Gestational Trophoblastic

Disease (GTD)

WAQAR ULLAH

08-207

IntroductionWhat is GTD ?

It is a clinical term used to indicate closely

related conditions characterized by active

abnormal proliferation of trophoblastic cells

It is too among the rare human

malignancies that can be cured

even in the presence of widespread metastases

Which does it include?

It includes a spectrum of interrelated tumors, including

hydatidiform mole (HM) 80 % of cases

invasive mole (IM) 12-15%

Choriocarcinoma (CH) 5-8%

Placental-site trophoblastic tumor (PSTT, borderline, very rare)

Relationship of HM. IM. CH

hydatidiform therapeutic or

mole spontaneous abortion

term pregnancy

ectopic

invasion mole choriocarcinoma.

Hydatidiform mole

Hydatidiform mole

Hydatidiform mole

It is a neoplastic proliferation of the trophoblast in which the terminal villiare transformed into vesicles filled with clear viscid material.

It is usually benign but has malignant potentiality.

Incidence:

south east Asia is 1/500-600

the US and Europe:1/500-2000

China:1/1238

Classification

It is divided into two classification

complete hydatidiform mole

partial hydatidiform mole

complete hydatidiform mole(CHM):

the entire uterus filled with abnormal vesicles, no signs of fetus.

partial hydatidiform mole

partial hydatidiform mole with evidence of a conceptus.

Etiology

Though it is not known a number of associated factors have been noted:

age:>45 years women are 10 times more likely to develop HM than those younger.

Previous hx of HM

Previous misscarriage

Excessive smoking

Poor nutrion,esp vit A deficiency

abnormal fertilization process:

the fertilization of a normal ovum with a duplicated haploid sperm:46XX

the fertilization of an empty egg by two sperms(dispermy):46XY

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

Partial Mole, Pathogenesis

69XXY

Normal ovum

23X

Dispermic triploidy

Paternal extra set

23Y 23X

23Y 23X23X

Pathologic findings

complete hydatidiform mole

pathology

Complete moles lack identifiable embryonic or fetal tissues, and the chorionic villi exhibit generalized hydatidiform swelling and diffuse trophoblastic hyperplasia.

Gross

we see a mass of vesicles, vary in size, grape-like with stems, blood and clot filling the inter-vesicle space

Microscopic(complete mole)

Cytotrophoblast &

syncytiotrophoblast

hyperplasia(variable)

Avascularity

No fetal parts

partial hydatidiform mole

It are characterized by the following pathologic features :

Chorionic villi if varying size with focal hydatidiform swelling and cavitation.

It contain identifiable embryonic or fetal tissues.

Gross

we see a mass of vesicles, vary in size, grape-like and identifiable embryonic or fetal tissues.

Microscopic(partial mole)

Vesicles have certain degree

of vascularity till fetal death

Fetal parts

Syncytiotrophoblast

hyperplasia

Fetal hand demonstrating syndactyly. The fetus had a triploid karyotype, and the chorionic

tissues were a partial mole

Feature Partial mole Complete mole

Karyotype

Most commonly

69, XXX or - XXY

Most commonly

46, XX or -,XY

Pathology

Fetus Often present Absent

Amnion, fetal RBC Usually present Absent

Villous edema Variable, focal Diffuse

Trophoblastic proliferation Focal, slight-moderate Diffuse, slight-severe

Clinical presentation

Diagnosis Missed abortion Molar gestation

Uterine size Small for dates 50% large for dates

Theca lutein cysts Rare 25-30%

Medical complications Rare 10-25%

Features Of Partial And Complete Hydatidiform Moles

HYDATIFORM MOLE

CLINICAL FEATURES

Vaginal bleeding (anemia) 97%

Excessive uterine size 50%

Theco-lutein ovarian cysts 50%

Preeclampsia 27%

Hyperemesis 25%

Hyperthyroidism 7%

Trophoblastic embolization 2%

(respiratory distress)

signs

1) abnormally enlarged and soft uterus

2) absence of braxton hicks contractions

3) Bilateral ovarian enlargement

4) Absence of fetal parts on palpation

5) Pre eclampsia

6) Hyperthyrodism

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

Hydatidiform Mole

Diagnosis:

• Serum hCG levels:

Serum hCG levels of greater than 92 000 IU/l associated with absent fetal heart beat indicate a diagnosis of complete hydatidiform moles (Romero et al, 1985)

Serum hCG level decreases quickly if the patient has an abortion, but it does not in molar pregnancy

Ultrasonography:

It is a reliable and sensitive technique for the diagnosis of complete molar pregnancy. Because the chorionic villi exhibit diffuse hydatidiformswelling. Complete moles produce a characteristic vesicular sonographic pattern, usually referred to as a “snowstorm” pattern.

Ultrasonography may also

contribute to the diagnosis of

partial molar pregnancy by

demonstrating focal cystic spaces

in the placental tissues and an

increase in the transverse

diameter of the gestational sac.

Differential diagnosis

abortion;

multiple pregnancy;

polyhydramnios

Hydatidiform Mole

Management:

Complete history and physical examination

Investigations

Medical and surgical care

1

3

2

Hydatidiform Mole Management:

• History and physcal examination:

Should aim to rule out the classic symptoms and signs that would lead to a diagnosis of:

• severe anemia

• dehydration

• preeclampsia

• thyrotoxicosis

The patient should be stabilized hemodynamically

Hydatidiform Mole Management:

• Investigations:

Laboratory:

Pre-evacuation hCG

Complete blood count

Electrolytes, BUN, creatinine

Liver function tests

Thyroid function tests

Imaging:

Pelvic ultrasound

Chest x-ray

Hydatidiform Mole

Management:

• Medical care:

Correction of:

Anemia

Dehydration

Hyperthyroidism

hypertension

Hydatidiform Mole

Management: Surgical care:

Suction curettage (with

oxytocin or prostaglandin infusion)

Hysterectomy

•The method of choice

•Increased risk of medical complications

•Associated with a markedly decreased rate of malignant sequelae (3.5%) when compared with suction evacuation.

Mangementsuction & curretage

Under GA.

Cervix dilation till 12mm.and S&C induced to the uterine cavity.

I.V oxytocin infusion is started .

S&C started by negative pressure of about 60 to 70cmHg.

The curette is genteelly rotated to ovoid perforation of the soft uterus, and the majority of the molar tissue is evacuated rapidly ,and the uterine size decreases

F0llow-up

After the uterus has been evacuated :

About 90% of cases ,the trophoblastic tissue

die out completely.

About 10% of cases the trophoblastic tissue

does not die out completely and may persist

or recur as : invasive mole or

choriocarcinoma.

Follow-up

So it is important that women who have had a hydatidiform mole:

should have close follow-up by serum hCG levels after the evacuation of the uterus,

To ensure early recognition of persistent

trophoblastic tissue .

F0llow-up

After a molar pregnancy ,the hCG

levels will usually have returned to non

pregnant levels by 4 to 6 weeks after

evacuation.

The follow-up is recommended for 2

years in cases of complete moles, and 6

months of cases of partial moles after

the evacuation of uterus.

F0llow-up

Serial quantitative measurement of serum hCG level at weekly intervals, after evacuation of moles till 4 to 5 weeks when the hCG become normal. Then every other week .When the titer gets negative the measurements are done every month fore 1 year.

chemotherapy

Indication of chemotherapy after

the evacuation of the hydatidiform

mole in:

Serum hCG >20000 i.u/L , at any

time after evacuation of mole.

Raised hCG at 4 to 6 weeks after

evacuation of mole.

F0llow-up

Evidence of metastases

,hepatic,brain,and pulmonary.

Persistent uterine hemorrhage

after evacuation of mole with

raised hCG levels.

pregnancy

To achieve effective follow-up ,the

pregnancy is better to be avoided ,and also

the use of oral contraceptive pills until the

hCG levels returns to normal after the

evacuation of the mole.

Early diagnosis of persistent trophoblastic

disease ensures a good prognosis and an

effective system of follow-up.

Invasion Mole

Introduction

Invasion Mole arises from HM

it has malignant potentialities, invades the myometrium and penetrates the uterine wall, extends into the broad ligament or peritoneal cavity.

in half or more of all cases invasive mole metastasizes through the peripheral circulation to distant sites, mostly to the lung.

Pathologic findings

excessive trophoblastic proliferation and invasiveness

the degree of anaplasia is variable: completely benign---highly malignant

differentiation between invasive mole and choriocarcinoma lies in whether the villous pattern is preserved:

if we see villi, it must be invasion mole;

if we can’t see villi, it is choriocarcinoma.

Clinical course

Symptoms caused by primary lesions

vaginal bleeding

pelvic examination reveals delayed involution of the uterus, persisting cyst .

abdominal pain

intra-abdominal hemorrhage, penetration of the uterus .

Metastatic symptoms

• cough, hemoptysis---positive X-ray signs

•profuse vaginal bleeding---vaginal or cervical metastasis, we can see bluish nodule in vaginal

•headache, nausea, vomit, paralysis or coma—it is caused by cerebral lesion.

Diagnosis

history and clinical manifestation

hCG assay:

diagnosis suspected if hCG titers persist to be high 12 weeks after evacuation of a HM, or once regress to normal range but rise rapidly.

possible reasons : retained HM

pregnancy

huge theca-lutein cyst persist

when we remove these reasons we can diagnosis invasive mole

other measurement

ultrasound

X-ray

Prophylaxis

respond well to chemotherapeutic agents

main causes of death:hemorrhage, metastasis and infection

Treatment:

Identical to that for choriocarcinoma

Choriocarcinoma

It is highly malignant GTT

It may follow HM, invasion mole, abortion, normal pregnancy, ectopic pregnancy.

Pathologic findings

Gross inspection

irregular or circumscribed hemorrhagic growth in the uterine wall

ulcerating surface opens into the endometrial cavity (rarely embedded in myometrium)

penetration into broad ligament or the peritoneal cavity

dark red blood:.it is filled metastatic nodules

ulcerating surface opens into the endometrial cavity (rarely embedded in myometrium)

Histologic findings

we see masses of anaplastic trophblastic cells in microscopy;

invasion into the uterine wall, destroying vessels, muscle tissue

prominent necrosis and hemorrhage

villi can not be recognized

spread through circulation

Clinical Manifestations

irregular bleeding after preceding gestation;

malignant tumor cells enter the circulation through the open blood vessels and are transported to lungs, brain or to other distant sites.

metastatic symptoms

pulmonary lesions

cerebral lesions

metastatic nodule in the vagina, vulva or cervix ,it is bluish nodule filled dark red blood.

Diagnosis

Diagnosis must be suspected as a possible reason for continued (irregular) bleeding after any form of pregnancy.

we assay hCG , the time of hCG change into normal is different in various diseases.

FIGO Staging

STAGE

I. Confined to the uterus

II. Outside of uterus, limited to genital structures

III. Extends to lungs +- genital tract involvement

IV. All other metastatic sites

Who Orgnaization prognostic scoring system for gestational trophoblastic neoplasia

Prognostic factor 0 1 2 4

Age <39 >39 _ -

Antecedent pregnancy Hydatidiform Abortion , ectipic Term pregnancy -

Interval (months) <4 4-6 7-12 >12

hCG level (IU/liter) <10 10-10 10-10 >10

ABO blood groups

(female/male)

O/A B A/O AB

Largest tumor (cm) <3 3-5 >5 _

Site of metastasis _ Spleen, kidney Gastrointestinal tract, liver Brain

Number of metastases _ 1-3 4-8 >8

Prior chemotherapy _ _ Single drug Multiple

druge

The total score is obtained by adding the individual scores for each prognostic factor . Total score :<4 , low risk ; 5-7 , intermediate risk ;>8 , high risk .Interval :between antecedent pregnancy and start of chemotherapy.

Treatment

highly sensitive to chemotherapy, which is invariably the treatment choice.

surgery has little place (because of the high vascularity and the effectiveness of chemotherapy). it is indicated for tumor resistant to chemotherapy and single metastases persisting despite chemotherapy.

Chemotherapy

most often used drugs

methotrexate (MTX)

actinomycin D (Act-D)

5-fluorouracil (5-Fu)

vincristine (VCR)

cyclophosphamide (CTX)

chlo-ranbucil, etc

principles low-risk patients are usually treated with a

single agent medium-risk patients are usually treated

with ABACA regimen with 80-90% survival rate. (Etoposide, Methotrexate,Hydroxyurea,6-mercaptopurine,Actinomycin-d,Folinic acid)

High-risk No. of regimens are used.mostcommon EMA/CO(etoposide,methotrexate,actinomycin-d,cyclophosphamide,vincristine)

Operation

unresponsive or drug fails to reach the tumor;

if the tumor can be eradicated by drug therapy, esp.in young women, there is no reason to remove the uterus;

the ovaries need not be removed.

Follow-up examinations

at 1-month interval for 1 year: at 3-month interval for 2 years

at 1-year interval for 3 years

at 2-year interval afterwards. pelvic examination

chest X-ray film

hCG

Placental-Site Trophoblastic Tumor (PSTT)

Originate from intermediate cytotrophoblast cells

Secrete human placental lactogen (hPL) B-hCG often normal Less vascular invasion, necrosis and

hemorrhage than choriocarcinoma Lymphatic spread Arise months to years after term pregnancy

but can occur after spontaneous abortion or molar pregnancy

Placental-Site Trophoblastic Tumor (PSTT)

Most common symptom is vaginal bleeding Tend to:

- Remain in uterus- Disseminate late- Produce low levels of B-hCG compared to other GTN- Be resistant to chemotherapy (treat with surgery)