Gestational Trophoblastic Gestational Trophoblastic Neoplasia Neoplasia Chris DeSimone, MD Chris DeSimone, MD Assistant Professor Assistant Professor Division of Gynecologic Oncology Division of Gynecologic Oncology Department of Obstetrics & Gynecology Department of Obstetrics & Gynecology
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Gestational Trophoblastic
Gestational Trophoblastic
Neoplasia
Neoplasia
Chris DeSimone, MD
Chris DeSimone, MD
Assistant Professor
Assistant Professor
Division of Gynecologic Oncology
Division of Gynecologic Oncology
Department of Obstetrics & Gynecology
Department of Obstetrics & Gynecology
Gestational Trophoblastic Neoplasia
Gestational Trophoblastic Neoplasia
(GTN)
(GTN)
•
•
Ancient disease
Ancient disease
•
•
Hippocrates documented a
Hippocrates documented a
hydatidiform
hydatidiform
mole in the 4
mole in the 4
th
th
century BC
century BC
•
•
William
William
Smellie
Smellie
(Scottish mid
(Scottish mid
-
-
wife, circa 1700) was the first
wife, circa 1700) was the first
to coin the terms
to coin the terms
Hydatid
Hydatid
and
and
Mole
Mole
What is a mole?
What is a mole?
What is a mole?
What is a mole?
•
•
A mole is the amount of pure substance containing the
A mole is the amount of pure substance containing the
same number of chemical units as there are atoms in
same number of chemical units as there are atoms in
exactly 12 grams of carbon
exactly 12 grams of carbon
-
-
12 (i.e., 6.023 X 10
12 (i.e., 6.023 X 10
23
23
). This
). This
involves the acceptance of two dictates
involves the acceptance of two dictates
--
--
the scale of
the scale of
atomic masses and the magnitude of the gram. Both
atomic masses and the magnitude of the gram. Both
have been established by international agreement.
have been established by international agreement.
Formerly, the connotation of "mole" was "gram
Formerly, the connotation of "mole" was "gram
molecular weight." Current usage tends to apply the
molecular weight." Current usage tends to apply the
term "mole" to an amount containing
term "mole" to an amount containing
Avogadro's
Avogadro's
number of whatever units are being considered. Thus, it
number of whatever units are being considered. Thus, it
is possible to have a mole of atoms, ions, radicals,
is possible to have a mole of atoms, ions, radicals,
electrons, or quanta. This usage makes unnecessary
electrons, or quanta. This usage makes unnecessary
such terms as "gram
such terms as "gram
-
-
atom," "gram
atom," "gram
-
-
formula weight," etc.
formula weight," etc.
What is a mole?
What is a mole?
What is a mole?
What is a mole?
Epidemiology
Epidemiology
•
•
Incidence
Incidence
–
–
Less than 1/1000 pregnancies (World)
Less than 1/1000 pregnancies (World)
–
–
Japan
Japan
-
-
2/1000 pregnancies
2/1000 pregnancies
•
•
Age
Age
–
–
Bandy et al. Obstet Gynecol. 1984.
Bandy et al. Obstet Gynecol. 1984.
–
–
Women < 15 years or > 40 years at increased risk
Women < 15 years or > 40 years at increased risk
–
–
Greatest risk > 50 years (RR
Greatest risk > 50 years (RR
-
-
519)
519)
•
•
Diet
Diet
–
–
Decreased animal fat and Vitamin A
Decreased animal fat and Vitamin A
•
•
Risk of another molar pregnancy
Risk of another molar pregnancy
–
–
Bagshawe
Bagshawe
et al. Cancer. 1976.
et al. Cancer. 1976.
–
–
1 in 76 pregnancies have a second mole
1 in 76 pregnancies have a second mole
–
–
1 in 6.5 pregnancies have a third mole with 2 prior molar
1 in 6.5 pregnancies have a third mole with 2 prior molar
pregnancies
pregnancies
The Changing Symptoms of a
The Changing Symptoms of a
Complete Mole
Complete Mole
12 weeks
12 weeks
-
-
1.3%
1.3%
8%
8%
28%
28%
84%
84%
1988
1988
-
-
1993
1993
P=0.005
P=0.005
P=0.02
P=0.02
P=0.001
P=0.001
P=0.001
P=0.001
P=0.001
P=0.001
P=0.001
P=0.001
Significance
Significance
16 weeks
16 weeks
Median Age of
Median Age of
Evacuation
Evacuation
7%
7%
Hyperthyroidism
Hyperthyroidism
27%
27%
Preeclampsia
Preeclampsia
26%
26%
Hyperemesis
Hyperemesis
51%
51%
Excessive Uterine Size
Excessive Uterine Size
97%
97%
Vaginal Bleeding
Vaginal Bleeding
1965
1965
-
-
1975
1975
Soto
Soto
-
-
Wright et al.
Wright et al.
Obstet Gynecol. 1995.
Obstet Gynecol. 1995.
Curry et al. Obstet Gynecol. 1975.
Curry et al. Obstet Gynecol. 1975.
Symptoms of a Complete Mole
Symptoms of a Complete Mole
•
•
Clinical hyperthyroidism occurs in less
Clinical hyperthyroidism occurs in less
than 1% of patients
than 1% of patients
•
•
10% of patients have an elevation of T3
10% of patients have an elevation of T3
and T4
and T4
•
•
Theca
Theca
-
-
lutein
lutein
cysts are found in 15% of
cysts are found in 15% of
complete moles
complete moles
•
•
57% of patients with a complete mole and
57% of patients with a complete mole and
theca
theca
-
-
lutein
lutein
cysts will have GTN
cysts will have GTN
Diagnosis
Diagnosis
•
•
Intact HCG
Intact HCG
•
•
Ultrasound
Ultrasound
•
•
Evacuation
Evacuation
–
–
Suction curettage
Suction curettage
surgery of choice
surgery of choice
–
–
Pre
Pre
-
-
Op checklist
Op checklist
•
•
CBC
CBC
•
•
Thyroid panel
Thyroid panel
•
•
Maternal
Maternal
Rh
Rh
factor
factor
•
•
Type & Cross
Type & Cross
Complete and Partial Moles
Complete and Partial Moles
46 XX (90%)
46 XX (90%)
46 XY (10%)
46 XY (10%)
Triploidy
Triploidy
XXX, XXY, XYY
XXX, XXY, XYY
Karyotype
Karyotype
19%
19%
3.5%
3.5%
GTN
GTN
Diffuse
Diffuse
Focal
Focal
Trophoblastic
Trophoblastic
Hyperplasia
Hyperplasia
Diffuse
Diffuse
Focal
Focal
Villous Edema
Villous Edema
Absent
Absent
Present
Present
Fetal Tissue
Fetal Tissue
Complete Mole
Complete Mole
Partial Mole
Partial Mole
Follow
Follow
-
-
up of Molar Pregnancy
up of Molar Pregnancy
•
•
Intact HCG test of choice
Intact HCG test of choice
•
•
Β
Β
-
-
HCG no longer used at
HCG no longer used at
UK and in Lexington
UK and in Lexington
•
•
Average time to reach
Average time to reach
undetectable HCG, 73
undetectable HCG, 73
days
days
(Ho Yuen et al. Am J Obstet
(Ho Yuen et al. Am J Obstet
Gynecol, 1981.)
Gynecol, 1981.)
•
•
CONTRACEPTION!
CONTRACEPTION!
•
•
1 week follow
1 week follow
-
-
up for 4
up for 4
weeks then…
weeks then…
•
•
Once every 2 weeks for 4
Once every 2 weeks for 4
weeks then…
weeks then…
•
•
Once a month for 4
Once a month for 4
months
months
(
(
Wolfberg
Wolfberg
et al. Obstet
et al. Obstet
Gynecol, 2006.)
Gynecol, 2006.)
•
•
Total of 6 months
Total of 6 months
•
•
0/238 women with partial
0/238 women with partial
molar pregnancies had
molar pregnancies had
GTN with declining
GTN with declining
HCG’s
HCG’s
•
•
Complete moles should
Complete moles should
be followed longer
be followed longer
Follow
Follow
-
-
up of Molar Pregnancy
up of Molar Pregnancy
•
•
Should the HCG rise or
Should the HCG rise or
•
•
Plateau (fails to drop by 10% of the
Plateau (fails to drop by 10% of the
previous HCG level in one week) then the
previous HCG level in one week) then the
diagnosis is…
diagnosis is…
•
•
Gestational Trophoblastic Neoplasia (GTN)
Gestational Trophoblastic Neoplasia (GTN)
Berkowitz. Gynecologic Oncology,
Berkowitz. Gynecologic Oncology,
1993.
1993.
Gestational Trophoblastic Neoplasia
Gestational Trophoblastic Neoplasia
•
•
Hydatidiform mole precedes GTN in 50% of
Hydatidiform mole precedes GTN in 50% of
patients
patients
•
•
Antecedent pregnancy 25%
Antecedent pregnancy 25%
•
•
Ectopic
Ectopic
pregnancy 25%
pregnancy 25%
•
•
15% local metastases
15% local metastases
•
•
4% distal metastases
4% distal metastases
•
•
Common sites: lung (60%), vagina (30%), liver
Common sites: lung (60%), vagina (30%), liver
(10%) and brain (10%)
(10%) and brain (10%)
Soper et al. Obstet Gyncol. 1994.
Soper et al. Obstet Gyncol. 1994.
Work
Work
-
-
up of GTN
up of GTN
•
•
History and Physical
History and Physical
•
•
Pretreatment HCG titer
Pretreatment HCG titer
•
•
CXR
CXR
•
•
CBC, CMP
CBC, CMP
•
•
CT of head, chest, abdomen and pelvis
CT of head, chest, abdomen and pelvis
•
•
Duke retrospectively evaluated 324 patients to
Duke retrospectively evaluated 324 patients to
determine whether full
determine whether full
radiologic
radiologic
imaging necessary
imaging necessary
•
•
Patients with vaginal or lung metastases had full
Patients with vaginal or lung metastases had full
evaluation: 100% sensitivity, 63% specificity for brain or
evaluation: 100% sensitivity, 63% specificity for brain or
liver involvement
liver involvement
Terminology of GTN
Terminology of GTN
•
•
Terminology
Terminology
–
–
Nonmetastatic GTN
Nonmetastatic GTN
–
–
Metastatic GTN
Metastatic GTN
•
•
Good prognosis
Good prognosis
•
•
Poor Prognosis
Poor Prognosis
•
•
Histology
Histology
–
–
Choriocarcinoma
Choriocarcinoma
•
•
anaplastic syncytiotrophoblasts and cytotrophoblasts
anaplastic syncytiotrophoblasts and cytotrophoblasts
–
–
Placental Site Trophoblastic Tumor
Placental Site Trophoblastic Tumor
•
•
intermediate trophoblasts
intermediate trophoblasts
Good vs. Poor Prognosis
Good vs. Poor Prognosis
•
•
Good prognosis
Good prognosis
–
–
Last pregnancy < 4
Last pregnancy < 4
months
months
–
–
High HCG titer <
High HCG titer <
40,000
40,000
mIU
mIU
/ml
/ml
–
–
No brain or liver
No brain or liver
metastasis
metastasis
–
–
No prior chemotherapy
No prior chemotherapy
•
•
Poor prognosis
Poor prognosis
–
–
Last pregnancy > 4
Last pregnancy > 4
months
months
–
–
High HCG titer >
High HCG titer >
40,000
40,000
mIU
mIU
/ml
/ml
–
–
Brain or liver
Brain or liver
metastasis
metastasis
–
–
Prior chemotherapy
Prior chemotherapy
–
–
Term pregnancy
Term pregnancy
FIGO Staging
FIGO Staging
•
•
Stage I: disease confined to the uterus
Stage I: disease confined to the uterus
•
•
Stage II: pelvic extension
Stage II: pelvic extension
•
•
Stage III: lung
Stage III: lung
•
•
Stage IV: all other sites
Stage IV: all other sites
•
•
A: no risk factors
A: no risk factors
•
•
B: 1 risk factor
B: 1 risk factor
•
•
C: 2 risk factors
C: 2 risk factors
•
•
Risk factors
Risk factors
–
–
HCG > 100,000
HCG > 100,000
mIU
mIU
/ml
/ml
–
–
Last pregnancy > 6 months
Last pregnancy > 6 months
WHO Staging System
WHO Staging System
8
8
4
4
-
-
8
8
1
1
-
-
4
4
Number of metastases
Number of metastases
2 drugs or
2 drugs or
more
more
Single Drug
Single Drug
Prior chemotherapy
Prior chemotherapy
Brain
Brain
GI
GI
Liver
Liver
Spleen
Spleen
Kidney
Kidney
Site of metastases
Site of metastases
5
5
3
3
-
-
5
5
Largest tumor (cm)
Largest tumor (cm)
B
B
AB
AB
O
O
×
×
A
A
A
A
×
×
O
O
ABO (female
ABO (female
×
×
male)
male)
10
10
5
5
10
10
4
4
-
-
10
10
5
5
10
10
3
3
-
-
10
10
4
4
10
10
3
3
HCG (IU/L)
HCG (IU/L)
12
12
7
7
-
-
12
12
4
4
-
-
6
6
4
4
Months from last
Months from last
pregnancy
pregnancy
Term
Term
Abortion
Abortion
HM
HM
Antecedent pregnancy
Antecedent pregnancy
> 39
> 39
≤
≤
39
39
Age
Age
4
4
2
2
1
1
0
0
Prognostic Factors
Prognostic Factors
•
•
Low risk
Low risk
≤
≤
4; middle risk 5
4; middle risk 5
-
-
7; high risk
7; high risk
≥
≥
8
8
GTN Staging
GTN Staging
•
•
A 41 year old Texas socialite developed vaginal bleeding. She so
A 41 year old Texas socialite developed vaginal bleeding. She so
ught care
ught care
with her OB/GYN and discovered that she was pregnant. An ultraso
with her OB/GYN and discovered that she was pregnant. An ultraso
und
und
diagnosed a molar pregnancy and bilateral cystic ovaries. A D&C
diagnosed a molar pregnancy and bilateral cystic ovaries. A D&C
was
was
performed; pathology returned as a complete mole. The patient wa
performed; pathology returned as a complete mole. The patient wa
s
s
followed once a week for HCG titers. Her pretreatment HCG was 21
followed once a week for HCG titers. Her pretreatment HCG was 21
2,000.
2,000.
After six weeks, she reached a nadir of 52,000 and then her HCG
After six weeks, she reached a nadir of 52,000 and then her HCG
titer rose
titer rose
to 96,000. Her local OB/GYN ordered a chest X
to 96,000. Her local OB/GYN ordered a chest X
-
-
ray and discovered a
ray and discovered a
suspicious nodule. A CT scan of the head, chest, abdomen and pel
suspicious nodule. A CT scan of the head, chest, abdomen and pel
vis
vis
identified 5 pulmonary nodules. The largest measured 3 cm. There
identified 5 pulmonary nodules. The largest measured 3 cm. There
were 2
were 2
liver nodules measuring 2 cm. The rest of the scan was normal.
liver nodules measuring 2 cm. The rest of the scan was normal.
•
•
What terminology?
What terminology?
•
•
Good or poor prognosis?
Good or poor prognosis?
•
•
What Stage?
What Stage?
•
•
What WHO score?
What WHO score?
Nonmetastatic GTN
Nonmetastatic GTN
•
•
Single agent chemotherapy treatment of
Single agent chemotherapy treatment of
choice
choice
•
•
Methotrexate or Actinomycin
Methotrexate or Actinomycin
-
-
D
D
•
•
Both are well tolerated and have minimal
Both are well tolerated and have minimal
side effects
side effects
•
•
Both have complete response rates of
Both have complete response rates of
around 90%
around 90%
Methotrexate (MTX)
Methotrexate (MTX)
•
•
2 regimens
2 regimens
–
–
1
1
st
st
Methotrexate 1mg/kg IM D 1,3,5,7
Methotrexate 1mg/kg IM D 1,3,5,7
•
•
alternate with folic acid 0.1 mg/kg IM D 2, 4,6,8
alternate with folic acid 0.1 mg/kg IM D 2, 4,6,8
–
–
2
2
nd
nd
Methotrexate 30 mg/m
Methotrexate 30 mg/m
2
2
IM Q week
IM Q week
•
•
No folic acid rescue
No folic acid rescue
Efficacy of MTX
Efficacy of MTX
•
•
Berkowitz RS. 10 year experience with methotrexate and
Berkowitz RS. 10 year experience with methotrexate and