage , intentional abortion, or tubal pregnancy .

Another quarter (25%) develop after normal pregnancy and delivery.

CHORIOCARCINOMA Symptoms & signs Bleeding Infection Abdominal swelling Vaginal mass Lung symptoms Symptoms from other metastases

MALIGNANT GTDS3. Placental-site trophoblastic tumor very rare form of GTD develops where the placenta attaches to the lining of the uterus. This tumor most often develops after a normal pregnancy or abortion,

It may also develop after a complete or partial mole is removed. They do not spread to other sites in the body. But these tumors have a tendency to invade the myometrium

They are treated with surgery, not sensitive to drugs.

MALIGNANT GTDS4. Epithelioid trophoblastic tumor (ETT) extremely rare type of GTD can be hard to diagnose. It can be found growing in the cervix, to be confused with cervical cancer.

ETT does not respond very well to chemotherapy the main treatment is surgery.

It might have already metastasized when it is diagnosed which carries a poorer prognosis.

DIAGNOSIS OF GTN If following are met after initial evacuation

Plateau of hCG lasting for four measurements over a period of 3 weeksE.g. days 1,7,14,21

Rise in Hcg for 3 weekly consecutive measurements Hcg remains elevated for 6months or more Histological diagnosis of choriocarcinoma

EARLY FEATURES SUGGESTING PERSISTENT GTD OR POST MOLAR SYNDROME1. Recurrent Or Persistent Vaginal Bleeding2. Subinvoluation 3. Amenorrhea 4. Persistence of ovarian enlargement.5. No malignancy in endometrial biopsy






Doppler color flow of uterus CT-scan and MRI-metastasis Histopathology(if curettage done)

DOPPLER SCANSchoriocarcinoma Invasive mole “snow storm”

CANNON BALL APPEARANCE ON X-RAY

PROGNOSTIC SCORING SYSTEM To predict the likelihood of drug resistance To assist in selecting appropriate chemotherapy Low risk GTD (WHO score 4 or less)

Intermediate risk GTD (WHO score 5–7)

High risk GTD (WHO score 8 or more)

Modified WHO Prognostic Scoring System

0 1 2 4

Age <40 ≥40 – –

Antecedent pregnancy mole abortion term –

Interval months from index pregnancy

<4 4–6 7–12 >12

Pretreatment serum hCG (IU/L) <103 103–104 104–105 >105

Largest tumor size (including uterus) <3 3–4 cm ≥5 cm –

Site of metastases lung spleen, kidney gastrointestinal liver, brain

Number of metastases – 1–4 5–8 >8

Previous failed chemotherapy – – single drug ≥2 drugs

SIGNIFICANCE OF WHO SCORINGWHO score 4 or less Commence treatment as soon as possible. A low risk of GTD can be managed with single-agent chemotherapy using methotrexate with folinic acid.

Other drugs include etoposide. If single-agent chemotherapy is used and is not working, a more aggressive treatment is warranted to prevent the emergence of drug resistance.

SIGNIFICANCE OF WHO SCORING Intermediate risk GTD (WHO score 5–7) Commence on regimen that includes combination chemotherapy methotrexate and actinomycin D.

If a complete response is not achieved on this regimen the patient should be commenced on etoposide, methotrexate and actinomycin D, alternating with cyclophosphamide and vincristine (EMA-CO).

SIGNIFICANCE OF WHO SCORING High risk GTD (WHO score 8 or more) These patients require significant chemotherapy because they include those with brain metastases, liver and gastrointestinal tract metastases and they are at significant risk from massive bleeding.

A combination of chemotherapy, either EMA-CO or methotrexate and folinic acid chemotherapy is indicated.

FIGO STAGING OF GTN Stage I:

Patients have persistently elevated hCG levels and tumor confined to the uterine corpus.

Stage II: Patients have metastases to the vagina and pelvis or both.

Stage III: Patients have pulmonary metastases with or without uterine, vaginal, or pelvic

involvement. The diagnosis is based on a rising hCG level in the presence of pulmonary lesions on

chest radiograph.

Stage IV: Patients have advanced disease and involvement of the brain, liver, kidneys, or

gastrointestinal tract. These patients are in the highest risk category, because they are most likely to be

resistant to chemotherapy. The histologic pattern of choriocarcinoma is usually present, and disease commonly

follows a nonmolar pregnancy.

TREATMENT It is important to begin treatment as soon as possible after GTN has been detected. The main methods of treatment are:

Chemotherapy Surgery Radiation therapy (which is used less often)

CHEMOTHERAPY FOR GTD. Chemotherapy uses anti-cancer drugs , useful for metastasized GTD. GTD cancers can almost always be cured by chemo no matter how advanced it is.

The drugs that can be used to treat GTD include:· Methotrexate (with or without leucovorin)· Actinomycin-D (dactinomycin),Cyclophosphamide (Cytoxan®)· Chlorambucil, Vincristine (Oncovin®)· Etoposide (VP-16)· Cisplatin· Ifosfamide (Ifex®)· Bleomycin· Fluorouracil (5-FU

CHEMOTHERAPY Depends on the FIGO scoringIn terms of score < than 6 (low risk) Single agent chemotherapy Methotrexate followed by folinic acid rescue 2>cycles after hCG negative Cure rate of 100%Score of >7(High risk) Combination of therapeutic drugs e.g. etoposide, methotrexate, actinomycin-D, cyclophosphamide, ncovin (EMACO)

3>cycles after hCG negative Cure rate of 70% Chemotherapy administered IV hCG measured after each cycle

SIDE EFFECTS OF CHEMOTHERAPY depends on the type, dose and duration of drugs given Common side effects of chemotherapy drugs include:· Hair loss· Mouth sores· Loss of appetite· Nausea and vomiting· Low blood counts

ROLE OF SURGERY Secondary role Chemotherapy is effective in vast majorityIndications Hysterectomy disease confined to uterus Placental site trophoblastic tumours epithelioid trophoblastic tumors.

Resection of Isolated chemotherapy-resistant nodules e.g. thoracotomy, craniotomy

Laparotomy for bowel or urinary tract obstruction Oophorectomy for torsion of ovarian cyst

RADIOTHERAPY For extensive metastases Brain and liver metastases In combination with chemotherapy

ACCORDING TO MW GUIDELINES(2015) Management of choriocarcinoma

• Chemotherapy is first then Refer to medical oncology• If older and multiparous woman, placental site choriocarcinoma uterine perforation failed chemotherapy refer to medical oncology and perform hysterectomy.

Pre-op chemo- for 5 days prevents dissemination Post-op chemo treats residual and disseminated tissue

FOLLOW-UP Pregnancy is allowed if the test remains negative for one year.

Persistent high level or Rising hCG level after disappearance means developing of Choriocarcinoma or a new pregnancy.

Serum B-hCG is undetectable 4 months after evacuation

Early ultrasound in next pregnancy to rule out GTDs

CONTRACEPTION AFTER GTDS The combined pill is started when the beta-HCG becomes negative.

oestrogen stimulates the growth of trophoblast Till this happens, the condom can be used. The intrauterine device is not used because it may lead to irregular uterine bleeding which confuses the follow up

ACCORDING TO MW GUIDELINES(2015) Follow up of molar pregnancy Follow up for 2 years Monthly follow up until urine pregnancy test is negative Send urine for serial pregnancy tests (should disappear by 6 wks post D&E)

Then follow up every 3 months in 1st year and every 6 months in 2ndyear

Conduct speculum exam of vagina and suburethral area for metastases

Conduct bimanual pelvic exam If pregnancy test remains positive at 3 months Order US to monitor ovarian cyst and residual/invasive mole CXR for metastasis Prescribe family planning, i.e. implants, depo-provera injections, COC condoms

early antenatal care, order early USS to look for recurrent mole

END“AMAT VICTORIA CURUM”

VICTORY LOVES PREPARATION

REFERENCES Williams Obstetrics, 22nd edition. TF Kruger, MH botha; Clinical Gynaecology FIGO 2012; gestational trophoblastic disease http://www.cancer.org/cancer/gestationaltrophoblasticdisease/detailedguide/gestational-trophoblastic-disease

http://www.rcog.org.uk/news/new-green-top-guideline-management-gestational-trophoblastic-disease

Obstetrics by Ten teachers, 16th edition. Breech and Novack’s gynaecology fourteenth edition

Health & Medicine

23. gestational trophoblastic diseases