Presented by: Dr. Mashael Shebaili Assistant Prof.

& Consultant Ob/Gyne Department

Classification of gestational Trophoblastic disease

WHO Classification
Malformations of the chorionic villi that are predisposed to develop trophoblastic malignacies
Hydatidiform moles Complete Invasive Partial

Malignant neoplasms of various types of trophoblats

Benign entities that can be confused with with these other lesions
Exaggerated placental site Placental site nodule

Choriocarcinoma Placental site trophoblastic tumor Epithilioid trophoblastic tumors

Hydatidiform Mole
Definition:
In latin

"hydatid" means "drop of water "mole" means "spot

Pathologically,

Hydatidiform moles represents placentas with abnormally developed chorionic villi (enlarged, edematous and

Hydatidiform Mole
Incidence:
In the United States,
1in 600 therapeutic abortions 1 in 1,500 pregnancies

Internationally:
In Japan & China, 1-2 in 1,000 pregnancies In Indonesia & India, 12 in 1,000 pregnancies

In the United Arab of Emirates,

2 in 1000 deliveries (population-based study; Graham IH, Fajardo AM; 1988)

In Saudi Arabia;
1.48 in 1000 live births (hospital-based study; Felemban AA, et al; 1969)

In the United States, 1in 600 therapeutic abortions 1 in 1,500 pregnancies

In Asian countries, The rate is 10 times higher than in Europe and North America

In Saudi Arabia;, 1.48 in 1000 live births (hospital-based study; Felemban AA, et al; 1969)

Table1: Factors Associated with GTD Occurrence and Corresponding Relative Risks
Odds ratio Factors Maternal age (years) <20 >40 Reproductive history Parity at conception 0 3 Spontaneous miscarriages >2 Problems with infertility Contraception Use of oral contraceptives ICUD user Age of 1st pregnancy <25 Previous molar pregnancy Complete Mole 1.5 5.2 Partial Mole

0.9 0.8 1.53.1 2.43.7 1.12.6 1.73.7 0.6 16.0

0.7 0.5 1.9 3.2

1.3

Table1:Factors Associated with GTD Occurrence and Corresponding Relative Risks

Odds ratio Factors Family history Spontaneous abortion (yes) Socioeconomic and lifestyle Education (years) >12 Marital status Never married Smoking Ex-smokers Current smokers >15 cigarettes per day Alcohol consumption <2 drinks Complete Mole 1.5 Partial Mole

0.92.1 2.1 1.1 2.2

2.1 2.1 0.7 1.8

2.1

1.4

Table1: Factors Associated with GTD Occurrence and Corresponding Relative Risks
Odds ratio Factors ABO blood types Maternal blood AB A Maternal A, husband O Nutrition Vitamin A in diet above control median Complete Mole Partial Mole

2.1 1.7 1.9 0.6

1.2 0.9

Pathogenesis and Cytogenetics of HM

Complete
Diploid
96% Fertilization of an empty ovum by one sperms that undergoes duplication Diandric diploidy 4% Fertilization of an empty ovum by two sperms Diandric dispermy

Partial
Genetic Constitution

Triploid/ teraploid
90% Triploid fertilization of a normal ovum by two sperms Dispermic triploidy 10% Tetraploid fertilization of a normal ovum by three sperms

Patho-genesis

Dispermic triploidy

46XX

46XX 46XY

Karyotype

69XXX 69YXX 69YYX

Complete Mole, Pathogenesis

Empty ovum Paternal chromosomes only

Duplication

46XX

23X Diandric diploidy Androgenesis

Complete Mole, Pathogenesis

Empty ovum 23X 23X 23X 23X 46XX Paternal chromosomes only

Dispermic diploidy

Partial Mole, Pathogenesis

Normal ovum 23Y 23X 23X 23Y 23X 69XXY Paternal extra set

23X

Dispermic triploidy

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 antiapoptosis genes

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

Trophoblastic hyperplasia

A log plot of microarray experiment demonstrating up-regulation of STAT5B expression and downregulation of 1GFBP5 expression in mole.

Hydatidiform Mole
Clinical Presentation:
Complete mole:

Vaginal bleeding Passage of hydropic villi

Severe anemia

Hydatidiform Mole
Clinical Presentation:
Complete mole:
Excessive uterine enlargement Theca lutein cysts

Usually, in association with,

Hyperthyroidism Hyperemesis gravidarum Preeclampsia Markedly elevated hCG 100,000

mIU/mL

Hydatidiform Mole
Accurate hCG testing Hugh resolution ultrasonography

The clinical presentation has changed

Per-vaginal bleeding

An ultrasound showing the classic findings of a snow storm pattern

Hydatidiform Mole
Table 2: The change of the clinical presentation of molar pregnancy among current patients Study, site, sample Soto-Wright et al, Gemer et al, size New England (n Israel (n 41) 74)
Mean maternal age 27.7 years (range 16-51) 11.8 weeks (range 6-22) 12.4 weeks (range 720) 345 415 mIU/ml (range 828 1680300) 30.1 years 10 weeks (range 714) 10 weeks

Lindholm & Flam, Sweden (n 75)

--

Mean estimated gestational age Mean uterine size

12.4 weeks

--

Mean level of preevacuation hCG

275 901 IU/l (range -2011 919 000).

Hydatidiform Mole
Table 2: The change of the clinical presentation of molar pregnancy among current patients Study, site, sample Soto-Wright et al, Gemer et al, size New England (n Israel (n 41) 74)
Vaginal bleeding Uterine size greater than that for the expected date Anemia Hyperemesis Preeclampsia Hyperthyroidism Asymptomatic 84% 28% 58% 44%

Lindholm & Flam, Sweden (n 75)

77% 20%

4% 8% 1.3% -9%

2% 2% 0% 0% 41%

-19% 1.3% -16%

Hydatidiform Mole
Clinical Presentation:
Partial mole:
History:
Vaginal bleeding Usually diagnosed as missed or incomplete abortion

Physical:
A uterus small or equal to gestational age

Hydatidiform Mole
Diagnosis:
History Clinical examination Ultrasound examination Serum hCG levels Histopathological examination Cytogenetic and molecular biological examination

Hydatidiform Mole
Diagnosis:
Ultrasonography:
* The diagnosis of molar pregnancy is nearly always made by ultrasonography

Complete mole

The classical finding is a snow storm" pattern Theca lutein cysts are frequent findings on ultrasound

The snow storm appearance of complete hydatidiform mole

Theca lutein cysts, a frequent finding on ultrasound

Hydatidiform Mole
Diagnosis:
Ultrasonography:

Partial mole

Abnormal gestational sac The classic vesicular sonographic findings of a complete mole are usually not seen Focal sonographic cystic changes and/or hydropic changes in the placenta are significantly associated with the diagnosis of a partial molar pregnancy

Hydatidiform Mole
Diagnosis:
Ultrasonography: However, based on ultrasound, correct diagnosis can be suspected in only:
84% of patients with complete mole and 30% of patients with partial mole

(Lindholm and Flam, 1999)

In comlete mole:

The accuracy of ultrasonogrophy is gestational age dependent

100% of cases cane be diagnosed at a gestational age of 13 eeks or more 50% of cases cane be diagnosed in earlier pregnancies

(Lazarus et al, 1999)

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

Hydatidiform Mole
Diagnosis:
Histopathological examination:
It should always be done as far as possible and samples should be kept for DNA analysis for a final diagnosis when histology can not differentiate molar pregnancy from abortion

Table3: Pathological features of complete and partial hydatidiform mole

Complete Mole Macroscopically Partial Mole
A mass of large, edematous The placental tissue is less villi that are diffusely bulky distributed, typically A few enlarged villi with a described as resembling a focal distribution cluster of grapes A fetus may be identified

grossly that often has multiple congenital anomalies including syndactyly of the fingers & toes

The grape like vesicles in gross appearance

Table3: Pathological features of complete and partial hydatidiform mole Complete Mole Partial Mole
Two distinct populations of villi. One with large, edematous villi with central cisterns. The other contains small villi that show some degree of stromal fibrosis Abnormal circumferential trophoblastic proliferation Irregular, scalloped outline to some of the villi, often referred to as fjordlike which appear in other microscopic as islands of trophoblast in the interior of villi referred to as trophoblastic pseudoinclusions which are highly suggestive of the diagnosis Fetal tissue, RBSs

Microscopically

Enlarged edematous villi which show a central acellular fluid-filled space referred to as a central cistern Abnormal trophoblastic proliferation that is circumferential in contrast to normal villi in which trophoblastic proliferation is at one end of the villus Absence of fetal tissue

Normal villi from first trimester placenta, showing directional, polar growth of trophoblast from one end of the villi toward the basal plate.

Villus from a complete mole demonstrating the characteristic large, acellular central cistern

Villus from a complete mole. There is florid, circumferential hyperplasia of the trophoblast around the periphery of the villi

Low power view of a partial hydatidiform mole showing the two distinct populations of villi. Asingle large villus with multiple smaller villi

Partial mole, showing irregular, scalloped outline and trophoblastic pseudoinclusion

Table3: Pathological features of complete and partial hydatidiform mole Partial Mole
Cytogenetics

Complete Mole

69, XXX triploidy most

maternal haploid set

46, XX diploidy most common All chromosomes of paternal common 2+ paternal haploid sets & 1 origin

Pathology features Hydropic villi Trophoblastic proliferation Fetus or fetal rbcs Clinical course Clinical or ultrasound diagnosis Uterus large for gestational dates Theca lutein cysts Pre-eclampsia Hyperemesis Thyrotoxicosis Malignant sequelae

Focal, variable Focal, usually slight Usually present Rare Rare Rare Rare Rare <5% Rarely metastatic Persistent mole

Diffuse, often marked Diffuse, variable intensity Absent >50% 2550% 2535% 1020% 510% 20% 1020% metastatic 2533% choriocarcinoma

Hydatidiform Mole
Management:
1 Complete history and physical examination

Investigations

Medical and surgical care

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) The method of choice

Hysterectomy

Increased risk of medical complications Associated with a markedly decreased rate of malignant sequelae (3.5%) when compared with suction evacuation.

Hydatidiform Mole
Complications associated with molar pregnacy:
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

Hydatidiform Mole, complications

Theca-lutein cysts:
Prevalence:
Clinically evident theca lutein cysts (usually >56 cm) are detected in about 25-35% of women with molar pregnancies

Association:
They usually correlate with marked elevation of serum hCG levels above 100,000 IU/l

Complications:
Pain or pressure that may require percutaneous aspirations. Torsion, rupture, or bleeding are rare complications that can require oophorectomy Bilateral theca letein cysts increase the risk of post-molar GTD

Course:
The mean time for theca luteal cysts to regress is approximately 8 weeks

Hydatidiform Mole, complications Respiratory distress syndrome:

Prevalence:
Rare

Pathophysiology:
Embolization of trophoblastic tissue Transient impairment of left ventricular function during induction of anesthesia for suction D&C of molar pregnancy coexisting conditions such as anemia, hyperthyroidism, hypertension from preeclampsia

Risk factors:
Uterine size larger than 14 to 16 weeks High levels of hCG

Hydatidiform Mole, complications Respiratory distress syndrome:

Presentation:
Tachypnia and tachycardia following evacuation Bilateral pulmonary infiltrates on chest x-ray

Management:
Central venous monitoring Ventilatory support

Course:
It should resolve within 24 to 48 hours after molar evacuation

Hydatidiform Mole, complications Hyperthyroidism:

Prevalence:
Clinical hyperthyroidism is seen in less than 10% of patients with molar pregnancies A small number of patients may have elevated thyroid function tests without clinical evidence of disease

Management:
Beta-blockers should be administered prior to molar evacuation to prevent thyroid storm that may be induced by anesthesia and surgery.

Hydatidiform Mole
A hydatidiform mole and a co-existent fetus:
Prevalence:
Rare (1 in 22,000100,000) partial moles and twin gestations with coexistent fetuses and molar gestations Usually, by ultrasound Few, after examination of the placenta following delivery Increased risk of medical complications Increased risk for postmolar gestational trophoblastic disease No clear guidelines for management

Diagnosis:

Complications:

Management:

Hydatidiform Mole
Risk Factors for post-molar gestational trophoblastic disease:
Advanced maternal age Factors that reflect the volume of trophoblastic tissue:Clinical factors that are associated with high hCG levels (>100,000 mIU/mL) uterus large for date, bilateral theca lutein cysts, Respiratory distress syndrome after molar evacuation, eclampsia, hyperthyroidism, Uterine subinvolution with post evacuation hemorrhage. (With any one of these factors or a combination of many, the risk of post-molar GTD has ranges from 25% to 100%)

Hydatidiform Mole
Risk Factors for post-molar gestational trophoblastic disease: The presence of invasive trophoblast antigen (ITA) which has 100% sensitivity and specificity for invasive trophoblastic tumors (Cole et la, 2003)

*There is no correlation between the degree of anaplasia and the risk of post-molar GTD

Hydatidiform Mole
Prophylactic Chemotherapy:
In one randomized clinical trial, a single course of methotrexate and folinic acid reduced the incidence of postmolar trophoblastic disease from 47.4% to 14.3% (P <.05) in patients with high-risk moles:
hCG levels greater than 100,000 mIU/mL, uterine size greater than gestational age, ovarian size greater than 6 cm),

However, the incidence was not reduced in patients with low-risk moles On the other hand, the use or prophylactic chemotherapy increases the risk of drug resistance Because of the excellent primary cure rates among women with post-molar GTD, and mortality achieved by monitoring patients with serial hCG determinations and instituting chemotherapy only in patients with postmolar gestational trophoblastic disease outweighs the potential risk and small benefit of routine prophylactic chemotherapy.

Hydatidiform Mole
Surveillance after molar pregnancy evacuation:
Rationale:
Prompt identification of patients who develop malignant postmolar gestational trophoblastic disease Serial quantitative serum hCG determinations using commercially availableassays capable of detecting -hCG to baseline values(<5 mIU/mL)
Frequency: within 48 hours of evacuation, weekly while elevated and then monthly when undetectable for 6 months in the case of partial moles and 12 months in the case of complete moles Duration: while hCG is elevated to monitor the involution of pelvic structures and to aid in the identification of vaginal metastasis

Method:

Pelvic examination:

Hydatidiform Mole
Surveillance after molar pregnancy evacuation:
Contraception:
Rationale: Pregnancy obscures the value of monitoring hCG levels during this interval and may result in a delayed diagnosis of postmolar malignant gestational trophoblastic disease Method: Oral contraceptive pills Advantages: They do not increase the incidence of postmolar gestational trophoblastic disease They do not alter the pattern of regression of hCG values In a randomizedstudy, by Berkowitz et al in 1998, patients treated with oral contraceptives had one half as many intercurrent pregnancies as those using barrier methods, and the incidence of postmolartrophoblastic disease was lower in patients using oral

Hydatidiform Mole
Surveillance after molar pregnancy evacuation:
What are the characteristics of false-positive hCG values, also known as phantom hCG? False positive hCG assays have been identified recently Cause: the presence of non-specific heterophil antibodies in the patients sera directed against animal antibodies present in commercial kits Should be suspected if hCG values plateau at relatively low levels and do not respond to therapeutic maneuvers Evaluation of patients with suspected false positive hCG:
Urinary hCG Serial dilutions of the serum

Hydatidiform Mole
Prognosis:
Post-molar gestational trophoblastic disease:
Risk:
Following complete mole: 20% Following partial mole: 5%

Type:
70% to 90% are persistent or invasive moles 10% to 30% are choriocarcinomas

Diagnosis:
A rising, plateauing, or persistent elevation of human chorionic gonadotropin after evacuation of a hydatidiform mole or an ectopic or term pregnancy

Hydatidiform Mole
The current FIGO criteria for diagnosis of post-molar GTD
a) Four values or more of hCG documenting a plateau (10% of hCG value) over at least 3 weeks: days 1, 7, 14, and 21. b) A rise of hCG of 10% or greater for 3 values or longer over at least 2 weeks; days 1,7 and 14. c) The presence of histologic choriocarcinoma. d) Persistence of hCG 6 months after mole evacuation.

Pregnancy after Hydatidiform Mole:

Risk of another molar pregnancy:
Increased by 10-fold (12% incidence)

Current recommendations for management of subsequent pregnancies:

an early ultrasound to confirm normal gestational development and dates A chest x-ray to screen for occult metastasis masked by the hCG rise of pregnancy Examination of the placenta or products of conception histologically at the time of delivery or evacuation for evidence of occult trophoblastic disease An hCG level should be obtained 6 weeks post evacuation or delivery to confirm normalization.