34 Gestational Trophoblastic Disease

Hydatidiform Mole, Nonmetastatic and Metastatic Gestational

Trophoblastic Tumor: Diagnosis and Management
Andra Nica, Geneviève Bouchard-Fortier, Allan Covens

KEY POINTS

Gestational trophoblastic disease (GTD) hydatidiform mole (PHM) -

- -

! -
-
-
placental site trophoblastic tumor (PSTT) epitheli-
- oid trophoblastic tumor (ETT)
- -
-
3 1
-
-
-
-

complete hydatidiform mole (CHM) partial

754
 CHAPTER 34 Gestational Trophoblastic Disease 755

BOX 34.1 World Health Organization Classification of Gestational 34

Trophoblastic Disease

BENIGN TROPHOBLASTIC LESIONS

Placental site nodule
Exaggerated placental reaction
HYDATIDIFORM MOLES
Complete hydatidiform mole Reproductive History
Partial hydatidiform mole
-
GESTATIONAL TROPHOBLASTIC NEOPLASIA
Invasive mole
Choriocarcinoma
Placental site trophoblastic tumor
Epithelioid trophoblastic tumor

HYDATIDIFORM MOLE
Epidemiology
Diet
-

Genetics

familial recurrent HM
-

NLRP7 KHDC3L

-
-
- -

-
Histopathology and Cytogenetic Features
Risk Factors
-
Age
756 PART IV Gynecologic Oncology

Loss

23,X 46,XX

23,X 46,XX

-
46,XX -
Paternal
chromosomes
only
-
Fig. 34.1 Paternal chromosomal origin of a complete classic mode
(46,XX). Left to right: Entry of normal sperm with haploid set of 23,X
into an egg whose 23,X haploid set is lost. The egg is taken over by
paternal chromosomes, which duplicate (without cell division) to reach
the requisite complement of 46. Observe that almost the same result
can be obtained through fertilization by two sperm gaining entry into
an empty egg (dispermy). (From Szulman AE, Surti UL. The syndromes 3 3
of partial and complete molar gestation. Clin Obstet Gynecol.
1984;27:172-180.)

-
-

-
-
! -
-

3 1 3
CDKN1C -

Fig. 34.2 Triploid chromosomal origin of partial mole (69,XXY dispermy). Fertilization of an egg equipped
with a normal 23,X complement by two independently produced sperm (dispermy) to give a total of 69
chromosomes. Observe that triploidy can also result through fertilization by sperm carrying father’s total
complement of 46,XY. (From Szulman AE, Surti UL. The syndromes of partial and complete molar gestation.
Clin Obstet Gynecol 1984;27:172-180.)
 CHAPTER 34 Gestational Trophoblastic Disease 757

TABLE 34.1 Features of Complete and Partial Hydatidiform Moles

34
Feature Complete Moles Partial Moles
Fetal or embryonic tissue Absent Present
Hydatidiform swelling of Diffuse Focal
chronic villi
Trophoblastic hyperplasia Diffuse Focal
Trophoblastic stromal Absent Present
inclusions
Genetic parentage Paternal Bipaternal
A
Karyotype 46,XX; 46,XY 69,XXX, 69,XXY;
69,XYY
Persistent human chorionic 15%-20% of cases 1%-5% of cases
gonadotropin
From Eifel PJ, Gershenson DM, Kavanagh JJ, Silva EG. Gynecologic
Cancer. New York: Springer-Verlag; 2006:230.

TABLE 34.2 Changing Clinical Presentation of Complete Hydatidiform

Mole at the New England Trophoblastic Disease Center (%)
1988-1993 1965-1975
Symptom or Sign (N ! 74) (N ! 306)
Vaginal bleeding 84 97
Size greater than dates 28 51
Anemia 5 54
Preeclampsia 1.3 27
Hyperemesis 8 26

B Hyperthyroidism 0 7
Respiratory distress 0 2
Fig. 34.3 A, Hydatidiform mole. A few vesicles approach 1 cm in
diameter. The background is formed by smaller vesicles. B, Hydatidi- Asymptomatic 9 0
form mole aborted by suction curettage. A large intact vesicle is near From Valena S-W, Bernstein M, Goldstein DP, Berkowitz R. The
the center. Many vesicles, however, have been ruptured and have col- changing clinical presentation of complete molar pregnancy. Obstet
lapsed. (From Bigelow B. Gestational trophoblast disease. In: Blaustein Gynecol. 1995;86:775-779.
A, ed. Pathology of the Female Genital Tract. 2nd ed. New York:
Springer-Verlag; 1982.)

!
- !
!
3 1
!
!
Clinical Features
-

-
-

-
758 PART IV Gynecologic Oncology

!
!
-

Treatment

-
Fig. 34.4 Ultrasound scan of uterus demonstrating snowstorm
appearance of hydatidiform mole. -

- !
-

-
-
Diagnosis
Suction Dilation and Curettage

- -
3
-

-
Hysterectomy
-

Human Chorionic Gonadotropin P" -

-
 CHAPTER 34 Gestational Trophoblastic Disease 759

Gestational trophoblastic tumor

34

Uterine evacuation

!-HCG level

Elevated

Pelvic examination
Normal Metastatic disease
Chest radiograph

Serial (3 consecutive) !-HCG level Plateau or increase Staging and risk assessment

Normal Low-risk disease

High-risk disease
veillance
Avoid pregnancy for 1 year Chemotherapy for
low-risk disease
age regimens or
vestigational treatments

Serologic remission not !-HCG titer normalization

attained or !-HCG levels rise
after normal value

veillance
Restaging Avoid pregnancy for 1 year

Fig. 34.5 Treatment algorithm. This is a diagnostic and therapeutic approach to gestational trophoblastic
disease as practiced at the University of Texas M.D. Anderson Cancer Center. !-HCG, Beta human chorionic
gonadotropin. (Modified from Eifel PJ, Gershenson DM, Kavanagh JJ, Silva EG. Gynecologic Cancer. New York:
Springer-Verlag; 2006:235.)

- !
-
-
!
-
Prophylactic Chemotherapy

#
" 3 5
760 PART IV Gynecologic Oncology

- P"

- Phantom !-HCG
!

Surveillance After Hydatidiform Mole Evacuation !

! !
-

-
! - !
"
- ! -

- Quiescent GTD

- ! -
! -
quiescent GTD.

!
! -

" !
-
!
! -

! - -
-

! Pituitary !-HCG

- " ! -
!
! !

-
!

!
- !

-
GESTATIONAL TROPHOBLASTIC NEOPLASIA

Characteristics
Histopathology and Cytogenetic Features
Invasive moles
 CHAPTER 34 Gestational Trophoblastic Disease 761

-
BOX 34.2 International Federation of Gynecology and Obstetrics 34
Criteria for Diagnosis of Gestational Trophoblastic Neoplasia
-
The International Federation of Gynecologists and Obstetricians
(FIGO) standardized criteria for diagnosing gestational trophoblastic
neoplasia GTN after an HM are as follows:
- 1. Four !-HCG values plateauing ($10%) over a 3-week period
(days 1, 7, 14, 21)
- 2. A rising !-HCG value of 10% or greater seen on three values
measured over a 2-week period (days 1, 7, 14)
! 3. Histologic diagnosis of choriocarcinoma
- 4. Evidence of metastases (clinically or radiologically)

!-HCG, Beta human chorionic gonadotropin; GTN, gestational

! trophoblastic neoplasia; HM, hydatidiform mole.
-
-

Malignant Gestational Trophoblastic Neoplasia

-

-
-
! -

-
-
- -

P!
-
! -
!

-
-

-
Clinical Features
! -

! -
-
Classification and Staging

-
! 3
! $ - -
3 3
! -

-
-

!
! !
!

!
762 PART IV Gynecologic Oncology

TABLE 34.3 International Federation of Gynecology and Obstetrics (FIGO) 2000 Classification for Gestational Trophoblastic Neoplasia

Staging Features
Stage I Disease confined to uterus
Stage II GTN extends outside uterus but is limited to genital structures (adnexa, vagina,
broad ligament)
Stage III GTN extends to lungs, with or without known genital tract involvement
Stage IV All other metastatic sites
Scoring
Parameter 0 1 2 4
Age (yr) "40 %40 — —
Antecedent pregnancy Mole Abortion Term —
Interval from index pregnancy (mo) "4 4-6 7-12 #12
Pretreatment !-HCG (IU/mL) "10 3
10 -10
3 4
10 -10
4 5
#105
Largest tumor size (cm; including uterus) "3 3 to "5 cm %5 cm —
No. of metastases 0 1-4 5-8 #8
Previous failed chemotherapy — — Single drug Two or more drugs
Site of metastasis Lung Spleen, kidney GI tract Brain, liver

!-HCG, Beta human chorionic gonadotropin; GI, gastrointestinal; GTN, gestational trophoblastic neoplasia.

Diagnosis
!
- -
!

!
! -
"

-
-
-
!
-
- -
-

-
-

-
-
 CHAPTER 34 Gestational Trophoblastic Disease 763

-
34
-
Treatment
Low-Risk Gestational Trophoblastic Neoplasia
Low-risk GTN -
-

-
!

!
-
-

-
-
- -

Dactinomycin or Methotrexate in Treating Patients With

Low-Risk Gestational Trophoblastic Neoplasia

!
-

- -

-
!
-
-
-

!
3 3
-
!
-
-
pulsed dose -
764 PART IV Gynecologic Oncology
BOX 34.3 Management of Low-Risk Gestational Trophoblastic
Neoplasia
After metastatic evaluation and determination of low-risk disease:
1. Initiate single-agent methotrexate or actinomycin D; consider
hysterectomy if fertility is not desired.
1. Monitor hematologic, renal, and hepatic indices before each
cycle of chemotherapy.
2. Monitor !-HCG levels while on treatment.
3. If severe toxicity or resistance develops, switch to the
alternative single agent.
If resistance to the alternative agent develops:
2. Repeat the metastatic evaluation.
3. If resistant or recurrent disease is present after second-line
single-agent chemotherapy, treat with combination EMA/CO
even if patient still meets low-risk criteria.
4. Consider hysterectomy if disease is confined to the uterus.
5. Treat with multiagent therapy with EMA/CO if patient meets
criteria for high-risk disease regardless of initial treatment choice
(see treatment of high-risk GTN, Box 34.4).
Remission is defined as three consecutive weekly !-HCG val-
ues in the normal range. After the first normal !-HCG, continue
with three cycles of maintenance or consolidation chemotherapy.
Monitor !-HCG levels for 12 months, with the patient counseled to
use reliable contraception in this period.
!-HCG, Beta human chorionic gonadotropin; EMA/CO, etoposide, metho-
trexate, actinomycin D, cyclophosphamide, vincristine; GTN, gestational
trophoblastic neoplasia.
High-Risk Gestational Trophoblastic Neoplasia
high-risk GTN
- trophoblastic tumor GTN, gestational trophoblastic neoplasia;
3 PSTT, placental site trophoblastic tumor.
EMA/CO (etoposide, MTX, ActD,
cyclophosphamide, vincristine [Oncovin])
3 -
- !
- -
-
BOX 34.4 Management of High-Risk Gestational Trophoblastic
Neoplasia (excluding PSTT/ETT)
After metastatic evaluation and determination of high-risk disease:
1. Initiate treatment with EMA/CO (see Table 34.4); monitor
hematologic, renal, and hepatic indices before each cycle
of chemotherapy.
1. Monitor !-HCG levels while on treatment.
2. Avoid extended intervals between courses because of
myelosuppression.
3. If severe myelosuppression develops, use granulocyte
colony-stimulating factor (G-CSF) to maintain neutrophil
count and treatment intensity.
4. Consider omitting the day 2 dose of etoposide and
actinomycin D occasionally if ongoing severe
myelosuppression occurs.
2. If patients meet criteria for ultra-high-risk disease, start with
low-dose induction etoposide and cisplatin (EP) treatment.
1. Etoposide and cisplatin only on days 1 and 2.
2. Repeat EP weekly for 1 to 2 cycles.
3. Start EMA/CO or EMA/EP.
3. In patients with CND disease:
1. Obtain neurosurgical consult.
2. Consider using one dose of single-agent methotrexate or
low-dose induction EP.
3. Use modified EMA/CO with high-dose intravenous
methotrexate (1000 mg/m2 over 24 hours) for high CNS
penetrance or with intrathecal methotrexate.
4. Consider whole-brain radiation therapy to control bleeding
and facilitate tumor shrinkage.
4. Surgery is reserved for recurrent or resistant foci of disease.
Remission is defined as three consecutive weekly !-HCG
values in the normal range. After the first normal !-HCG, continue
with four cycles of maintenance or consolidation chemotherapy.
Monitor !-HCG levels for 24 months, with the patient counseled to
use reliable contraception in this period.
!-HCG, Beta human chorionic gonadotropin; CNS, central
nervous system; EMA/CO, etoposide, methotrexate, actinomycin
D, cyclophosphamide, vincristine (Oncovin); ETT, epithelioid
-
-
 CHAPTER 34 Gestational Trophoblastic Disease 765

TABLE 34.4 Chemotherapy Regimen for Intermediate- and High-Risk

Gestational Trophoblastic Disease 34
Drug Regimen Administration
EMA/CO (PREFERRED REGIMEN)—COURSE I (EMA)*
Day 1
Etoposide 100 mg/m2 IV over 30 min
Methotrexate 100 mg/m2 IV bolus
Methotrexate 200 mg/m2 IV as 12-hr continuous infusion
Actinomycin D 0.5 mg IV bolus
Day 2
Etoposide 100 mg/m2 IV over 30 min Pulmonary Metastases
Folinic acid 15 mg IV/IM/PO every 12 hr for four doses,
-
to be started 24 hr after start of methotrexate
Actinomycin D 0.5 mg IV bolus
Course II (CO)
-
Day 8
Cyclophosphamide 600 mg/m2 IV over 30 min
-
Vincristine 1 mg/m2 IV bolus
Modified from Kantarjian HM, Wolf RA, Koller CA. M.D. Anderson
Manual of Medical Oncology. New York: McGraw-Hill; 2006.
*Cytokine support may be used.
EMA/CO, Etoposide, methotrexate, actinomycin D, cyclophosphamide,
vincristine (Oncovin)—EMA alternates with CO every week; IV,
intravenous.

Liver Metastases

Ultra-High-Risk Gestational Trophoblastic -

Neoplasia
-
Vaginal Metastases
-

- Resistant or Recurrent Disease

!-
-

Central Nervous System Metastases

-
-

-
766 PART IV Gynecologic Oncology

-
-

- Surveillance After Gestational Trophoblastic

Neoplasia
!

-
-

Ave- -
lumab in Chemo-resistant Gestational Trophoblastic Neoplasias
- -

Treatment of Placental Site Trophoblastic Tumor

and Epithelioid Trophoblastic Tumor
Pregnancy After Gestational Trophoblastic
Neoplasia

-
-

-
!
-

-
Psychosocial Considerations
-

-
-

-
Centralization of Care
 CHAPTER 34 Gestational Trophoblastic Disease 767

- 34
Gynecol Oncol.
-

-
REFERENCES Int J Gynecol Cancer.

Cochrane Database Syst Rev. -

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Ann Oncol.
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