GESTATIONAL TROPHOBLASTIC DISEASES BY DR SHASHWAT JANI

Dr. Shashwat Jani.M. S. ( Obs – Gyn )

Diploma in Advance Laparoscopy.

Consultant Assistant Professor,Smt. N.H.L. Municipal Medical College.

Sheth V. S. General Hospital , Ahmedabad.

Mobile : +91 99099 44160.E-mail : [email protected]

WHOClassification Of GTD

• Hydatidiform mole- Complete- Partial

• Invasive hydatidiform mole• Choriocarcinoma • Placental site trophoblastic tumor• Trophoblastic lesions, miscellaneous

Exaggerated placental sitePlacental site nodule

• Unclassified trophoblastic lesions6/5/2017

Dr Shashwat Jani. 99099 44160.

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GTD = A heterogeneous group of lesions

characterized by an abnormal proliferation of trophoblast.

Profound differences in the pathogenesis, morphology, and clinical behavior of various forms of the disease.

Trophoblastic Diseases

6/5/2017Dr Shashwat Jani.

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Hydatidiform moles (complete, partial, and invasive) represent abnormally formed placentas with specific genetic abnormalities that are related to villous trophoblast.

Choriocarcinoma and the placental site trophoblastic tumor are true neoplasms and are related to previllous and extravilloustrophoblast.


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What goes wrong ?• Normal gestational trophoblast :

Aggressively invades endometrium

& uterine vasculature placenta.

Complex biologic & immunologic mechanisms control relationship between fetal trophoblast & maternal host prevent circulating trophoblast metastases

• When GTD arises: normal regulatory mechanisms are lost. Excessively proliferating trophoblast may invade thru myometrium, developing rich maternal bldsupply, with tumor emboli & hematogenous spread


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They are characterized by pregnancy associated trophoblastic proliferations.

They range from tumor like conditions to malignancy.

H. mole is a common complication of gestation (1 in 1000 to 2000).

They can be monitored by measuring HCG levels (to detect early recurrence and response to Tx)

Choriocarcinomas are highly responsive to chemotherapy.

Trophoblastic Diseases


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Hydatidiform Mole (VESICULAR MOLE)(Molar pregnancy)

Definition

• In latin

"hydatid" means "drop of water”

"mole" means "spot”.

• H. mole is a pregnancy characterized by vesicular swelling of placental villi and usually the absence of an intact fetus.


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Incidence

• Wide range in geographical & ethnic variation of prevalence.

• Common in oriental countries.

• Highest in Philippines 1 : 80

• Lowest in European countries 1 : 750

• India 1 : 400 .


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• Approximately 10-17% of

H. moles will result in Invasive mole.

• Approximately 2-3% of

H. Moles progress to choriocarcinoma

( most of them are curable)

Not definitely benign disease , has a tight relationship with GTT


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Etiology • Geographical distribution

• Racial factors

• Age -Early teenage pregnancies < 15yrs or

-In pregnancies of > 35yrs.

• Nutritional factors- low socio-economic status, carotene & animal fat soluble vitamin deficiency.

• Disturbed maternal immune mechanism

– ↑ in γ globulin level in absence of hepatic disease

– ↑ed association with AB blood group which possesses no ABO antibody.


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• H/o previous H.mole– recurrence chance 1-4%

• High parity, malnourished & Debilitated diseases like TB.

• Cytogenic Abnormality.


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Emptyovum

Emptyovum

46XX

46XX or 46XY

23X or Y23X

23XComplete Mole (46XX diploid)

Complete Mole (46XX or 46XY, diploid)

A single sperm fertilizes an empty ovum, with duplication of the 23X

haploid set of chromosomes, giving rise to a homozygous diploid

complete mole.

Two sperms with two independent haploid sets of chromosomes fertilize

an empty ovum, producing a dyspermic

complete mole with either 46XX or 46XY karyotype.

Complete Mole

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Hydatidiform Mole

Alterations in gene expression profiles

Up-regulation and down-regulation of proteins committed to cell growth control

e.g. Up-regulation of growth factor and cytokine mediated pathways, and antiapoptosisgenes

Trophoblastic hyperplasia

e.g. Down-regulation of insulin growth factor binding proteins and tumor necrosis factor receptor

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Hydatidiform Mole

• Clinical Presentation:

– Complete mole:

Vaginal bleeding

Severe anemia

Passage of hydropic

villi


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Usually, in association with,

Excessive uterine enlargement 50 %

Hyperemesis gravidarum 25 %

Preeclampsia 25%

Markedly elevated hCG 100,000

mIU/mL

Hyperthyroidism 5%

Theca lutein cysts 50 %

Clinical Presentation: Complete mole:

Vaginal Bleeding 95 %


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Diagnosis

Suspicion:Abnormal bleeding after amenorrhea

Inappropriately enlarged uterus;

Absence of fetal heart sounds or could not feel fetal parts by palpation between 16-20th week

Hyperemesis gravidarum

Bilateral ovarian cysts


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Serum hCG monitorAn unusually high titer of hCG, especially

after the 100th day of pregnancy, help to confirm the diagnosis of HM.

• Serum βhCG > 1,00,000 mIu/ml• Plain X-Ray abdomen negative fetal shadow.• Chest X-ray to R/O pulmonary embolism.• CT & MRI to detect metastasis.


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Ultrasonography:It is a reliable and sensitive technique

for the diagnosis of complete molar pregnancy.

Because the chorionic villi exhibit diffuse hydatidiform swelling.

A characteristic vesicular sonographic pattern,

usually referred to as a “Snowstorm” Pattern.


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Snowstorm Pattern


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Differential Diagnosis

1. Threatened abortion

2. Fibroid uterus with pregnancy.

3. Ovarian tumour with pregnancy

4. Multiple pregnancy.


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MANAGEMENT

Principles in management :

• Suction evacuation of uterus

(safe upto 28 wks of gestation).

• Supportive therapy – correction of anemia & infection if any.

• Counseling for regular follow-up.


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Evacuation & Mx of Molar Pregnancies

Complete history & medical exam (anemia/ dehydration/ preeclampsia &/or thyrotoxicosis)

Appropriate lab & radiologic evaluation,….stabilize hemodynamically (preevacuation hCG, CBC, LFT, BUN, creatinine, TFT, pelvic USG, chest x-ray)

Based on these findings, perioperative complications shd be anticipated …preopn.ABG, postevacuation chest

x-ray, central monitoring in ICU setting

Suction evacuation gives the lowest incidence of sequelae

(metal canula, medical induction, prostaglandins …NO )


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Evacuation Technique• Stabilize hemodynamically, address all medical

complication (antihypertensive, β blocker)

• Large bore intravenous line… central venous monitoring

• Two units blood, laparotomy tray in O.R.

• Cx grasped with single tooth tenaculum,

• NO sounding,

• Cx dilated gently to accommodate 12-14mm cannula.


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• Cannula only up to lower portion of uterus,

• Start Oxytocin, massage fundus gently to assist involution, rotate cannula…advance only after involution

• Sharp curettage…both specimen separately for HPE

• Oxytocin to be cont. for 24hrs. evacuation, ...avoid fluid overload.


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Complications of Suction evacuation.

• Injury to uterus Perforation, infection.

• Hemorrhage.

• Shock

• Acute pulmonary insufficiency.

• Thyroid storm.


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Hysterectomy (↓ risk of GTN by 5%)

Indicated in • Patient with age > 35 yrs

• Completed family irrespective of age.

• Uncontrolled hemorrhage/perforation during suction evacuation.


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Hysterotomy• Rarely done.

Indicated in

• Profuse vaginal bleeding.

• Cervix unfavorable for immediate vaginal evacuation.

• Accidental perforation of uterus during evacuation.


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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.


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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.

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Partial Or Incomplete Mole

• Affection of Chorionic Villi is focal.

• Fetus/Amniotic sac is present.


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23X 23X

Dyspermy 23X/23Y or 23X/23X

23Y

Partial Mole (69XXY, or 69XXX, or 69XYY

triploid)

Partial Mole

23X

23X

23Y

69XXY

Fertilization of a normal 23X haploid ovum by two sperms, producing a triploid partial mole with either 69XXY, 69XXX or

69XYY karyotype


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Signs / Symptoms


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Vaginal bleeding

Absence of fetal heart tones

Uterine enlargement and preeclampsia is reported in only 3% of patients.

Theca lutein cysts, hyperemesis is rare.

Williams Obstetrics6/5/2017Dr Shashwat Jani.

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USG features of Partial Mole :

Gestational sac must be present empty , amorphous echoes.

Increase in transverse to A- P diameter of gestational sac > 3:2 .

(90% positive predictive value).

If fetus present, it is often growth retarded.

Placenta is excessively large, relative to size of uterine cavity & contain focal cystic spaces.


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Partial Mole: Complex mass with many cystic

areas (between arrowheads) and an embryo (arrow) in a patient with a β-HCG of 280,000 mIU/ml.

Management • If fetus is not alive termination of

pregnancy.

• If fetus is alive woman counseled about ↑ed risk of perinatal morbidity & outcome of GTN. Terminate the pregnancy.


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Partial Mole In Twins

• Many cases have been reported of second normal live fetus up to age of viability.

• Can continue pregnancy after explaining all possible maternal & fetal complications.


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Contraception during follow up

• The combined pill is started when the beta-HCG becomes negative. Till this happens, the condom can be used.

• If the pill is used early the beta-HCG will take a longer time to become negative as oestrogen stimulates the growth of trophoplast.


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The intrauterine device is not used because it may lead to irregular uterine bleeding which confuses the follow up & also increases chances of perforation.

IUD during follow up


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Follow Up

• Objective to diagnose persistent GTT that is

considered malignant.

• If hCG Normal within 56 days follow up will be for 6 months from date of uterine evacuation.

• If hCG Not normal within 56 days then follow up will be for 6 months from normalization of hCG level.

• Woman with chemotherapy should follow up for 1 year after hCG has been normal.


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Follow up protocol

History

Physical examination

hCG assay

Chest X-ray


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• History :– h/o irregular P/V bleeding.

– Hemoptysis

– Breathlessness

– CNS disturbance like headache, blurring of vision, neurological deficit.

– Epigastric pain, hematuria, jaundice


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Physical examination

• General examination

• P/A

– Sub-involution of uterus,

– Palpation of mass

– Tenderness

– Hepatomegaly

• P/S Vaginal metastasis

• P/V Sub-involution of uterus,

Regression of theca lutein cyst .6/5/2017


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• Quantitative serial βhCG level.

• Chest X-ray

If preevacuation shows metastasis Repeat at 4 wk interval until remission confirmed then 3 month interval during rest of follow-up.

If pre-evacuation chest x-ray normalrepeated only when hCG titre plateaus or rises.


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PROPHYLACTIC CHEMOTHERPHY

Prevent metastasis & reduce morbidity.

• 80% pts spontaneous regression.

• Sensitive β hCG assay can identify rest that develop malignancy.

• Chemotherapy is toxic ↑ chance of premature ovarian failure & menopause.


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Advised in

hCG level fails to become normal by stipulated time (10-12 wk) or re-elevation at 4-8 wk.

Rising β hCG level after reaching normal level.

Post evacuation hemorrhage.

Follow up facilities not adequate.

Evidence of metastasis, irrespective of β hCG level.

When malignant sequelae is higher.


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• Single drug regimen

• Course is to be repeated at interval of 7 days.

• Alternatively IV Actinomycin-D

12μgm/kg x 5 days.

Methotrexate 1-1.5mg/kg IM/IV Day 1,3,5,7

Folinic Acid 0.1-0.15 mg/kg IM Day 2,4,6,8


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RH ISOIMMUNISATION

If <12 wks gestation 50 μgm Anti-D

If >12 wks gestation 300 μgm.

In Complete Mole poor vascularisation of chorionic villi & absence of anti-D antigen so Anti –D prophylaxis not required.

BUT required in partial mole.


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Placental Site Trophoblastic Tumour (PSTT)

• Rare

• Histological Diagnosis syncytotrophoblastic cells are generally absent persistent low level of serum or urinary hCG.

• Tumor from intermediate trophoblasts of placental bed composed mainly of cytotrophoblastic cells.


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• C/F Vaginal bleeding.

• Local invasion of Myometrium & Lymphatics.

• PSTT is not responsive to chemotherapy.

• Rx Hysterectomy.


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Invasive mole


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Invasive moleDefinition:

An invasive hydatidiform mole is one in which hydropic chorionic villi are within the myometrium or its vascular spaces or at distant sites, notably the vagina or lung.

“Mole that penetrates and even perforates the uterine wall”.


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Invasive mole

• Invasive hydatidiform mole is a sequela to hydatidiform mole, complete or partial.

• The pathologic diagnosis of invasive mole is made by establishing the presence of molar villi growing into the myometrium and broad ligament.

• The diagnosis of an invasive mole cannot be made on examination of curettage specimens except when curetted fragments of myometrium contain invasive molar villi.


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Clinically identified by:

Combination of Abnormal uterine USG

Persistent / rising hCG level after uterine evacuation for mole

Theca lutein cysts & uterine subinvolution

Histologic verification is rarely required

Repeat D&C contraindicated….risk of uterine perforation, infection, life threatening hemorrhage ..hysterectomy


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Persistent Gestational Trophoblastic Disease

• Definition it is the persistence of trophoblastic activity as evidenced by clinical, imaging, pathological &/or hormonal study following initial treatment.

• Post Molar GTD

– Benign.

– Malignant.

Post Molar GTD after non-molar pregnancy is always choriocarcinoma.


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Incidence :• 50% following H.Mole

• 25% following abortion or ectopic pregnancy.

• 25% following normal delivery.


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DIAGNOSIS

During post-evacuation follow-up period

• Continued vaginal bleeding.

• Persistent Theca Lutein Cysts.

• Persistent soft & enlarged uterus.

• hCG titer either fail to become negative or plateau or re-elevation after initial fall by 8 wk post molar evacuation.

• Local, systemic metastasis ruled out by x-ray chest, CT, MRI of brain, Liver etc.


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FIGO Anatomic Staging of GTT

Stage I – Lesion is confined to Uterus

Stage II – Lesion spreads outside uterus but confined to genital organs

Stage III – lesion metastatises to lungs

Stage IV – Lesion metastatise to sites such as Brain, Liver, GIT.


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All stages subdivided as

• No risk factors

• One risk factor

• Two risk factors

Risks

• hCG > 1,00,000 mIu/ml

• Duration of disease > 6 mts from termination of antecedent pregnancy.


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WHO prognostic scoring system of GTT as modified by FIGO (2000)

Score

Characteristic 0 1 2 4

Age <40 ≥40 - -

Antecedent preg Mole Abortion Term -

Interval from index pregnancy

<4 months

4-6 months

7-12 months >12 months

Pretreatment HcG <103 103- 104 104-105 >105

Largest tumor size (including uterus)

< 3cm 3-4 cm ≥5cm -

Site of metastases Lung Spleen, kidney

GI tract Liver, brain

Number of metastases - 1-4 5-8 >8

Previous failed chemotherapy

- - Single drug ≥2 drugs


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Low risk = 6 single agent chemotherapy

High risk = 7 combination chemotherapy


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MAC protocol in low risk cases

Methotrexate Folinic Acid Actinomycin D Cyclophosphamide

1-1.5mg/kg 0.1-0.15mg/kg 12mcg/kg 3mg/kg

IM/IV IM IV IV

Day 1,3,5,7 Day 2,4,6,8 Day 1-5 Day 1-5


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EMA-CO Protocol in poor prognosis metastatic disease

Day 1 Etoposide

Actinomycin D

Methotrexate

100 mg/m2 in 200ml saline infused over 30 min.

0.5mg IV bolus

100mg/m2 bolus followed by 200mg/m2 IV infusion over 12 hr.

Day 2 Etoposide

Actinomycin D

Folinic Acid

100mg/m2 in 200ml saline infused over 30 min.

0.5 mg IV bolus.

15mg IM every 12 hrs x 4 doses beginning 24 hrs after starting Methotrexate.

Day 8 Cyclophospamide

Vincristine(Oncovin)

600mg/m2 IV in saline over 30 min.

1mg/m2 IV bolus.

Course will restart in 7-14 days if possible. 2 additional course given after hCG level is normal.


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• During Chemotherapy serum hCG level checked weekly.

• Chemotherapy should be changed if no fall in hCG titer by atleast 25% after treatment cycle.

Place of Hysterectomy :• Reduce trophoblastic tumour burden.• Decrease no. of courses of chemotherapy.• Total Hysterectomy Ovaries usually not involved. If

involved- actively cured with post-op chemotherapy.

Radiation :

• Brain Metastasis whole brain radiation therapy 3000cGy over 10 days.

• Liver Metastasis whole liver radiation therapy 2000cGy over 10 days.


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Prognosis • Low risk almost 100%

• High risk 70%.

Recurrence • Non-metastatic GTN 2-3%

• Good prognosis metastatic disease 3-5%

• Poor prognosis disease 21%.

• Recurrence following 12 mts of normal hCG level < 1%.


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ROLE OF SURGERY

Surgery has been limited to the treatment of :-

- Resistant cases to chemotherapy,

- Uncontrollable haemorrhage from the uterus

- Tumour perforation of the uterus

- Infected uterine tumour not responding to antibiotics, thus delaying chemotherapy..


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Newer Regimen

• Newer chemotherapy agents

• Autologous bone marrow transplant

• Peripheral stem cell support

• colony stimulating factors

• Selective arterial embolisation.

FOLLOW-UP

• BhCG Titre wkly until 3 consecutive normal titres• Monthly for 12 months • 3 monthly for 1 additional year• 6 monthly indefinitely• Contraception for at least 1yr after remission(OCP,

Condom)

• Gynaecologic examination started 1 week post evacuation – assess Ut size, adnexal masses, check for metastases on the vulva, vagina, urethra, and cervix. If no complication repeat exam 4 wkly throughout period of surveillance.


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Health & Medicine

GESTATIONAL TROPHOBLASTIC DISEASES BY DR SHASHWAT JANI