Gestational Trophoblastic

Neoplasia

Chris DeSimone, MD
Assistant Professor
Division of Gynecologic Oncology
Department of Obstetrics & Gynecology
Gestational Trophoblastic Neoplasia
(GTN)
• Ancient disease
• Hippocrates documented a
hydatidiform mole in the 4th
century BC
• William Smellie (Scottish mid-
wife, circa 1700) was the first
to coin the terms Hydatid and
Mole
What is a mole?
What is a mole?
• A mole is the amount of pure substance containing the
same number of chemical units as there are atoms in
exactly 12 grams of carbon-12 (i.e., 6.023 X 1023). This
involves the acceptance of two dictates -- the scale of
atomic masses and the magnitude of the gram. Both
have been established by international agreement.
Formerly, the connotation of "mole" was "gram
molecular weight." Current usage tends to apply the
term "mole" to an amount containing Avogadro's
number of whatever units are being considered. Thus, it
is possible to have a mole of atoms, ions, radicals,
electrons, or quanta. This usage makes unnecessary
such terms as "gram-atom," "gram-formula weight," etc.
What is a mole?
What is a mole?
Epidemiology
• Incidence
– Less than 1/1000 pregnancies (World)
– Japan- 2/1000 pregnancies
• Age
– Bandy et al. Obstet Gynecol. 1984.
– Women < 15 years or > 40 years at increased risk
– Greatest risk > 50 years (RR-519)
• Diet
– Decreased animal fat and Vitamin A
• Risk of another molar pregnancy
– Bagshawe et al. Cancer. 1976.
– 1 in 76 pregnancies have a second mole
– 1 in 6.5 pregnancies have a third mole with 2 prior molar
pregnancies
The Changing Symptoms of a
Complete Mole
Soto-Wright et al. 1965- 1988- Significance
Obstet Gynecol. 1995. 1975 1993
Vaginal Bleeding 97% 84% P=0.001

Excessive Uterine Size 51% 28% P=0.001

Hyperemesis 26% 8% P=0.001

Preeclampsia 27% 1.3% P=0.001

Hyperthyroidism 7% - P=0.02

Median Age of 16 weeks 12 weeks P=0.005

Evacuation
Symptoms of a Complete Mole

• Clinical hyperthyroidism occurs in less

than 1% of patients
• 10% of patients have an elevation of T3
and T4
• Theca-lutein cysts are found in 15% of
complete moles
• 57% of patients with a complete mole and
theca-lutein cysts will have GTN
Curry et al. Obstet Gynecol. 1975.
Diagnosis
• Intact HCG
• Ultrasound
• Evacuation
– Suction curettage
surgery of choice
– Pre-Op checklist
• CBC
• Thyroid panel
• Maternal Rh factor
• Type & Cross
Complete and Partial Moles
Partial Mole Complete Mole

Fetal Tissue Present Absent

Villous Edema Focal Diffuse

Trophoblastic Focal Diffuse

Hyperplasia
Karyotype Triploidy 46 XX (90%)
XXX, XXY, XYY 46 XY (10%)
GTN 3.5% 19%
Follow-up of Molar Pregnancy
• Intact HCG test of choice
• Β-HCG no longer used at
UK and in Lexington
• Average time to reach
undetectable HCG, 73
days (Ho Yuen et al. Am J Obstet
Gynecol, 1981.)
• CONTRACEPTION!
• 1 week follow-up for 4
weeks then…
• Once every 2 weeks for 4
weeks then…
• Once a month for 4
months (Wolfberg et al. Obstet
Gynecol, 2006.)
• Total of 6 months
• 0/238 women with partial
molar pregnancies had
GTN with declining HCG’s
• Complete moles should
be followed longer
Follow-up of Molar Pregnancy

• Should the HCG rise or

• Plateau (fails to drop by 10% of the
previous HCG level in one week) then the
diagnosis is…

• Gestational Trophoblastic Neoplasia (GTN)

Gestational Trophoblastic Neoplasia

• Hydatidiform mole precedes GTN in 50% of

patients
• Antecedent pregnancy 25%
• Ectopic pregnancy 25%

• 15% local metastases

• 4% distal metastases
• Common sites: lung (60%), vagina (30%), liver
(10%) and brain (10%)

Berkowitz. Gynecologic Oncology,

1993.
Work-up of GTN
• History and Physical
• Pretreatment HCG titer
• CXR
• CBC, CMP
• CT of head, chest, abdomen and pelvis

• Duke retrospectively evaluated 324 patients to

determine whether full radiologic imaging necessary
• Patients with vaginal or lung metastases had full
evaluation: 100% sensitivity, 63% specificity for brain or
liver involvement

Soper et al. Obstet Gyncol. 1994.

Terminology of GTN
• Terminology
– Nonmetastatic GTN
– Metastatic GTN
• Good prognosis
• Poor Prognosis
• Histology
– Choriocarcinoma
• anaplastic syncytiotrophoblasts and cytotrophoblasts
– Placental Site Trophoblastic Tumor
• intermediate trophoblasts
Good vs. Poor Prognosis
• Good prognosis • Poor prognosis
– Last pregnancy < 4 – Last pregnancy > 4
months months
– High HCG titer < – High HCG titer >
40,000 mIU/ml 40,000 mIU/ml
– No brain or liver – Brain or liver
metastasis metastasis
– No prior chemotherapy – Prior chemotherapy
– Term pregnancy
FIGO Staging
• Stage I: disease confined to the uterus
• Stage II: pelvic extension
• Stage III: lung
• Stage IV: all other sites

• A: no risk factors
• B: 1 risk factor
• C: 2 risk factors

• Risk factors
– HCG > 100,000 mIU/ml
– Last pregnancy > 6 months
WHO Staging System
Prognostic Factors 0 1 2 4
Age ≤ 39 > 39
Antecedent pregnancy HM Abortion Term
Months from last 4 4-6 7-12 12
pregnancy
HCG (IU/L) 103 103-104 104-105 105
ABO (female × male) O×A B
A×O AB
Largest tumor (cm) 3-5 5
Site of metastases Spleen GI Brain
Kidney Liver
Number of metastases 1-4 4-8 8
Prior chemotherapy Single Drug 2 drugs or
more

• Low risk ≤ 4; middle risk 5-

5-7; high risk ≥ 8
GTN Staging
• A 41 year old Texas socialite developed vaginal bleeding. She sought care
with her OB/GYN and discovered that she was pregnant. An ultrasound
diagnosed a molar pregnancy and bilateral cystic ovaries. A D&C was
performed; pathology returned as a complete mole. The patient was
followed once a week for HCG titers. Her pretreatment HCG was 212,000.
After six weeks, she reached a nadir of 52,000 and then her HCG titer rose
to 96,000. Her local OB/GYN ordered a chest X-ray and discovered a
suspicious nodule. A CT scan of the head, chest, abdomen and pelvis
identified 5 pulmonary nodules. The largest measured 3 cm. There were 2
liver nodules measuring 2 cm. The rest of the scan was normal.

• What terminology?
• Good or poor prognosis?
• What Stage?
• What WHO score?
Nonmetastatic GTN

• Single agent chemotherapy treatment of

choice
• Methotrexate or Actinomycin-D
• Both are well tolerated and have minimal
side effects
• Both have complete response rates of
around 90%
Methotrexate (MTX)

• 2 regimens
– 1st Methotrexate 1mg/kg IM D 1,3,5,7
• alternate with folic acid 0.1 mg/kg IM D 2, 4,6,8

– 2nd Methotrexate 30 mg/m2 IM Q week

• No folic acid rescue
Efficacy of MTX
• Berkowitz RS. 10 year experience with methotrexate and
folinic acid as primary therapy for gestational
trophoblastic disease. Gynecol Oncol 1986; 23: 111.

• Every other day regimen

• Complete remission with 162/185 patients (88%)
• 23 patients resistant to MTX
– 14 patients cured with Act-D
– 9 with combination chemotherapy
• Side effects
– Thrombocytopenia, 11 (6%)
– Neutropenia, 3 (1.6%)
– Hepatotoxicity, 26 (14%)
Efficacy of MTX
• Homesley HD. Weekly intramuscular methotrexate for
nonmetastatic gestational trophoblastic disease. Obstet
Gynecol 1988; 72: 413-418.

• Weekly regimen
• Complete remission with 51/63 patients (81%)
• 12 patients resistant to MTX
– 11 patients cured with Act-D
– 1 refused further treatment
• Side effects
– Thrombocytopenia, 3 (5%)
– Neutropenia, 13 (20%)
Efficacy of Actinomycin-D
• Petrilli ES. Single-dose actinomycin-D treatment for
nonmetastatic gestational trophoblastic disease. A
prospective phase II trial of the Gynecologic Oncology
Group. Cancer 1987; 60: 2173-6.

• Act-D 1.25 mg/m2 IM Q 2 weeks

• Complete remission with 29/31 patients (94%)
• 2 patients resistant to Act-D
– Both cured with MTX
• Side effects
– Mild to moderate neutropenia
– Alopecia
 Prognosis for Stage I or
Nonmetastatic GTN
Remission Therapy Patients N Remissions N • New England
(%) (%) Trophoblastic
Initial 485 (91.9) Disease Center,
Sequential MTX/Act-
MTX/Act-D 446 (92) July 1965 to
Hysterectomy 31 (6.4) May 2002
MAC 3 (0.6) • Hoskins 4th ED.
EMA 5 (1)
Resistant 43 (8.1)
MAC 16 (37.2)
EMA 20 (46.5)
EITP 1 (2.3)
Hysterectomy 3 (7)
Local uterine resection 2 (4.7)
Pelvic infusion 1 (2.3)
Total 528 528 (100)
Prognosis for Stage I or
Nonmetastatic GTN
Therapy Remission N
(%)
Chemotherapy 106/122 (86)
Chemotherapy + hysterectomy (2°) 9/122
Chemotherapy + pelvic infusion 3/122
Chemotherapy + pelvic infusion + 4/122
hysterectomy (3°)
Chemotherapy + hysterectomy (1°) 17/17
Total 139/139 (100)

• Hammond CB. The role of operation in the current therapy of gestational

gestational
trophoblastic disease. Am J Obstet Gynecol 1980; 136: 844.
• Southeastern Trophoblastic Center (Duke)
• DiSaia 6th ED.
Metastatic, Good Prognosis GTN

• Pelvic or lung involvement

• WHO score of ≤ 7
• 1st therapy is single agent MTX or Act-D

• If elevated HCG’s occur…

– Switch to other single agent chemotherapy
– Consider TAH for local disease (provided the patient
does not want further children)
– Combination chemotherapy (MAC or EMA-CO)
 Prognosis for Stage II GTN
Remission Therapy Patients N (%) Remissions N • New England
(%) Trophoblastic
Disease
Low risk 20 (71.4) Center, July
Initial 1965 to May
Sequential MTX/Act-
MTX/Act-D 18 (80) 2002
Resistant
• Hoskins 4th
ED.
MAC 1 (10)
EMA-
EMA-CO 1 (10)
High Risk 8 (28.6)
Initial
Sequential MTX/Act-
MTX/Act-D 2 (25)
MAC 4 (50)
Resistant
MAC 1 (12.5)
CHAMOCA 1 (12.5)

Total 28 28 (100)
 Prognosis for Stage III GTN
Remission Therapy Patients N Remissions N • New England
(%) (%) Trophoblastic
Low risk 104 (68) Disease Center,
Initial July 1965 to
Sequential MTX/Act-
MTX/Act-D 85 (81.7) May 2002
Resistant • Hoskins 4th ED.
MAC 12 (11.5)
EMA 5 (4.8)
EMA-
EMA-CO 2 (1.9)
High Risk 49 (32)
Initial
Sequential MTX/Act-
MTX/Act-D 13 (26.5)
MAC 14 (28.6)
EMA-
EMA-CO 13 (26.5)
Resistant
MAC 2 (4.1)
CHAMOCA 1 (2)
5-FU-
FU-Adria 1 (2)
VPB 2 (4.1)
EMA 1 (2)
EMA-
EMA-EP 1 (2)
Total 153 153 (99.3)
Prognosis for Metastatic, Good
Prognosis GTN

Therapy Remission N
(%)
Chemotherapy 35/40 (88)
Chemotherapy + hysterectomy (2°) 5/40
Chemotherapy + hysterectomy (1°) 15/15
Total 55/55 (100)

• Hammond CB. The role of operation in the current therapy of

gestational trophoblastic disease. Am J Obstet Gynecol 1980;
136: 844.
• Southeastern Trophoblastic Center (Duke)
• DiSaia 6th ED.
Poor Prognosis GTN

• Brain or liver involvement

• WHO score ≥ 8
• Resistance to first line chemotherapy
• Initiate treatment with MAC or EMA-CO

• Brain or liver metastases require XRT

MAC
• Berkowitz RS. Modified triple therapy in the management of high -
risk metastatic gestational trophoblastic tumors. Gynecol Oncol
1984; 19: 173-81.
• Cyclophosphamide IV 3 mg/kg/day D1 -5
• Act-D IM 12 µg/kg/day D1-5
• Methotrexate IV 1 mg/kg/day D1,3,5,7
• Brain metastases received 3000 cGy of whole brain irradiation (2
patients)
• 10/14 patients (71%) achieved CR with MAC
– 2 patients received VBP
– 1 patient received CHAMOCA
– 1 patient DOD
– 2 patients had a hysterectomy
– 2 patients had a pulmonary resection

• 13/14 patients (93%) achieved a CR with multi -agent chemotherapy

• Main side effect neutropenia
EMA-CO
• The standard of care for poor prognosis GTN
• Week #1
– Etoposide 100 mg/m2 IV (30 minute) D1&2
– Methotrexate 100 mg/m 2 IV push D1
– Methotrexate 200 mg/m 2 IV (12 hour) D1
– Act-D 350 µg/m2 IV push D1&2
– Folinic acid 15 mg Q 6hrs for 4 doses

• Week #2
– Cyclophosphamide 600mg/m2 IV (1 hour) D8
– Vincristine 1 mg/m2 IV push D8
 EMA-CO
Author N 1st 2nd line 3rd Surgery Liver Brain CR (N) Survival
line (N) line (N) (N) (N) (N)
(N) (N)
Bolis G. Gynecol 36 22 14 - 5 3 1 31 86% 29 81%
Oncol. 1988
Schink J. Obstet 12 12 - - 3 1 1 10 83% 12 100%
Gynecol. 1992
Soper J. Obstet 22 6 16 - 12 6 5 11 69% 15 68%
Gynecol. 1994
Bower M. J Clin 272 151 121 - n/a 17 34 213 78% 234 86%
Oncol. 1997
Kim S. Gynecol 165 96 61 8 42 6 19 138 84% 138 84%
Oncol. 1998
Total 507 287 212 8 62 33 60 403 79% 428 84%
57% 41% 2% 12% 6.5% 12%

• Surgery: hysterectomy, pulmonary resection, nephrectomy,

splenectomy, colon resection, cardiac surgery
Brain Metastases
• Recommend 3000 cGy whole brain irradiation (10 treatments)
• Evans AJ. Gestational trophoblastic disease metastatic to the ce ntral
nervous system. Gynecol Oncol 1995; 59: 226.
– Reported that 12/16 patients (75%) had a CR with XRT and
combination chemotherapy
• Schechter NR. Prognosis of patient treated with whole -brain
radiation therapy for metastatic gestational trophoblastic disea se.
Gynecol Oncol 1998; 68:183.
– Dose > 2200 cGy versus 91% 5 year survival versus 24% 5 year
survival with a dose < 2200 cGy
– Survival based upon responsive multi-agent chemotherapy
• Newlands ES. Management of brain metastases in patients with
high-risk gestational trophoblastic tumor. J Reprod Med 2002; 47:
465.
– 31/35 patients (86%) cured with EMA-CO and intrathecal MTX
• Intrathecal MTX not standard of care for prophylaxis of CNS
metastases in patients with pulmonary metastases
Liver Metastases
• Extremely poor prognosis

• Crawford RA. Gestational trophoblastic disease with liver

metastases: the Charing Cross experience. Br J Obstet Gynecol
1997: 104:105.
– 46 of 1676 women with GTN (2.7%)
– Concurrent metastatic disease to the lung (93%) and brain (33%)
– 5-year survival 27%
– 5-year survival 10% if the patient had brain metastases

• Hemorrhage worrisome; some recommend 2000cGy to prevent

hemorrhage
Resistance to EMA-CO
• Bower M. EMA/CO for high-risk gestational
trophoblastic tumors: results from a cohort of
272 patients. J Clin Oncol 1997: 15: 2636.
– EMA-EP (etoposide, cisplatin) ± surgery induced
remission in 16/21 patients (76%)

• Cisplatin, vinblastine, bleomycin (PVB) has some

efficacy
– 3 studies with few patients
– CR of 20-50%
Placental Site Trophoblastic Tumor
(PSTT)
• 100 reported cases
• Bleeding most common symptom
• Intermediate trophoblasts
• HCG weakly positive
• Human placental lactogen (HPL) serum marker
• Hysterectomy treatment of choice
• Mainly benign tumor, although 15-20% mortality
rate for advanced stage tumors
Subsequent Pregnancy after Partial
Mole
Outcome N % N/Deliveries
(%) • New England Trophoblastic
Term Delivery 189 75.3 Disease Center, January
1979 to November 2001
Stillbirth 1 0.4
• Hoskins 4th ED.
Preterm delivery 4 1.6
SAB
1st trimester 38 15.1
2nd trimester 1 0.4
Therapeutic AB 11 4.4
Ectopic 1 0.4
Repeat Mole 6 2.4

Total 251
Congenital 3/194 (1.5)
malformation
Primary 29/194 (14.9)
Cesarean section
Subsequent Pregnancy after
Complete Mole
Outcome N % N/Deliveries • New England
(%)
Trophoblastic Disease
Term Delivery 877 68.6
Center, January 1979 to
Stillbirth 7 0.5
November 2001
Preterm delivery 65 7.4
SAB • Hoskins 4th ED.
1st trimester 221 17.3
2nd trimester 8 0.6
Therapeutic AB 41 3.2
Ectopic 11 0.9
Repeat Mole 18 1.4
Total 1278
Congenital 40/979 (4.1)
malformation
Primary 70/373 (18.8)
Cesarean section
Subsequent Pregnancy after GTN

Outcome N % N/Deliveries • New England

(%)
Trophoblastic Disease
Term Delivery 393 67.6
Center, January 1979 to
Stillbirth 9 1.5
November 2001
Preterm delivery 35 6
• Hoskins 4th ED.
SAB
1st trimester 92 15.8
2nd trimester 7 1.2
Therapeutic AB 28 4.8
Ectopic 7 1.2
Repeat Mole 8 1.4
Total 581
Congenital 10/437 (2.3)
malformation
Primary Cesarean 68/335 (20.3)
section
Secondary Malignancies
• Rustin GJ. Combination but not single-agent
methotrexate chemotherapy for gestational trophoblastic
tumors increases the incidence of second tumors. J Clin
Oncol 1996; 14: 2769.
– RR leukemia 16.6
– RR melanoma 3.4
– RR colon 4.6
– RR breast 5.8
• 1.5% of all patients treated with etoposide developed
leukemia
• Increased risk for breast cancer is not apparent until
after 25 years