Milagros T.

Jocson, MD
Gestational Trophoblastic Disease (GTD )

A gp. of Pregnancy –
related Diseases char.
by abnormal
trophoblastic
proliferation

➢ 3 types of Trophoblasts
- Cytotrophoblasts
- Syncytiotrophoblasts
- Intermediate
Trophoblasts Cytotrophoblasts

Syncytiotrophoblasts Intermediate Trophoblasts

 GTD: Classification
I. Hydatidiform Mole –
A. Complete Mole
B. Partial Mole

II. Gestational Trophoblastic Neoplasia (GTN):

A. Invasive Mole
B. Choriocarcinoma
C. Placental Site Trophoblastic Tumour ( PSTT)
D. Epithelioid Trophoblastic Tumour (ETT)
GTD: Modified WHO Classification

I. Molar Lesions
A. Hydatidiform Mole –
1. Complete Mole
2. Partial Mole
B. Invasive Mole
II. Non-molar Lesions
A. Choriocarcinoma
B. Placental Site Trophoblastic Tumour ( PSTT)
C. Epithelioid Trophoblastic Tumour (ETT)
D. Misc Trophoblastic Lesions
1. Exaggerated Placental Site
2.Placental Site Nodule
 D. Misc. Trophoblastic Lesions
1. Exaggerated Placental Site:
also known as Syncytial Endometritis

• Defined as exuberant infiltration of the

endometrium and myometrium at the
implantation site by intermediate trophoblastic Numerous multinucleate
intermediate trophoblasts

• ( IT) cells. infiltrating the myometrium

• It is a relatively rare, benign lesion related to pregnancy.

Seen in 1.6% of first trimester abortions but can also
occur after full term pregnancy
• Resolves spontaneously after curettage
• No specific treatment or follow up is necessary
 D. Misc. Trophoblastic Lesions
2. Placental Site Nodule (PSN):
 A rare benign lesion of the IT
surrounded by hyaline material,
found either in the endometrium
or superficial myometrium

 Represents an involuted placental site

that has not completely resorbed

 Usually found at curettage

 GTD: Classification
I. Hydatidiform Mole –
A. Complete Mole
B. Partial Mole

II. Gestational Trophoblastic Neoplasia (GTN) –

A. Invasive Mole
B. Choriocarcinoma
C. Placental Site Trophoblastic Tumour ( PSTT)
D. Epithelioid Trophoblastic Tumour (ETT)
 Hydatidiform Mole:
Abnormal pregnancy

char. by placenta that

presents with

• Grape-like vesicles
• Trophoblastic
hyperplasia
 Types of Hydatidiform Mole

Complete H. Mole or Incomplete H. Mole or

Classic H. Mole Partial H. Mole
 Complete Mole: Characteristics

 Diffuse swelling of chorionic villi

 Complete Mole: Characteristics

• Diffuse swelling of chorionic villi

• Proliferation of trophoblasts
Complete Mole: Characteristics

• Diffuse swelling of chorionic villi

• Proliferation of trophoblasts
• No fetus nor any fetal membrane
Complete Mole:Charactericstics

• Diffuse swelling of chorionic villi

• Proliferation of trophoblasts
• No fetus nor any fetal membrane
• Androgenetic conception (diandrid diploidy)
(both sets of chromosomes are paternal in origin )
Types of Fertilization in Complete Mole

1. An “empty” ovum by a single haploid sperm,

w/ch duplicates its chromosomal complement
(endoreplication) 46 XX ( 75-85%)

2. An “empty”ovum by 2 haploid sperms

46 XX or 46 XY (15%-25%)
 Partial Mole: Characteristics

• Localized hydropic villi

• Presence of embryo/fetus
or fetal membrane
 Partial Mole: Characteristics

• Localized hydropic villi

• Presence of embryo/fetus or
fetal membrane

• Edematous villi w/ scalloping

• Localized trophoblastic
hyperplasia
• Normal placental villi
w/ blood vessels
 Partial Mole: Characteristics

• Hydropic swelling less extensive

• Normal placental villi with blood vessels
• Localized trophoblastic hyperplasia
• Presence of fetus or at least amniotic sac
( fetus w/ severe growth restriction, congenital anomaly)

• Diandric triploidy karyotype (extra paternal haploid)

 Types of Fertilization in
Partial Mole

 A haploid egg w/ 2 haploid

sperms 69 XXX, 69 XXY
or 69 XYY.

▪ A haploid egg by a single

haploid sperm w/ch then
replicates 69 XXX or 69
XYY
Hydatidiform Mole: Cytogenetics
 Complete Mole - chromosomes completely paternal in
origin (purely androgenetic)

 Partial Mole – 2 paternally & at least 1

maternally derived sets of chromosomes

* trophoblastic overgrowth assoc w/ > 1 set of

paternal chromosomes chromosome
.
 Hydatidiform Mole

Risk factors:

• Race ( Asians, Hispanic, Am. Indians)

• Maternal age) ( extremes of age )
- adolescent & 36-40 y/o = 2 fold
- > 40y/o = 10 fold
• Prev. H. Mole
1 = 1.5% - 2.7%
2 = 23%
 Hydatidiform Mole
Clinical manifestations:
• Asymptomatic except for amenorrhea – 41%
because of early diagnosis
• Vaginal bleeding – 58%
• Anemia – 2 %
• Hyperemesis – 2%
• Nausea & vomiting
• Theca lutein cysts – 25% to 60%
• Hyperthyroidism
• Preeclampsia & Eclampsia
 Theca lutein cysts ( 25-60% in H Mole)
 Hydatidiform Mole
Diagnosis:

• Clinical manifestations
• bHCG titer:
single determination is sufficient if –
1,000,000 mIU/ ml at any time
>320,000 mIU/ml after 100 days AOG
Romero,et al, Obstet Gyne 1985

• Ultrasonography – accurate & sensitive

 Complete Hydatidiform Mole

Ultrasound Features:

• “ Snow-Storm Pattern”-
Echogenic uterine mass w/
numerous anechoic cystic
spaces but w/out a fetus or
amnionic sac
 Partial Mole

Ultrasound features:

• Focal cystic spaces in the placenta

• Gestational sac, embryo or fetus

 Diagnosis: Complete Mole

Grossly - Large
edematous
villi ( cluster
of grapes )
 Complete Mole:
Microscopic findings:

▪ Edematous
chorionic villi
 Trophoblastic
hyperplasia
(cytotrophoblasts,syncytio-
trophoblasts, intermediate
trophoblasts)
 W/ cytologic atypia
 Partial Mole
Grossly:

 Normal placental tissue

admixed w/ vesicles

 Embryo/fetus or fetal
membrane present
 Partial Mole :
Microscopic findings:

 Mixture of edematous
and normal-sized villi
 Trophoblastic proliferation
 Irregular scalloping
outline
 Presence of blood vessels
 Hydatidiform Mole: Diagnosis
Histological Immunostaining to identify the presence of :

p57 nuclear protein which is expressed by maternally donated

genes

❑ Complete H. Moles contain only

paternal genes do not produce p57
and thus do not pick up the
immunostain. Complete Mole

❑ Partial H. Moles contain maternal genes

produce p57; will pick up the
immunostain.
Partial Mole
 Hydatidiform Mole: Diagnosis

Pathologic Diagnosis: (combine Ploidy Analysis

and Immunostaining)

H. Mole – Diploid and P57 (-)

Partial mole – Triploid and P57 (+)

Spontaneous Abortion – Diploid and P57 (+)

 Hydatidiform Mole: Management
➢ Medical Evaluation: Lab tests – CBC,
Blood Typing, Rt urinalysis, Chest x-
ray, bHCG, Thyroid function tests

➢ Treat medical complications

- Anemia
- Hyperthyroidism
- Preeclampsia
- Rh immune globulin for Rh (-) pt

➢ Evacuation of the H Mole

 Procedures for Evacuation of H Mole:

▪ Suction curettage –
recommended for those
desirous of future pregnancy

▪ Hysterectomy w/ mole-in-situ

▪ Hysterotomy – for Partial Mole w/ fetus, or twins w/ H.

Mole & normal pregnancy
Hydatidiform Mole:
Hysterectomy: > 35 y/o or with completed family

risk for post-molar GTD:

20% 3.5% ( Curry, et al. Obstet Gynecol 1975 )

33% 10 % ( Bahar, et al. J Reprod Med 1994 )

 Risk of Malignant Sequela

Transformation into Gestational Trophoblastic

Neoplasia ( GTN ):

 Complete H. Mole – 15 to 20%

 Partial H. Mole – 1 to 5 %
Risk Factors for Malignant Sequela:

• Maternal age (> 35 years)

• Large for dates uterus

• Pre-evacuation hCG titer of >100,000 mIU/m

• Theca lutein cysts > 6 cm

• Recurrent molar pregnancy

Hydatidiform Mole:
Prophylactic chemotherapy :

- Administration of Methotrexate or
Actinomycin D
prior to or w/in 2 wks after to evacuation

- Not shown to improve long-term prognosis

- Not recommended routinely ( ACOG)

Hydatidiform Mole: Rare Cases

❖ Recurrent / Familial H. Mole:

• Single gene disorder w/ autosomal recessive

inheritance pattern

• Both maternal & paternal genomes present (biparental)

Hydatidiform Mole: Rare Cases

❖ H. Mole with a live twin fetus

• Rare : 1 / 22,000 – 100,000 pregnancies

• Diff Dx - Twin pregnancy vs Partial Mole w/live fetus

 Hydatidiform Mole: Rare Cases
❖ H. Mole with a live twin fetus

Outcome:
42% - Pregnancy loss (miscarriage, IUFD)
For those w/ surviving fetus:
60% - Preterm birth
40% - Term birth

Clinical course depends on behavior of H mole:

either quiescent or grows extensively leading to
fetal death & maternal complications
Surveillance after Molar Evacuation:

• Serial BhCG titer 48 hrs after evac, then 1-2

wks until N x 3 consecutive determination,
then q month X 6 mos

• Contraception x 6 yr
Regressing Pattern of serial βHCG Titer

Median time for resolution

of βhCG:

• Complete Mole – 9 wks

• Partial Mole – 7 wks

Gestational Trophoblastic
Neoplasia
Gestational Trophoblastic Neoplasia

Antecedent Pregnancy:

 H. Mole – 50%
 Abortion/Ectopic – 25%
 Term or preterm pregnancy – 25%
Gestational Trophoblastic Neoplasia

• Invasive Mole
• Choriocarcinoma
• Placental Site Trophoblastic Tumour
• Epitheloid Trophoblastic Tumour
 Invasive Mole
 An H. mole that
has invaded
into the
uterine wall or
has produced
distant
metastasis
 Invasive Mole
Clinical manifestations:

 Persistent vaginal bleeding after

molar evacuation
 Uterine subinvolution
 Abnormal hCG regression pattern
 May be self-limiting, but may produce
life-threatening complications
 Invasive Mole : Diagnosis

Ultrasound:

❖ An abnormal

focal area in the

uterine wall
 Invasive Mole : Diagnosis

➢ Hyperplastic cytotrophoblasts
& syncitiotrophoblasts
w/ villous stroma w/in
the myometrium and/or
in metastatic lesions
 Choriocarcinoma
❖ A highly malignant, rapidly metastasizing tumor

❖ Lesion appears necrotic, hemorrhagic mass

❖ May follow any form of pregnancy

❖ May present with irregular vaginal bleeding

or as an isolated finding of distant metastatic
disease
 Choriocarcinoma
Diagnosis:

❖ Pure epithelial tumor

composed of syncy-
tiotrophoblasts and
cytotrophoblasts
(w/out villous stroma)
 Tumor Marker
 Sensitive TUMOR
MARKER for both
Serum βhCG = Invasive Mole and
Choriocarcinoma
has se

• Therefore, diagnosis of GTN will not require biopsy and

histopath diagnosis.
• Presence of abnormal serum βhCG is sufficient to make a Dx
of GTN.
 Placental Site Trophoblastic Tumor ( PSTT )

Pathology:

Arises from Intermediate

Trophoblasts found at the
placental implantation site
 PSTT
Gross appearance is variable:

❖ Solid polypoid mass may fill the

endometrial cavity

❖ May infiltrate the myometrium

❖ May appear circumscribed or

diffuse
 PSTT
Clinical manifestations:

• May follow a term pregnancy, molar pregnancy

or abortion
• Presents mostly as abnormal vaginal bleeding
or amenorrhea w/ uterine enlargement
• May appear weeks to years following
a pregnancy
• May follow either a benign or malignant course
 PSTT
Diagnosis:
❑ Histopathological evaluation w/
presence of Intermediate Trophoblasts

❑ Serum βHCG not a sensitive marker

 Epithelioid Trophoblastic Tumour (ETT)

• Rare but distinctive type of GTN

( 110 reported cases )

• First described in 1998 by Shih and

Kurman

• Arises from the Intermediate

Trophoblasts w/ch originates from the
Chorionic Laeve
 ETT

Clinical Presentation:
• Abnormal uterine bleeding ( 67%)

• Primary uterine tumor (40%)

Cervical Lesion ( 31%)

• Extrauterine lesion ( 25-35%) –

Lungs (most common site)

• bHCG elevated ( < 2,500 in 69%

of cases)
 Diagnosis of GTN:
 High index of suspicion – most important factor
in its recognition

 Unusually persistent bleeding after any type of

pregnancy should prompt measurement of
bHCG

 Tissue diagnosis is unnecessary, thus biopsy is

not required and may cause significant bleeding
 Criteria for Dx of GTN:
• Abnormal regression pattern of bHCG titer after
Molar evacuation
- plateauing titer - < 10% or < 10% wkly
during 3 wk period (4 measurements)
- rising titer - >10% wkly during 2 wk period
( 3 measurements )
• BhCG level remains detectable for 6 mos or
more after Molar evacuation

• Positive serum bHCG in the absence of pregnancy

• Histologic criteria for GTN lesion

 Post-molar evacuation hCG Regression Pattern - Plateauing Titer
60,000
50,000
50,000
h
C
G 40,000

t 30,000
i 20,000
t 20,000 15,000 5% 5.5% 5.5%
e
10,000 9,500 9,000 8,500
r 10,000

0
1 2 3 4 5 6 7
# of wks post-molar evacuation
 28.5%
40%
Management of GTN:
• Evaluation to search for local disease
& metastases:

CBC, liver and renal function test,

TVS, Chest CT scan or x-ray, brain &
abdominopelvic CT scan or MR imaging
Treatment of GTN:

 Chemotherapy ( primary )

 Surgery ( adjunctive )
FIGO – WHO Prognostic Scoring System:
FIGO Score 0 1 2 4

Age < 39 > 39

Antecedent H. Mole Abortion Term
pregnancy
Interval ( mos) <4 4–6 7-12 >12
Pretreatment bHCG < 103 103 – 104 > 104 - 105 >105
Largest tumor size < 5 cm > 5 cm
Site of metastases spleen GIT brain
Number of kidney liver
metastases 0 1-4 4-8 >8
Previous failed single >2
chemotherapy drug drugs
FIGO - WHO Prognostic Scoring System:

Low risk = <6

High risk = >7

FIGO Staging of GTN:
I – confined to the uterus
II – outside the uterus but within
pelvic cavity
III- pulmonary metastasis
IV – distant metastasis
Chemotherapy Regimen:

Stage I & Low risk Stage II & III :

- single agent chemotherapy

Methotrexate or Actinomycin given for 5 days

High risk – multiple agent chemotherapy

EMA-CO or EMA-CE
 PSTT : Management

Hysterectomy – primary treatment

If metastatic– (+) multi–agent chemotherapy

 ETT : Management

Definitive treatment not known because of

limited experience due to its rarity

May not be responsive to chemotherapy

Hysterectomy and lung resection have been

used successfully

One fourth will have metastatic disease and will

require combination chemotherapy