Philippine Society for the

Study of Trophoblastic Diseases,

Diseases, Inc

CLINICAL PRACTICE GUIDELINES

FOR THE
DIAGNOSIS AND MANAGEMENT OF
GESTATIONAL TROPHOBLASTIC DISEASES

November, 2011
 DISCLAIMER, RELEASE AND WAIVER OF TABLE OF CONTENTS
RESPONSIBILITY

• This is the Clinical Practice Guidelines (CPG) on Diagnosis and CONTENT PAGE
Management of Gestational Trophoblastic Diseases, Second NUMBER
Edition, November 2011. Foreword
• This is a publication of the Philippine Society for the Study of Message
Trophoblastic Diseases, Inc. (PSSTD). PSSTD Officers 2011-2012
• This is the ownership of the PSSTD, its officers, and its entire PSSTD General Membership
membership. Ad Hoc Committee for the Clinical Practice
• The obstetrician-gynecologist, the general practitioner, the patient, Guidelines
the student, the allied medical practitioner, or for that matter, any CLINICAL PRACTICE GUIDELINES
capacity of the person or individual who may read, quote, cite, Hydatidiform Mole
refer to, or acknowledge, any, or part, or the entirety of any topic,
Gestational Trophoblastic Neoplasia
subject matter, diagnostic condition or idea/s willfully release and
waive all the liabilities and responsibilities of PSSTD, its officers Placental Site Trophoblastic Tumor
and general membership, as well as its Ad Hoc Committee on the Epithelioid Trophoblastic Tumor
Clinical Practice Guidelines and its Editorial Staff in any or all Human Chorionic Gonadotropin
clinical or other disputes, disagreements, conference Appendix
audits/controversies, case discussions/critiquing. Levels of Evidence and Grades of
• The reader is encouraged to deal with each clinical case as a Recommendations
distinct and unique clinical condition, which will never fit into an Trophoblastic Disease Specialists by Region
exact location if reference is made into any or all part/s of this
CPG.
• The intention and objective of the CPG is to guide clinicians in
their decision-making and to clarify issues in the field of
trophoblastic disease. However, it is not the intention or objective
of this CPG to serve as an exact and precise answer, solution and
treatment for clinical conditions and situations. Clinicians are
always encouraged to refer to their individual clinical case as the
one and only answer to the case in question, not this CPG.
• It is hoped that the clinician will find this CPG a handy guide that
will lead to a clue, to a valuable pathway that will lead to the
discovery of clinical tests leading to clinical treatments and
eventually recovery.
• In behalf of the PSSTD, its officers and Ad Hoc Committee on the
Clinical Practice Guidelines, 2011, this CPG is meant to make
each one of us a perfect image of Christ, the healer.
 FOREWORD MESSAGE

PHILIPPINE SOCIETY FOR THE PHILIPPINE OBSTETRICAL

STUDY OF TROPHOBLASTIC AND GYNECOLOGICAL
DISEASES, INC. SOCIETY (Foundation), INC.

The Officers and Members of the Board of Trustees of the Philippine

Society for the Study of Trophoblastic Diseases takes pride in launching the
second edition of the Clinical Guidelines on Gestational Trophoblastic
Diseases. The first edition was developed by a group of specialists and
Congratulations to the officers and members of the Board of
published in 2006 under the able leadership of Dr. Lourdes Blanco-Capito. Trustees of the Philippine Society for the Study of Trophoblastic
This was revised in 2009 under the presidency of Dr. Bernadette Octavio- Diseases for taking the initiative of updating the Clinical Practice
Cruz, which however was not published. Further updates and revisions were Guidelines on Trophoblastic Diseases. This will be a welcome
undertaken by the present authors. Likewise, it was deemed necessary to reference for the OB-GYN practitioners in the management of their
add a chapter on Human Chorionic Gonadotropin to the present edition. patients with Trophoblastic Diseases. I commend the work and effort
After a thorough search of current literature, levels of evidence and of the authors, contributors and reviewers. May you continue to strive
grades of recommendations were incorporated in this new edition. It is the to improve the quality of care of patients by keeping up with recent
sincere hope of the Society that these will assist the general OB-GYN arrive advances in the management, which are evidence-based.
at decisions on appropriate therapy and make timely referrals to the
Trophoblastic Disease specialist.
The Mother Society, Philippine Obstetrical and Gynecological
Society, has been publishing CPGs on commonly encountered conditions in
OB-GYN. We were invited to present these guidelines to the general
membership before final review and printing. For this, we would like to thank Sylvia A. Carnero, MD
the POGS Committee on CPG as well as those members who spared their
time to give their comments and suggestions.
I would like to congratulate the team for their unselfish time and
commitment in the formulation of these guidelines since its very first edition.
I wish to dedicate this CPG to all our patients suffering from Trophoblastic
diseases, who deserve our utmost attention, care and compassion.

MA. CARMEN HERNANDEZ-QUEVEDO, MD FPOGS

President
PHILIPPINE SOCIETY FOR THE STUDY OF PHILIPPINE SOCIETY FOR THE STUDY OF
TROPHOBLASTIC DISEASES, INC TROPHOBLASTIC DISEASES, INC
OFFICERS 2011-2012 LIST OF MEMBERS
2011
MA. CARMEN H. QUEVEDO, MD Abad, Leopoldo III M.
President
Balete, Susan C.
FILOMENA S. SAN JUAN, MD, PhD Bislumbre, Aileen Frances B.
Vice President
Burog, Honorata P.
AGNES S. ESTRELLA, MD, MHPEd Cagayan, Ma. Stephanie Fay S.
Secretary
Capito, Lourdes B.
MARILYN D. RUARO, MD Castillo, Ma. Del Carmen R.
Treasurer
Chan, Paulene Trixie C.
ANNE MARIE C. TRINIDAD, MD Chua, Angelica Anne A.
Auditor
Cosculluela, Ma. Irene Josefa G.
MA. DEL CARMEN R. CASTILLO, MD Delos Santos, Rosalee T.
PRO
Dy, Mary Ruth E.
BOARD OF MEMBERS Dy, Ma. Theresa G.
LEOPOLDO M. ABAD III, MD Estrella, Agnes S.
QUENNIE S. QUIÑO, MD Evangelista, Nelia B.
DIANA L. SARMIENTO, MD
Fernandez, Estrella Sebe S.
Fortun, Vincent Lohengrin A.
Gacoba, Ma. Cresencia R
Jacinto, Elizabeth K.
Jocson, Milagros T.
Lagrosa, Editha A.
Laguimon, Ma. Lucia B.
Lasala, Lynette L.
Llarena, Raquel T.
Magallanes, Maria Suyen O.
Mondragon, Laureen Honor F.
Octavio-Cruz, Bernadette R.
Oras, Celestrell May W.
Par, Carolyn P.
Pastorfide, Greg B.
Quevedo, Ma. Carmen H.
Quiño, Queenie S.
Quiroga, Ma. Cristina O.
Ruaro, Marilyn D.
San Juan, Filomena S.
Sarmiento, Diana L.
Solamo, Joyce Ruth T.
Tabio, Rowena J.
Tolentino, Criseline D.
Torres, Mary Carol C.
Trinidad, Anne Marie C.
 AD HOC COMMITTEE FOR THE HYDATIDIFORM MOLE
CLINICAL PRACTICE GUIDELINES
Agnes S. Estrella, MD, MHPEd
Raquel T. Llarena, MD
CHAIR AND EDITOR

Ma. Carmen H. Quevedo, MD DEFINITION

Hydatidiform moles (HM) are abnormal conceptions with excessive
1
placental, and little or no fetal, development. Grossly, a HM resembles a
MANAGING EDITOR bunch of grapes, with or without fetal components. It is subdivided into
complete hydatidiform mole (CHM) and partial hydatidiform mole (PHM)
1-5
Agnes S. Estrella, MD, MHPEd based on morphologic, cytogenetic, and clinicopathologic features.

MEMBERS
Stephanie Fay S. Cagayan, MD
Lourdes B. Capito, MD
Paulene Trixie C. Chan, MD
Ma. Bernadette O. Cruz, MD, MSc
Estrella Sebe S. Fernandez, MD
Elizabeth K. Jacinto, M.D.
Milagros T. Jocson, MD
Raquel T. Llarena, MD
Laureen Honor F. Mondragon, MD
Anne Marie C. Trinidad, MD
INCIDENCE
The incidence of molar pregnancy varies in different parts of the
world. It is believed that these differences are due to difference in
prevalence, discrepancies between population-based and hospital-based
pregnancy data or variations in availability of a national referral center and
6,7
central pathology review.
The reported worldwide incidence of HM is 1-2 per 1,000
1
pregnancies. However, for reasons that are still not understood, the
incidence of molar pregnancy in Southeast Asia remains to be 7 to 10 times
6
higher than in Europe or North America. Indonesia has one of the highest
8,9
reported incidence rates with 1 in 77 pregnancies (1 in 57 deliveries).

In the Philippines, the reported national prevalence rate of

hydatidiform mole in the years 2002 to 2008 is 2.4/1000 pregnancies. At the
10
UP-PGH the prevalence rate is 14 in every 1,000 pregnancies.

RISK FACTORS
Various factors have been considered as potential risk factors in the
development of hydatidiform mole. However, until the present time, the exact
etiology is still unknown.
1. Maternal Age
Maternal age has consistently been considered as an important
risk factor with age-specific incidence reports revealing a ‘J curve’. That
is, teenagers have higher incidence rates, and reproductive-aged women
40 years of age or older have incidence rates that are substantially
higher. There is about a 20-fold increase in risk among teenagers under
15 years of age. Among women over 40 years of age, there is a higher
than 10-fold increase in risk of developing HM, such that for women over
50 years old, the risk that a pregnancy will result in HM is about 200
8 of vaginal bleeding (in 89-97% of cases), a uterine size more than the
times greater than for women 20 to 35 years of age. These age-specific
trends affecting younger and older women suggests that defects in ovoid
function is one etiologic factor contributing to the risk for GTD.
2. Paternal Age
Data on paternal age as a risk factor for the development of HM are
conflicting. However, Parazzini et. al. reported that older paternal age
(greater than 45) was related to the risk of complete mole but not of
partial mole.
11
3. Reproductive and Obstetric History
A history of a previous HM is a strong and well-established risk
factor predisposing to another molar pregnancy. After the first HM, a
12
second molar pregnancy occurs in 0.6-2.60% of pregnancies. There is
an elevated risk of HM in nulliparous women with a history of miscarriage
8,9
and those who have conceived twin pregnancies. A higher rate of HM
has been observed after artificial insemination by donor compared with
9
normally conceived pregnancies.
4. Racial Factors
Due to differences in the geographical distribution, race or
ethnicity has been investigated as a potential risk factor for HM. Matsura
et al. reported that the rate of HM per 1,000 pregnancies was 17.5 in
13
Filipinos, 16.5 in Japanese, 8.0 in Caucasians, and 7.7 in Hawaiians.
5. Diet and Nutrition
Studies regarding the role of nutrition in the development of GTD
are inconclusive. Some have cited that decreased dietary carotene and
11,14
animal fat may be associated with GTD.
PRESENTATION AND DIAGNOSIS OF MOLAR PREGNANCY
1. The clinical diagnosis of hydatidiform mole is based on
the patient’s clinical presentation supported by typical
ultrasonographic findings and an elevated βhCG titer.
(Level III, GPP)
In majority of cases, the diagnosis is made in a patient
presenting with amenorrhea, a positive pregnancy test, varying amounts
age of gestation (in 40-50% of cases) and absence of fetal heart tones.
Other classic signs and symptoms that may be present in a patient
include presence of theca lutein cysts (20%), hyperemesis (15-25%),
pre-eclampsia (12-27%), hyperthyroidism (2-7%), and respiratory
1,3,4,5,10,15
insufficiency (2%).
Partial hydatidiform mole, has less prominent clinical features
compared with CHM. Because of this, most PHMs are initially managed
as cases of incomplete or missed abortion and diagnosis is made only
16
after histologic examination of the curettage specimen.
2. Pelvic ultrasound is the most accurate noninvasive
imaging modality for hydatidiform mole. (Level III, Grade
C)
The overall sensitivity for the ultrasound diagnosis of
hydatidiform mole is 50-86%. Factors that influence diagnosis are
gestational age and operator expertise. Cases of CHM may be
diagnosed by ultrasonography in approximately 80% of the cases
particularly during the second trimester when the grape-like or hydropic
16
villous change occurs. This is seen in the ultrasound as the classic
snowstorm-like appearance. During the first trimester, there is minimal
hydropic change present making early sonographic diagnosis less
1
reliable.
Ultrasound diagnosis of PHM is less accurate and nearly 70% of
16
cases will be missed. Two sonographic findings are significantly
associated with the diagnosis of PHM: focal cystic changes in the
placenta and a ratio of the transverse to antero-posterior dimension of
17
the gestational sac >1.5. Changes in the gestational sac may be part of
the embryopathy of triploidy. When both findings are present, the positive
predictive value for PHM approaches 90%. The ultrasound may also
 show the presence of a growth-retarded fetus with multiple congenital
4
anomalies attached to a hydropic placenta.
3. Correlation of the ultrasonographic findings with βHCG
levels can further improve the recognition of a molar
pregnancy prior to surgical evacuation. (Level III, Grade
C)
The combination of typical ultrasound findings with elevation of
hCG above expected for gestational age is highly suggestive of molar
18
pregnancy. Patients with CHM commonly have markedly elevated pre-
evacuation HCG levels with majority of patients presenting with a titer of
>100,000mIU/mL. On the other hand, patients with PHM less commonly
4
present with markedly elevated HCG values.
4. Although ultrasound and βHCG titers can be helpful in
the diagnosis of molar pregnancies, histological
confirmation is mandatory for the diagnosis of
hydatidiform mole. (Level III, Grade C)
Because the diagnosis of a hydatidiform mole is not definitive
until histopathological examination, all products of conception from non-
viable pregnancies should be submitted for routine pathological
1,6,19
examination irrespective of ultrasound findings.
In the classic, fully developed complete hydatidiform mole,
pathological examination shows swollen villi often with marked
circumferential villous trophoblasts. Clusters of similar cyto- and
syncytiotrophoblasts and some intermediate trophoblasts are also often
seen among the villi. Nuclear pleomorphism is usually more intense than
in normal pregnancy. Because of the fluid collection in ‘cisterns’ located
at the middle of the villi, there is compression of other components of
villous stroma beneath the cytotrophoblastic layer, which shows few or
20
no blood vessels. This hydropic change tends to be generalized.
In partial mole, the characteristic changes affect only part of the
placenta. There is a mixture of swollen and normal-sized villi. A fetus,
often with congenital malformations is frequently found and excessive
20
trophoblastic proliferation is either absent or very mild.
5. Immunostaining may be performed in cases where the
histologic diagnosis is in doubt (Level III, Grade C).
With the advent of ultrasonography, cases of hydatidiform moles
are diagnosed quite early in some centers. As such, morphologic
differentiation between CHM and PHM, and between PHM and non-
molar gestations can be difficult. Recently, immunostaining with p57kip2,
a product of CDKN1C has been used to differentiate between these
pregnancies. p57kip2 is expressed by the maternal allele and is visible
on histology as nuclear staining of cytotrophoblasts and villous
mesenchyme in the placenta of all gestations except androgenetic
21,22
complete moles.
PHLDA2 is another maternally imprinted gene that is present in
partial moles and absent in complete moles and has been also shown to
23
be useful for facilitating differentiation between the two.
6. Cytogenetic examinations are recommended when the
diagnosis of hydatidiform mole is in doubt. (Level III,
Grade C)
Ploidy studies by in situ hybridization or flow cytometry can
distinguish between diploid and triploid conceptions helping to diagnose
24
CHM and PHM.
MANAGEMENT
1. The following medical complications should be promptly
recognized and treated. (Level III, GPP)
a. Anemia
b. Preeclampsia
c. Hyperthyroidism
d. Electrolyte imbalance
e. Hyperemesis gravidarum
f. Pulmonary insufficiency
g. Disseminated intravascular coagulopathy
2. Initial evaluation should include a baseline hCG titer and
chest x-ray, as well as work up for anemia, preeclampsia,
electrolyte imbalance, infections and hyperthyroidism.
(Level III, Grade C)
Laboratory examinations include complete blood count with
differential and platelet counts, liver function test (ALT & AST), renal
function test (BUN & creatinine), thyroid function test (FT3, FT4, TSH)
6,18,19,24
and urinalysis.
 A baseline chest x-ray (PA and Lateral) helps rule out metastatic
lesions and complications from molar pregnancy such as pulmonary
6,18
hemorrhage, congestion and infection.
The preoperative evaluation should also include blood typing and
crossmatching, serum hCG level, and electrocardiogram if appropriate.24
3. Surgical evacuation of molar products is the definitive
management of hydatidiform moles. (Level III, GPP)
a. Suction curettage is the preferred method to evacuate molar
products regardless of uterine size.
4,6,7,18,19,24
Medical evacuation
of molar products as well as hysterotomy are not recommended
since these methods increase the risk of severe blood loss,
incomplete evacuation, trophoblastic dissemination and the
development of postmolar trophoblastic disease requiring
chemotherapy.
25
Additionally, hysterotomy would necessitate a
cesarean delivery for subsequent pregnancies.
General Guidelines for Suction Curettage
i. After induction of anesthesia, the patient is placed in a
semi-Fowler’s dorsolithotomy position.
ii. Mechanical cervical dilatation is done if the cervix is
unyielding to allow introduction of a 12-mm cannula
iii. At the start of curettage, oxytocin infusion (10 units of
oxytocin incorporated into 1 liter of Lactated Ringer’s
solution) is administered and continued for a few hours
post-operatively. Although concern has been expressed
regarding the theoretical risk of trophoblastic
embolization following oxytocin administration, there is
4,5,24
little supporting evidence of such a risk.
iv. During suctioning, the surgeon’s other hand should be
positioned on the uterine fundus to continuously assess
uterine size and tone.
v. To ensure complete removal of all chorionic tissues,
sharp curettage is performed after suction curettage.
b. All tissues obtained during molar evacuation should be submitted
for histologic evaluation. Specimens obtained from suction
curettage are submitted separately from tissues obtained by
sharp curettage.
c. Because the risk of bleeding increases with uterine size, at least
2 units of blood should be immediately available especially when
the uterus is more than 16-weeks’ gestational size.
d. The use of prostanoids to ripen the cervix prior to curettage
should be avoided to reduce the risk of pulmonary embolization
1,6,7,18,19
and dissemination of trophoblastic cells. Instead,
laminaria tent may be used to dilate the cervix pre-operatively
without the risk of tumor embolization.
e. Use of hysterometer for measurement of pre- and post-uterine
depth is avoided since it may lead to uterine perforation.
f. Patients who are Rh negative should receive Rh immune
globulin at the time of evacuation because the Rh D factor is
4,6,7,,18,19,24
expressed on trophoblast.
g. Routine repeat curettage after the diagnosis of a molar
pregnancy is not warranted.19
h. Hysterectomy with mole in-situ may be considered for patients
who have completed the desired family size or have life
1,4,6,7, 19
threatening hemorrhage. Removal of the adnexae may be
done if the patient is perimenopausal. Although hysterectomy
decreases the risk for local invasion, it does not eliminate the
probability of postmolar trophoblastic disease. Hence, post-
1,4,6,19
evacuation monitoring of HCG should still be done.
i. Theca lutein cysts are best left alone during laparotomy. They
26
regress spontaneously within 8-12 weeks post evacuation.
THE ROLE OF CHEMOPROPHYLAXIS
1. Chemoprophylaxis may be useful in situations where
patients are at high risk of postmolar GTD and when
post-evacuation surveillance is doubtful. (Level I, Grade
A)
The risk of malignancy after a complete or partial mole is 15-25%
1,4
and 0.5-4%, respectively. Patients with signs and symptoms of marked
trophoblastic proliferation are at high risk for persistent disease. The
following clinical features put the patient at risk of postmolar trophoblastic
disease:
a. Advanced maternal age > 35 years
b. Gravidity of > 4
c. Uterine size larger than gestation by > 6 weeks
d. Serum β-hCG titer > 100,000 mIU/ml
e. Theca lutein cyst(s) > 6cm
 f. Presence of any medical complication associated with increased Serum ß-hCG level is measured 1 week after molar evacuation,
trophoblastic proliferation: preeclampsia, thyrotoxicosis, then every 2 weeks until the level becomes normal (<5miu/ml). After 3
pulmonary insufficiency and disseminated intravascular consecutive biweekly normal levels, the monitoring is every month for 6
coagulopathy months, then at two monthly intervals for the next six months to insure
g. Repeat molar pregnancy that the hCG levels remain undetectable for one year following
remission. More than half of patients will have complete regression of
24
Randomized trials have shown that the use of chemoprophylaxis hCG to normal within two months of evacuation.
at the time of evacuation of high risk CHM significantly decrease the
27-29
development of GTN from approximately 50% to 10-15%. Therefore, 2. It is important to use a reliable contraception during the
women at high risk for malignant degeneration should be identified and entire follow up period (Level III, Grade C).
offered chemoprophylaxis. This should also be administered in
situations when hCG monitoring is not available or follow up is An essential component in the follow-up of patients who had
3,4
unreliable. molar disease is the use of an effective contraception. This eliminates
the potential confusion that arises in the interpretation of a rising hCG in
2. Methotrexate is the drug of choice for a patient not using a reliable form of contraception.
chemoprophylaxis. (Level III, Grade C)
A low-dose combined oral contraceptive pill is the preferred
Methotrexate is administered intramuscularly, and not in oral method of artificial contraception because they have the advantage of
form. Actinomycin D may be given in the presence of hypersensitivity to suppressing endogenous LH, which may interfere with the measurement
24
Methotrexate or liver toxicity. For chemoprophylaxis, only 1 course is of hCG at low levels. Data from a prospective trial and other studies
given. The following are the contraindications to chemoprophylaxis: have shown that the use of oral contraception is safe and does not
increase the risk of gestational trophoblastic neoplasia.30,31
a. Hemoglobin <100mg/dl, hematocrit <0.30
b. WBC count <3 x 109 PREGNANCIES AFTER A MOLAR PREGNANCY
c. Absolute neutrophil count(ANC) <1.5
d. Platelet count <100
e. Any active infection
1. Pregnancy may be allowed after 6 months of normal
f. Presence of liver or renal dysfunction serum ß-hCG level (Level III, Grade C).

3. Administration of chemoprophylaxis does not obviate Persistent trophoblastic disease are diagnosed within six months
6
of molar evacuation. Moreover, studies have shown a negligible risk of
the need for post-evacuation hCG surveillance. (Level III, PTD once normal hCG values are reached.32,33 As such, it would be safe
GPP) to allow patients to get pregnant six months after achieving normal hCG
levels.
Chemoprophylaxis does not completely eliminate the possibility
of postmolar gestational trophoblastic neoplasia. Monitoring of hCG 2. For every succeeding pregnancy, an early ultrasound
levels remains to be the mainstay in the diagnosis of any malignant
sequelae following a molar pregnancy.
should be performed because of the risk of another
molar pregnancy. (Level III, Grade C)
FOLLOW UP
Majority of women who have been treated for hydatidiform mole
are in the prime of their reproductive years, and many desire future child
1. After molar evacuation, all patients must have serial bearing. Studies have shown that after a molar pregnancy, the risk of
βhCG monitoring to detect malignant 8
another molar pregnancy rises to 1-2%. After 2 molar gestations, the risk
12
degeneration.(Level III, GPP). for a third mole is 15-20%. This risk is not decreased by a change in
 34
sexual partner, or the gestational age when the molar pregnancy was ALGORITHM FOR THE DIAGNOSIS AND MANAGEMENT OF
35
evacuated. The risk for stillbirth, prematurity, spontaneous abortion, and HYDATIDIFORM MOLE
12
congenital malformation is similar to that in the general population.
Therefore, after a woman has had a molar pregnancy, she should be
reassured as to the likely normal outcome of future pregnancies but she
should be aware of the increased risk of a recurrent molar gestation. Clinical History and Pelvic Ultrasound Serum ßhCG titer
Physical Examination
Because of the potential of a recurrent mole, an early
sonographic evaluation should be performed for each succeeding
pregnancy to ensure immediate diagnosis and prompt institution of the
18
necessary treatment.
HYDATIDIFORM MOLE
3. For each succeeding pregnancy following a molar
gestation, βhCG should be monitored at 6 weeks Completed Family Size
postpartum (Level III, GPP).
Determination of the βhCG level should be done six weeks after Total Hysterectomy + Suction Curettage
each succeeding pregnancy to detect any occult gestational BSO
trophoblastic neoplasia.

4. Placenta in subsequent pregnancies should be submitted With Risk

Factor No Risk
for histopathologic examination (Level III, GPP). Factor

Histopathologic examination of the placenta of subsequent Post-evacuation hCG

Chemoprophylaxis
pregnancies is done for early detection of an occult GTN. Monitoring
(under the supervision
of trophoblastic
disease specialist)

IN THE PRESENCE OF THE FOLLOWING, IMMEDIATE REFERRAL TO A

TROPHOBLASTIC DISEASE SPECIALIST SHOULD BE DONE:

Spontaneous Gestational Trophoblastic

1. High levels of ßhCG more than 4 weeks post-evacuation (serum level of
Neoplasia
20,000mIU/ml; urine level of 30,000 mIU/ml) Resolution
2. A rise in ßhCG of 10% or greater (2 consecutive weekly determinations)
3. Plateauing ßhCG values (<10% decline or rise) at any time after
evacuation (minimum of 3 consecutive weekly determinations)
4. Clinical or histologic evidence of metastasis at any site.
5. Persistently elevated ßhCG titer at 14 weeks post-evacuation.
6. Elevation of a previously normal ßhCG titer after evacuation provided the
diagnosis of pregnancy is excluded REFER TO A TROPHOBLASTIC
DISEASE SPECIALIST

REFERENCES
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management of hydatidiform mole. BMJ. 2008 Aug 15;337:a1193.
2. Soper JT, Mutch DG, Schink JC. Diagnosis and treatment of gestational
trophoblastic disease. Gynecol Oncol 2004 Jun; 93(3):575-85.
3. Garner EI, Goldstein DP, Feltmate CM, Berkowitz RS. Gestational
trophoblastic disease. Clin Obstet Gynecol 2007 Mar;50(1):112-22.
4. Berkowitz RS, Goldstein DP. Current management of gestational
trophoblastic diseases. Gynecol Oncol. 2009 Mar; 112(3):654-62.
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rd
Cole. Gestational Trophoblastic Disease, 3 edition, 2010, 249-76.
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Obstetricians and Gynecologists. Diagnosis and treatment of gestational
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7. Seckl MJ, Sebire NJ, Berkowitz RS. Gestational trophoblastic disease.
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16. Alhamdan D, Bignardi T, Condous G. Recognising gestational
trophoblastic disease. Best Pract Res Clin Obstet Gynaecol. 2009
Aug;23(4):565-73.
17. Fine C, Bundy AI, Berkowitz RS, Boswell SB, Berezin AF, Doubllet PM.
Sonographic diagnosis of partial hydatidiform mole. Obstet Gynecol
1989 Mar; 73 (3 Pt 1)414-8.
18. Soper JT. Gestational trophoblastic disease. Obstet Gynecol. 2006
Jul;108(1):176-87.
19. Tidy JA, Hancock BW, Newlands ES. The management of gestational
trophoblastic neoplasia. Clinical Guideline 38. London: Royal College of
Obstetricians and Gynaecologists 2004.
www.rcog.org.uk/resources/Public/pdf.
20. Sebire NJ, Lindsay I, Paradinas F. Pathology. In: Hancock, Barry W.,
M.J. Seckl, R.S. Berkowitz and L.A. Cole. Gestational trophoblastic 3rd
edition 2010: 97-147.
21. Soma H, Osawa H, Oguro T, Yoshihama I, Fujita K, Mineo S, Kudo M,
Tanaka K, Akita M, Urabe S, Kudo Y. p57kip2 immunohistochemical
expression and ultrastructural findings of gestational trophoblastic
disease and related disorders. Med Mol Morphol 2007 Jun;40(2):95-102.
22. McConnell TG, Murphy KM, Hafez M, Vang R, Ronnett BM. Diagnosis
and subclassification of hydatidiform moles uding p57
immunohistochemistry and molecular genotuyping:validation and
prospective analysis in routine and consultation practice settings with
development of an algorithmic approach. Am J Surg Pathol 2009
Jun;33(6):805-817.
23. Thaker HM, Berlin A, Tycko B, Goldstein DP, Berkowitz RS, Castrillon
DH, Genest DR. Immunohistochemistry for the imprinted gene product
IPL/PHLDA2 for facilitating the differential diagnosis of complete
hydatidiform mole. J Reprod Med. 2004 Aug;49(8):630–636.
24. Lurain JR. Gestational trophoblastic disease I: epidemiology, pathology,
clinical presentation and diagnosis of gestational trophoblastic disease,
and management of hydatidiform mole. Am J Obstet Gynecol. 2010
Dec;2003(6):531-9.
25. Tidy JA, Gillespie AM, Bright N, Radstone CR, Coleman RE, Hancock
BW. Gestational trophoblastic disease: a study of mode of evacuation
and subsequent need for treatment with chemotherapy. Gynecol Oncol
2000 Sep;78(3 Part 1):309-12.
26. Montz, FJ, Schlaerth, JB, Morrow CP. The natural history of theca lutein
cysts. Obstet Gynecol 1988 Aug;72(2), 247-51.
27. Kashimura Y, Kashimura M, Sugimori H, et al. Prophylactic
chemotherapy for hydatidiform mole: Five to fifteen years follow-up.
Cancer 1986 Aug;58(3):624-9.
28. Kim DS, Moon H, Kim KT, Moon YJ, Hwang YY. Effects of prophylactic
chemotherapy for persistent trophoblastic disease in patients in complete
hydatidiform mole. Obstet Gynecol 1986 May; 67(5):690-4
29. Limpongsanurak S. Prophylactic actinomycin D for high-risk complete
hydatidi- form mole. J Reprod Med. 2001 Feb;46(2): 110–6.
30. Curry SL, Schlaerth JB, Kohorn EI, et al. Hormonal contraception and
trophoblastic sequelae after hydatidiform mole (a gynecologic oncology
group study). Am J Obstet Gynecol 1989 Apr;160(4):805-11.
31. Costa HL, Doyle P. Influence of oral contraceptives in the development
of post-molar gestational trophoblastic neoplasia:a systematic review.
Gynecologic Oncology 2006 Mar;100(3):579-85.
32. Wolfberg AJ, Feltmate C, Goldstein DP, Berkowitz RS, Lieberman E.
Low risk of relapse after achieving undetectable HCG levels in women
with complete molar pregnancy. Obstet Gynecol. 2004 Sep;104(3):551–
4.
33. Wolfberg AJ, Growdon WB, Feltmate CM, Goldstein DP, Genest DR.
Low risk of relapse after achieving undetectable HCG levels in women
with partial molar pregnancy. Obstet Gynecol. 2006 Aug;108(2):393–
396.
34. Tuncer ZS, Bernstein MR, Wang J, Goldstein DP, Berkowitz RS.
Repetitive hydatidiform mole with different male partners. Gynecol Oncol
1999 Nov;75(2): 224-26.
35. Sebire NJ, Foskett M, Paradinas FJ, Fisher RA, Francis RJ, Short D,
Newlands ES, Seckl MJ.. Outcome of twin pregnancies with complete
hydatidiform mole and healthy co-twin. Lancet 2002 Jun
22;359(9324):2165-6.
GESTATIONAL TROPHOBLASTIC
NEOPLASIA
Stephanie Fay S. Cagayan, MD
Ma. Bernadette O. Cruz, MD, MSc
Ma. Carmen H. Quevedo, MD,
Gestational trophoblastic neoplasias (GTNs) represent the malignant
end of the gestational trophoblastic disease spectrum and include invasive
mole, choriocarcinoma and the rare types, placental-site trophoblastic tumor
(PSTT) and epithelioid trophoblastic tumor (ETT). Although GTN can occur
after any type of pregnancy, their incidence is 2000-fold greater following
premalignant complete hydatidiform mole (CHM) and partial hydatidiform
mole (PHM).1
Incidence of the various forms of gestational trophoblastic disease
varies. United States, Australia and Europe report the lowest rate while
Asian countries followed by Latin America and Africa give the highest. The
international rate of choriocarcinoma has been reported to be as high as 1 in
500-600 pregnancies in India to 1 in 50,000 pregnancies in Mexico,
Paraguay, and Sweden.2 The national prevalence rate of choriocarcinomas
and other trophoblastic neoplasias (GTNs) has remained almost constant at
0.56 per 1,000 pregnancies to 857/1,531,453 pregnancies.3
DEFINITION OF CLINICAL TERMS:
Persistent Trophoblastic Disease (PTD): a clinical term that denotes a
post-molar disease state in which there is a rise, plateau or persistence of
elevated beta hCG beyond 14 weeks without evidence of tumor. This term is
presently not being used and this definition falls under gestational
trophoblastic neoplasia.
Gestational Trophoblastic Neoplasia (GTN): a clinical term that denotes a
disease state in which there is physical, biochemical and radiologic evidence
of invasive mole, choriocarcinoma, placental site trophoblastic tumor, or
4
epithelioid trophoblastic tumor.
DEFINITION OF HISTOLOGIC TERMS Lateralizing neurologic signs may be evidence of CNS metastasis.

Invasive Mole (IM): a tumor or tumor-like process invading the myometrium DIAGNOSTIC TESTS
and characterized by trophoblastic hyperplasia and persistence of placental
5
villous structures. 1. Serum β human chorionic gonadotropin (βhCG) should
be obtained initially for diagnosis and subsequently for
Choriocarcinoma (ChorioCA): an epithelial malignancy of trophoblastic
cells formed by the abnormal proliferation of cytotrophoblasts and monitoring. (Level III, Grade A) 5,10
6
syncitiotrophoblasts in the absence of chorionic villi.
2. Transvaginal sonography is helpful to determine the
Placental Site Trophoblastic Tumor (PSTT): a rare neoplastic proliferation extent of disease and monitor response to treatment.
of intermediate trophoblasts that invade the myometrium at the placental site
7 (Level III, Grade C) 9
after a pregnancy.
Color flow doppler can define regions of increased vascularity
Epithelioid Trophoblastic Tumor (ETT): a rare trophoblastic neoplasm
representative of invasive disease and enhanced uterine perfusion.
which is the malignant counterpart of the intermediate trophoblasts of the
8
chorion leave.
3. Initial evaluation should include work up for anemia,
DIAGNOSIS preeclampsia, electrolyte imbalance, infections and
hyperthyroidism. (Level III, GPP)11
1. The clinical presentation of GTN is more important in
Laboratory examinations include CBC with differential and
determining treatment and outcome than the precise platelet counts, blood typing, liver function test (ALT & AST), renal
histologic diagnosis. (Level III) 5,6 function test (BUN & creatinine), thyroid function test (FT3, FT4, TSH)
and urinalysis.
Patients may present with any of the following signs and symptoms:
4. Complete metastatic work-up must establish whether
a. Vaginal bleeding
b. Anemia
the disease is locally invasive or metastatic and whether
c. Uterine enlargement the risk of therapeutic failure is high or low. (Level III,
d. Acute abdomen secondary to tumor perforation GPP) 5,11
e. Infection
The pattern of metastatic spread is hematogenous, and
2. One must search for signs and symptoms pertaining to metastasis to the lungs is the most common, therefore baseline Chest x-
the site of metastasis. (LeveI III, GPP) 5,6,7
12
ray (PA and Lateral) helps rule out metastatic lesions

In the presence of a suspicious vaginal mass, biopsy should not Systemic dissemination to the liver should be sought through
be done as hemorrhage from the biopsy site may ensue. ultrasound of the whole abdomen.

Patients may present with signs and symptoms of respiratory Organ-specific computed tomography (CT) scan or magnetic
11,13
distress or pulmonary insufficiency indicative of pulmonary metastasis. resonance imaging (MRI) as needed.

Metastatic tumors may bleed and present as hemoptysis,

cerebrovascular accident and intraperitoneal bleed.
MANAGEMENT
2. Unlike other cancers, treatment can be started without
1. All patients must be staged and scored using the FIGO histopathologic confirmation of the disease.5
2000 Anatomic Staging and WHO Prognostic Scoring Chemotherapy is the principal mode of treatment.
System (Tables 3 and 4). (GPP) Surgery and irradiation are adjunctive treatments. (Level
III, Grade C) 5,7,16
The FIGO anatomic staging system defines the extent of disease
while the WHO prognostic scoring system predicts the possible 3. Nonmetastatic and low-risk metastatic patients (Stage I,
13,14,15
resistance of the tumor to single-agent chemotherapy. Stage II low risk & Stage III low risk) are almost always
ultimately cured using single agent chemotherapy using
Table 2.1 FIGO 2000 Anatomic Staging
methotrexate with or without folic acid rescue or
STAGE I Disease confined to the uterus dactinomycin. (Level I, Grade A) 17,18,19
STAGE II Disease extends to outside the uterus but
confined to the pelvic organs 4. Combination chemotherapy EMACO (Etoposide,
STAGE III Pulmonary metastases Methotrexate, Actinomycin D, Cyclophospahamide and
STAGE IV Metastases to other sites Vincristine) has been the widely accepted treatment
regimen for high-risk patients (Stage II high risk, Stage
Table 2.2 WHO Prognostic Scoring System
III high risk & stage IV). (Level III) 22,23
Prognostic SCORE
Factors 0 1 2 4 5. Patients who relapse after their treatment or become
Age (years) <40 ≥40 resistant to drugs are given salvage chemotherapy.
Antecedent Mole Abortion Term (Level III) 24,25
Pregnancy
Pregnancy <4 4-6 7-12 >12 When resistance develops with EMACO several regimens may
Interval be used. Etoposide, Methotrexate, Actinomycin D and Cisplatin
(Months)
(EMACE), Carboplatin-Paclitaxel, Ifosfamide, Cyclophosphamide,
Beta-hCG titer <1,000 1,000- 10,000- >100,000
Etoposide(ICE) or Cisplatin, Vinblastine and Bleomycin (PVB)
(mIU/ml) <10,000 100,000
Largest tumor, <3 3 to 5 >5 combination may be given. Salvage therapy may also be instituted by
in cm. substituting Cisplatin and Etoposide (EMA-EP). 26
including the
uterine tumor 6. Clean-up or consolidation therapy consists of 2 cycles
Site of Spleen, GI tract Liver, for low risk and 3 cycles for high risk given after the first
metastases kidney Brain normal hCG value (<5 mIU/mL). (Level III)
Number of 1-4 5-8 >8
metastases
Prior Single >2 7. Surgery is an adjunctive treatment for appropriately
chemotherapy agent agents selected patients in order to reduce tumor load and
decrease the number of chemotherapeutic courses.
Interpretation: Low risk < 7, High risk : ≥7 (Level III, Grade C)16,27,28
 Hysterectomy has an important role in several cases of GTN.
Primary hysterectomy may be considered in selected high-risk metastatic
cases who have small extrauterine tumor burdens and who do not desire
to maintain fertility. Hysterectomy may also be indicated in cases of
uterine focus of drug resistance, uterine perforation or profuse uterine
bleed. 5,8 It is imperative to document the presence of uterine disease by
scans when performing hysterectomy for chemotherapy-resistant, high-
risk GTN. Patients >35 years or with completed family size are also
candidates for hysterectomy.
To induce remission, solitary drug-resistant pulmonary focus
may be resected by thoracotomy or thoracoscopy. It is imperative to
exclude disease elsewhere with CT or MRI of the brain, chest, abdomen
8
and pelvis before the resection is performed.
Craniotomy may be indicated for decompression of brain
metastasis with signs and symptoms of increased intracranial
pressure.8,29 Craniotomy for resection of drug-resistant focus is rarely
performed.
Surgery may also play a role in controlling tumor hemorrhage
such as oversewing of an actively bleeding vaginal lesion.
8. Concurrent radiation therapy with chemotherapy is used
to control as well as to limit acute hemorrhagic
complications from brain metastases.28 (Level III)
9. Response to treatment is based on serial serum β-hCG
determinations:
a. Adequate response – one log fall, or >50% fall from baseline
b. Partial Response – <50% fall from baseline
c. Plateau – <10% fall, or rise from baseline
d. Biochemical remission – 3 consecutive weekly normal serum T-
hCG levels (<5 mIU/mL)
e. Resistance – >3 plateauing values, rising weekly hCG titers or
appearance of new metastasis
10. Clinical examination should be performed during each
follow-up. If upon completion of chemotherapy there
remains some radiographic evidence of residual lung
tumor, further radiographs are required yearly. In
patients with intact uteri, transvaginal pelvic ultrasound
is recommended every six months. (Level III, GPP)
11. After biochemical remission, serum J-hCG is
determined monthly for the 1st 6 months, every two
months for the next 6 months, every 3 months for the
second year of follow-up, and every 6 months thereafter.
(Level III, GPP)
12. The patient is advised to avoid pregnancy during the 1st
2 years following biochemical remission. She is
prescribed a safe and effective form of contraception,
preferably a low-dose combined oral contraceptive pill. 5
(Level III, GPP)
 ALGORITHM FOR THE
DIAGNOSIS AND MANAGEMENT OF
GESTATIONAL TROPHOBLASTIC NEOPLASIA
REFERENCES:
Clinical History and Serum β- Radiograph and 1. Ngan S, Seckl MJ. Gestational trophoblastic neoplasia management: an
Physical Examination hCG titer Imaging Modality update. Curr Opin Oncol. 2007 Sep;19(5): 86-91.
2. Grimes DA. Epidemiology of gestational trophoblastic disease. Am J
Obstet Gynecol 1984 Oct;150(3):309-18.
3. Cagayan SF. Changing trends in the management of gestational
Gestational Trophoblastic Neoplasia trophoblastic diseases in the Philippines. J Reprod Med 2010 May-
Jun;55(5-6):267-72
4. Ng TY and Wong LC. Diagnosis and management of gestational
trophoblastic neoplasia. Best Pract Res Clin Obstet and Gynaecol 2003
Referral to Trophoblastic Disease Dec;17(6):893-903.
Specialist 5. Committee on Practice Bulletins-Gynecology, American College of
Obstetricians and Gynecologists. ACOG Practice Bulletin #53. Diagnosis
and treatment of gestational trophoblastic disease. Obstet Gynecol 2004;
103:1365.
6. Soper JT, Lewis JL Jr, Hammond CB. Gestational Trophoblastic
Disease. Ln: Hoskins WJ, Perez CA, Young RC, editors. Principals and
Stage Stage II/III Stage IV Practice of gynecologic oncology. 2nd ed. Philadelphia (PA): Lippincott-
I Raven; 1997. P. 1039-77.
7. Feltmate CM, Genest DR, Wise L, Bernstein MR, Goldstein DP,
Berkowitz RS. Placental site trophoblastic tumor: a 17-year experience at
Low Risk the New England Trophoblastic Disease Center. Gynecol Oncol 2001
High Risk
Sep;82(3):415-9.
8. Lurain JR. Gestational trophoblastic disease II: classification and
management of gestational trophoblastic neoplasia. Am J Obstet
Gynecol 2011 Jan;204(1):11-8.
9. Taylor KJ, Schwartz PE, Kohorn El. Gestational trophoblastic neoplasia:
Single Agent EMACO Irradiation diagnosis with doppler ultrasound. Radiology 1987;165:445-448.
10. Cole LA., Kohorn EI, Kim GS. Detecting and monitoring trophoblastic
Chemotherapy + +Hysterectomy
disease. New perspectives on measuring human chorionic
Hysterectomy gonadotropin levels. J Reprod Med 1994 Mar;39(3):193-200.
11. Kohorn EI. The New FIGO 2000 staging and risk factor scoring system
for gestational trophoblastic disease: description and clinical
assessment. Int J Gynecol Cancer 2001 Jan-Feb;11(1): 73-7.
12. Berkowitz Ross, Goldstein Donald: Gestational Trophoblastic
Neoplasia. In Novak's Gynecology. 13th edition. Edited by: Berek JS.
Lippincott, Williams and Wilkins; 2002.
13. Kohorn EI, McCarthy SM, Taylor KJ. Nonmetastatic gestational
trophoblastic neoplasia. Role of ultrasonography and magnetic
resonance imaging. J. Reprod. Med 1998 Jan;43(1):14-20.
14. FIGO Oncology Committee. FIGO staging for gestational trophoblastic 27. Lehman E, Gershenson DM, Burke TW, Levenback C, Silva EG, Morris
neoplasia 2000. Int J Gynecol Obstet 2002 Jun; 77(3):285-7. M. Salvage surgery for chemorefractory gestational trophoblastic
15. Kohorn El, Goldstein, DP, Hancock BW, et al. Combining the staging disease. J Clin Oncol 1994 Dec;12(12):2737-42.
system of the International Federation of Gynecology and Obstetrics with 28. Suzuka K, Matsui H, Iitsuka Y, Yamazawa K, Seki K, Sekiya S. Adjuvant
the scoring system of the World Health Organization for trophoblastic hysterectomy in low-risk gestational trophoblastic disease. Obstet
neoplasia. Report of the Working Committee of the International Society Gynecol 2001 Mar;97(3):431-4.
for the Study of Trophoblastic Disease and the International Gynecologic 29. Evans AC Jr, Soper JT, Clarke-Pearson DL, Berchuck A, Rodriguez GC,
Cancer Society. Int J Gynecol Cancer 2000: 10, 84-88. Hammond CB. Gestational trophoblastic disease metastatic to the
16. Hammond CB, Weed JC Jr, Currie JL. The role of operation in the central nervous system. Gynecol Oncol 1995 Nov;59(2):226-30.
current therapy of gestational trophoblastic disease. Am J Obstet
Gynecol 1980 Apr 1;136(7):844-58.
17. Carney ME. Treatment of low risk gestational trophoblastic disease. Clin
Obstet Gynecol 2003 Sep;46(3):579-92.
18. Roberts JP, Lurain JR. Treatment of low-risk metastatic gestational
trophoblastic tumors with single-agent chemotherapy. Am J Obstet
Gynecol 1996 Jun;174(6):1917-24.
19. Soper JT, Evans AC, Conaway MR, Clarke-Pearson DL, Berchuck A,
Hammond CB. Evaluation of prognostic factors and staging in
gestational trophoblastic tumor. Obstet Gynecol 1994 Dec;84(6):969-73.
20. Homesley HD, Blessing JA, Rettenmaier M, Capizzi RL, Major FJ,
Twiggs LB. Weekly intramuscular methotrexate for nonmetastatic
gestational trophoblastic disease. Obstet Gynecol 1988 Sep;72(3 Pt
1):413-8.
21. Soper JT, Clarke-Pearson DL, Berchuck A, Rodriguez G, Hammond CB.
5-day Methotrexate for women with metastatic gestational trophoblastic
disease. Gynecol Oncol 1994 Jul;54(1):76-9.
22. Wright JD, Mutch DG. Treatment of high risk gestational trophoblastic
tumors. Clin Obstet Gynecol 2003 Sep; 46(3): 593-606.
23. Schink JC, Singh DK, Rademaker AW, Miller DS, Lurain JR. Etoposide,
methotrexate, actinomycin D, cyclophosphamide, and vincristine for the
treatment of metastatic, high-risk gestational trophoblastic disease.
Obstet Gynecol 1992 Nov;80:817-20.
24. Newlands ES. The management of recurrent and drug-resistant
gestational trophoblastic neoplasia. Best Pract Res Clin Obstet Gynaecol
2003 Dec;17(6):905-23.
25. Newlands ES, Mulholl ND, Holden L, Seckl MJ, Rustin GJ. Etoposide
and Cisplatin/Etoposide, Methotrexate, Actinomycin D (EP-EMA)
chemotherapy for patients with high risk gestational trophoblastic tumors
refractory to EMA/Cyclophosphamide and Vincristine chemotherapy and
patients presenting with metastatic placental site trophoblastic tumors. J
Clin Oncol 2000 Feb;18(4):854-9.
26. Berkowitz RS, Goldstein DP. Current management of gestational
trophoblastic diseases. Gynecol Oncol 2009 Mar;112(3):654-62.
 include nephritic syndrome, galactorrhea, polycythemia, hematuria and
2,3,5
virilization.
PLACENTAL SITE TROPHOBLASTIC
TUMOR It has been reported that > 50% (44-69%) are diagnosed with Stage I
4
Disease confined to the uterus while the rest are metastatic in nature. The
most common site of metastasis is the lung, followed by the vagina and
Paulene Trixie C. Chan, MD liver.
2,4
Other reported sites are the ovaries, lymph nodes, brain, stomach,
2,4
Agnes S. Estrella, MD, MHPEd spleen, bowel, bladder, kidneys and skin.
Estrella Sebe S. Fernandez , MD PROGNOSTIC FACTORS
Elizabeth K. Jacinto, MD
1. FIGO Stage

The most important prognostic factor in PSTT is the FIGO Stage.

Patients who were initially diagnosed as FIGO I and II showed a higher
DEFINITION survival rate 0f 93.5% compared to those patients with a diagnosis of
7
FIGO III and IV who had a survival rate 33.3% . Moreover, only 5% of
Placental site trophoblastic tumor (PSTT) is a neoplastic proliferation patients with early stage disease will have recurrence of disease while
of intermediate trophoblasts that invades the myometrium at the implantation 70% of stage III and 90% of stage IV patients will be diagnosed with
1 4
site. Because PSTT is rare, information on its natural history is limited. recurrence.

INCIDENCE 2. Interval From The Antecedent Pregnancy

The incidence of PSTT is reported at around 1 – 2% of trophoblastic The interval from the last known antecedent pregnancy appears
2
tumors. Since it was first described by Kurman et al in 1976, less than 100 to be the second major prognostic factor in PSTT. Studies have reported
2
cases have so far been reported in literature. Based on the Philippine that an interval from the previous pregnancy of more than two years
2,8
Obstetrical and Gynecological Society statistics, there were only 18 cases appeared to be an independent adverse prognostic factor.
reported from 2001-2009.
3. Mitotic count
PSTT affects women in the reproductive age group with a mean age
2,3 Mitotic count is not a reliable factor in predicting the clinical
at diagnosis between 31 to 33 years. It may arise from any form of
pregnancy although term delivery is the most frequent antecedent course of patients with PSTT. In earlier reports, patients who had poor
2 outcomes had a mitotic count of more than 5 per high power field.
pregnancy, followed by abortion, hydatidiform mole and ectopic pregnancy.
However, recent findings have shown that tumors with low mitotic counts
8
also had the potential to metastasize.
CLINICAL PRESENTATION
The clinical presentation of patients with PSTT is similar to the signs
4. Others
and symptoms of patients with other forms of gestational trophoblastic
disease. Symptoms may present weeks to years after the antecedent Other poor prognostic factors reported in literature include age
pregnancy, with irregular vaginal bleeding following a period of amenorrhea more than 35 years, higher gravidity and term deliveries with female
being the most common presenting symptom.
1-5
Often, an asymmetrical fetuses. Microscopically, implication of poor prognosis include a depth of
2,3,4
enlarged uterus may be found. Patients may also report signs and tumor invasion and vascular space involvement. These however
6
symptoms referable to the site of metastasis. Other reported manifestations need to be studied more to confirm their role as prognostic factors.
DIAGNOSIS
1. PSTT should be considered in patients presenting with
low levels of βhCG despite a relatively large tumor.1,6
(Level II, Grade A)
Patients with PSTT have less pronounced elevations of serum
βhCG levels despite a huge uterine mass or disseminated disease. It is
reported that serum βhCG is usually below 1000mIU/ml in 79% and
3,6
below 500mIU/ml in 58%. This is explained by the predominance of
intermediate trophoblasts which produce little βhCG compared to the
4
syncythiotrophoblasts. Therefore, patients who have a radiologic
finding of a relatively large uterine tumor but only mild elevation of βhCG
should be suspected of having PSTT.
2. hCG free β-subunit measurements have been found to
discriminate malignant PSTT clinically, from
choriocarcinoma, quiescent GTD and non-trophoblastic
malignancies like germ cell tumors. Production of hCG
free β-subunit by non-trophoblastic malignancies has
likewise been well established.9 (Level III, Grade B)
hCG is composed of an α and a β subunit. Our test for serum
hCG is dependent on an antibody for the β subunit of the intact dimer.
PSTT, on the other hand, appears to produce hCG subunits in
insufficient concentrations including a combination of the subunits thus
leading to production of hCG free β-subunit. Production of hCG free β-
subunit by non-trophoblastic malignancies has likewise been well
established and therefore has to be considered in the differential
diagnosis in PSTT.
4,9
In the USA hCG Reference Service, proportion free β-subunit
[(free β subunit x total hCG) / 100 ] was used as a test for predicting
PSTT cases short of the gold standard of histology. Proposed cutoff
values of >35% to rule out choriocarcinoma and quiescent GTD and
>80% to rule out non trophoblastic malignancies like germ cell tumors
9
were suggested.
3. β core fragment is a degradation product of the free β
subunit and therefore may be considered as a
complimentary test to the βhCG in PSTT.4 (Level III,
Grade B)
4. Serum human placental lactogen (hPL) is not a useful
marker of PSTT.10 (Level III, Grade A)
Intermediate trophoblasts produce large quantities of human
placental lactogen (hPL). However, this fact does not make hPL a useful
tumor marker for PSTT. Rather, the test is frequently limited to
immunohistochemistry rather than to serum tumor marker
measurements. Serum hPL titers is not available in the Philippines.
5. Ultrasound examination is helpful in identifying the
vascularity of the tumor after clinical suspicion but the
definitive diagnosis is made by histological examination
of the mass.1,3 (Level III, GPP)
On ultrasound, the tumor may appear as an echogenic mass
involving the endometrium and myometrium. On color flow doppler, both
hypervascular and hypovascular forms are identified which will be helpful
in the management. A dilatation and curettage should not be done in
hypervascular tumors and a local resection will be applicable to the
1,3
hypovascular type. If the plan of management is local resection,
ultrasound, MRI and/or PET scan may be used to accurately determine
3
the size and location of the tumor and identify site of residual tumor.
6. Histopathologic examination is very important in the
diagnosis of PSTT. (Level III, GPP)
Gross: Most lesions are located in the endomyometrium
presenting as well-circumscribed polypoid or nodular projections into the
uterine cavity, 0.7 to 9 cm in widest dimension. Cut section shows a
11,12,13
solid, often fleshy, and usually yellow or tan surface.
Microscopic: PSTT is characterized by a monomorphic cell
population of implantation site intermediate trophoblasts that separate
11,12,13
muscles bundles as they invade the myometrium.
7. Immunohistochemical staining with hPL is important in
the diagnosis of PSTT.2
PSTT shows a high proportion of cells positive for HPL and a
relatively small proportion of cells staining for hCG.
2,4
MANAGEMENT 3. After a complete metastatic work-up, all patients are staged
using the FIGO 2000 Staging system.
The rarity of this disease and its variable clinical course has
The FIGO 2000 Staging of Gestational Trophoblastic Disease is
made the establishment of treatment guidelines difficult.
used to stage PSTT. The WHO Scoring System used for GTN is not
applicable for PSTT since it has been shown that it does not correlate
1,3,14
1. The following medical complications should be promptly with outcome.
recognized and treated. (Level III, GPP)
4. Unlike choriocarcinoma or invasive mole, surgery is the
a. Anemia primary treatment for PSTT.1,2,3,4 (Level III, GPP)
b. Preeclampsia
c. Hyperthyroidism PSTT is relatively resistant to chemotherapy. As such, surgery
remains the cornerstone in management, with total hysterectomy being
d. Electrolyte imbalance the optimal therapy for both metastatic and non-metastatic disease.
1,2,3,14

e. Pulmonary insufficiency Because metastasis to the ovaries is rare, these may be left behind if
f. Disseminated intravascular coagulopathy grossly normal, especially since most of the patients with PSTT are less
4
than 40 years old.
2. The following laboratory tests are done to determine the
extent of the disease and as prerequisites before institution Among patients who are desirous of pregnancy and with disease
of chemotherapy. (Level III, GPP) limited to the uterus, conservative surgical management in the form of
curettage or resection of the uterine mass by laparotomy, laparoscopy or
3,4
hysteroscopy may be performed.
a. CBC with platelet count
b. Blood typing In cases when resection of the uterine mass is contemplated, an
c. Liver profile (ALT, AST) ultrasound with Doppler, MRI, and/or PET scan should be performed
6
d. Renal function test (BUN, creatinine) pre-operatively to identify the size, location and vascularity of the tumor.
e. Thyroid function test (FT3, FT4, TSH)
The role of pelvic and para aortic lymphadenectomy is unclear
f. Serum electrolytes especially if surgery is done in early disease.
2,4
In a recent report,
g. Urinalysis however, lymph node dissection has been recommended because of the
15
h. Ultrasound of the Whole Abdomen and transvaginal tendency for lymphatic spread in PSTT.
pelvic ultrasound with color flow Doppler
i. Chest x-ray (PA and lateral)
j. Organ-specific computed tomography (CT) scan or 5. Chemotherapy may be given for patients with early
magnetic resonance imaging (MRI) as needed, or in stage disease associated with poor prognostic factors
the following instances: (interval > 2 years, volume of disease and mitotic count
>5/10hpf) or in patients with advanced stage disease.1-5,
15
i. Chest CT scan with contrast is requested when (Level III, GPP)
baseline chest x-ray is normal.
ii. Brain CT scan with contrast is requested in a EMACO is the most frequently used and reported primary multi-
agent chemotherapy with quoted total response rate of 71% and a
neurologically asymptomatic patient when chest 14
complete response rate of only 38%. EMA EP is given for patients
radiograph demonstrates lesion(s) at least 3 cm resistant to, or relapse after EMACO.
2,14
Alternative salvage therapies
in diameter.
 given were BEP (bleomycin, etoposide and cisplatin) and VIP (etoposide,
ifosfomide and cisplatin).2
6. Metastasectomy may be done for chemoresistant
metastatic PSTT.2 (Level III, GPP)
Among patients with locally advanced and metastatic disease,
recent reports have recommended resection of all extrapelvic tumors if is
3
technically possible. Unlike choriocarcinoma where metastasectomy is
advised when the primary malignancy is controlled and with only a
solitary site of metastasis, bilateral and multifocal metastases are not
contraindications to resection in PSTT especially in young patients with
4
poor prognostic variables.
7. Radiation may be useful in combination with surgery
and chemotherapy in cases with pelvic residual disease,
isolated recurrence or palliative therapy.1,2,3 (Level
III,GPP)
There have been 2 reported cases of radiotherapy contributing to
remission. It may be useful in cases of isolated and localized
recurrences.2 Its use must be individualized and currently no
1,3
recommendations can be formulated regarding its use.
8. Serum human chorionic gonadotropin (ßhCG) still
remains as the most important serum marker to monitor
the disease and treatment course.4 (Level III, GPP)
FOLLOW UP
1. After treatment, all patients should undergo serial hCG
monitoring to detect recurrence. (Level III, GPP)
After biochemical remission, serum hCG must be done every
st
month for the 1 6 months of follow-up, then every two months for the
nd
next 6 months (to complete one year). On the 2 year, serum hCG is
determined every 3 months, and then every 6 months thereafter.
2. Young patients with intact uteri are advised to avoid
pregnancy until one year from the first normal hCG titer.
(Level III, GPP)
These patients are prescribed contraception, preferably low
dose combined oral contraceptive pills which may be given immediately
following treatment.
3. Clinical examination is performed every follow-up. (Level
III, GPP)
4. Annual chest radiograph is recommended when there is
radiographic residual lung tumor in a patient who
completed treatment and whose hCG titer has remained
normal. (Level III, GPP)
REFERENCES
1. Kim SJ. Placental site trophoblastic tumor. Best Pract Res Clin Obstet
Gynaecol 2003 Dec;17(6):969-84.
2. Ajithkumar TV, Abraham EK, Rejnishkumar R, Minimole AL. Placental
site trophoblastic tumor. Obstet Gynecol Surv 2003 Jul;58(7):484-8.
3. Behtash N, Karimi Zarchi M. Placental site trophoblastic tumor. J
Cancer Res Clin Oncol 2008 Jan;134(1):1-6.
4. Dainty LA, Winter WE 3rd, Maxwell GL. The clinical behavior of
placental site trophoblastic tumor and contemporary methods of
management. Clin Obstet Gynecol 2003 Sept;46(3):607-11.
5. Mardi K, Kaushal V. Placantel site trophoblastic tumor-a challenging,
rare entity. Taiwn J Obstet Gynecol 2009 Dec;49(4):533-5.
6. Behtash N, Ghaemmaghami F, Hasanzadeh M. Long term remission of
metastatic placental site trophoblastic tumor (PSTT): case report and
review of literature. World J Surg Oncol 2005 Jun 15;3(1):34.
7. Chang YL, Chang TC, Hsueh S, Huang KG, Wang PN, Liu HP, Soong
YK. Prognostic factors and treatment for placental site trophoblastic
tumor-report of three cases and analysis of 88 cases. Gyncol Oncol
1999 May;73(2):216-22.
8. Gillespi AM, Hancock BW. Placenatl site trophoblastic tumor. In
Gestational trophoblastic disease, 3rd edition, by Seckl MJ, Berkowitz,
RS, Cole LA Hancock BW. 2010:420-9.
9. Cole LA, Khanlian SA, Muller CY, Giddings A, Kohorn E, Berkowitz R.
Gestational trophoblastic disease: human chorionic gonadotropin free β-
subunit, a reliable marker of placental site trophoblastic tumors. Gynecol
Oncol 2006 Aug;102(2):160-4.
10. Hassadia A, Gillespi A, Tidy J, Everard RGN, Wells M, Coleman R,
Hancock B. Placental site trophoblatic tumor: clinical features and
management. Gynecol Oncol 2005 Dec;99(3):603-7.
11. Shih IM, Kurman RJ. Epithelioid trophoblastic tumor: a neoplasm distinct
from choriocarcinoma and placental site trophoblastic tumor simulating
carcinoma. Am J Surg Pathol 1998 Nov;22(11):1393-403. EPITHELIOID TROPHOBLASTIC TUMOR
12. Shih IM, Mazur M, Kurman R. Gestational trophoblastic disease and
related lesions. In Kurman RJ (Ed) Blaustein's Pathology of the Female Paulene Trixie C. Chan, MD
Genital Tract, 5th edition. Springer; 2002. Chapter 24:1193-1247.
13. Shih IM, Kurman RJ. Pathology of intermediate trophoblastic tumors and Estrella Sebe S. Fernandez, MD
tumor-like lesions. Int J Gynecol Pathol 2001 Jan;20(1):31-47. Elizabeth K. Jacinto, MD
14. Baergen RN, Rutgers JL, Young RH, Osann K, Scully R. Placental site
trophoblastic tumor: a study of 55 cases and review of the literature
emphasizing factors of prognostic significance. Gynecol Oncol 2006
Mar;100(3):511-20.
15. Lurian JR. Gestational trophoblastic disease II: classification and DEFINITION
management of gestational trophoblastic neoplasia. Am J Obstet
Gynecol 2011 Jan;204(1):11-18.
Epithelioid trophoblastic tumor (ETT) refers to an unusual type of
trophoblastic proliferative disease distinct from placental site trophoblastic
tumor and choriocarcinoma with features that resemble a carcinoma. Just
recently described, this trophoblastic neoplasm is thought to be a malignant
counterpart of the intermediate trophoblasts of the chorion leave having an
epithelioid appearance.1,2

PRESENTATION AND PROGNOSTIC FACTORS

1. The age at presentation of patients with ETT is

variable.3

In an earlier review, the age range of patients with ETT was

reported to be from 15 to 48 years old with a median age of 36.1
1,2,3
years. With reported ETT cases in patients above 50, a more recent
study in 2008 reported the age range from 15 to 66 years old with a
4
median age of 38 years.

2. The antecedent pregnancy of patients with ETT is

67% for full term, 16% for spontaneous abortion, and
16% for molar pregnancy. 1,2

Interval between antecedent pregnancy and diagnosis is 1 to 18

years. Like choriocarcinoma, extrauterine ETT can develop after a long
latent period without evidence of disease.
3. The most common symptom of ETT is abnormal from choriocarcinoma and PSTT. The masses of cells are intimately
vaginal bleeding.1,2,4 associated with eosinophilic, fibrillar hyaline-like material and necrotic
debris. Typically, small blood vessels are located within the center of the
The site of ETT lesion(s) are as follows: Uterine corpus tumor. Apoptotic cells and apoptotic bodies are diffusely distributed
(30%), lower uterine segment (50%), extrauterine: lungs (20%), throughout the tumor.7
small bowel. Because of the tendency of ETT to grow in the lower Immunochemistry: ETT stains diffusely positive with pLAP
uterine segment and the cervix, an initial diagnosis of carcinoma (placental alkaline phosphatase) and cytokeratin and only weakly
of the cervix may be made and has to be ruled out.1,2 The most positive with hCG and hPL. It is reported to be positive also in epithelial
common site of metastasis is the lungs.4 membrane antigen and inhibin. p63 which is positive in ETT is useful in
differentiating ETT from PSTT.8
4. Prognostic factors are difficult to identify because of
the small number of cases and the short period of MANAGEMENT
follow-up reported.4
1. The following baseline laboratory examinations are
Studies show that histopathologic features like tumor size, extent done to determine the extent of disease and/or for
of necrosis and cytologic atypia have no relation to the aggressive chemotherapy prerequisites. (Level III, GPP)
behavior in ETT. Even high mitotic index and level of serum hCG were
4
not shown to be associated with malignant behavior in ETT. a. CBC with differential and platelet count
b. Blood typing
DIAGNOSIS c. Transvaginal pelvic ultrasound with color flow doppler
d. Pre-treatment diluted serum β-hCG
e. Liver transaminases
1. In ETT, there is elevated but generally low serum β- f. Renal function test (BUN, creatinine)
hCG.1,2,4 (Level III, GPP) g. Thyroid function test (FT3, FT4, TSH)
h. Urinalysis
In a review of cases, majority of patients presented with βhCG i. Chest x-ray (PA and lateral)
levels below 2500IU/l (69%). There were a small number of patients j. Metastatic work-up (as outlined in the GTN section)
4
(14%) reported to have normal hCG levels below 2.0 IU/l.
Other examinations (if indicated):
2. Histopathologic examination is important in the
a. Serum electrolytes
diagnosis of ETT. (Level III, GPP) b. 2-lead ECG

Gross: Solitary, discrete nodules that deeply invade the cervix 2. Epithelioid trophoblastic tumor may not be
and myometrium are usually seen. On cut-surface, it is either solid or responsive to chemotherapy.
cystic. Solid areas are typically tan to brown, with varying amounts of (Level III, GPP)
7
hemorrhage and necrosis.
ETT may be considered in patients initially diagnosed to have
Microscopic: In ETT, monomorphic cell population of the
GTN but unresponsive to chemotherapy. Further histologic examinations
chorionic-type intermediate trophoblastic cells arranged in nests and 1,2,3,4
are recommended in these patients. Hysterectomy and lung
cords are seen with a predominantly nodular architecture distinguishing it
resection have been used successfully in ETT. In relation to these, doing
 thoracotomy solely in patients presenting with lung lesions has been
reported to be effective without the need for additional chemotherapy.
HUMAN CHORIONIC GONADOTROPIN
However, in those patients with multiple sites of metastases or
associated medical conditions where surgery cannot be performed,
4 Lourdes B. Capito, MD
chemotherapy may be considered. There has been no recommendation
as to the type of chemotherapy because of the paucity of cases. Laureen Honor F. Mondragon, MD
The effectiveness of curettage and chemotherapy for the
treatment of early lesions requires further evaluation.
1. Human chorionic gonadotropin (hCG) is a glycoprotein
FOLLOW UP hormone that comprises two dissimilar subunits (α-
subunit of 92 amino acids and a β- subunit of 145 amino
The same follow-up schedule as in PSTT is acids) with 8 sugar side chains.1
recommended for ETT patients who have completed
treatment. (Level III, GPP) 2. The key hCG-related molecules that are detected in
serum and urine samples are: 1
REFERENCES a. regular hCG
b. hCG free β-unit
1. Shih IM, Kurman RJ. Epithelioid trophoblastic tumor: a neoplasm distinct c. nicked hCG
from choriocarcinoma and placental site trophoblastic tumor simulating d. hCG missing the β-subunit C- terminal peptide
carcinoma. Am J Surg Pathol 1998 Nov; 22(11);1393-1403. e. hyperglycosylated hCG (hCG-H)
2. Vencken PMLH, Ewing PC, Zweener RP. Epithelioid trophoblastic f. urine β-core fragment (urine only)
tumour: A case report and review of the literature. J Clin Pathol 2006
Dec;59(12):1307-8. 3. It is the hCG-H, produced by stem cytotrophoblast cells,
3. Coulson LE, Kong C, Zaloudek C. Epithelioid trophoblastic tumor of the
uterus in a postmenopausal woman: a case report and review of
that is shown to be the autocrine promoter of growth
literature. Am J Surg Pathol 2000 Nov; 24(11):1558-62. and malignancy in gestational trophoblastic neoplasms
4. Palmer JE, Macdonald M, Wells M, Hancock BW, Tidy JA. Epithelioid and persistent mole.2-5
Trophoblastic Tumor: A Review of the Literature. J Reprod Med 2008
Jul;53(7):465-475. 4. hCG-H is the principal hCG variant produced and
5. Shen DH, Khoo US, Ngan HY, Ng TY, Chau MT, Xue WC, Cheung AN.
Coexisting epithelioid trophoblastic tumor and choriocarcinoma of the
detected in active gestational trophoblastic neoplasms.6-
8
uterus following a chemoresistant hydatidiform mole. Arch Pathol Lab (Table 5.1)
Med 2003 Jul;127(7);e291-3.
6. Sternberg S. Diagnostic Surgical Pathology. Fourth edition. Lippincott 5. hCG free β-subunit is the principal hCG form detected in
Williams & Wilkins 2004. PSTT and non-trophoblastic neoplasms.1 (Table 5.1)
7. Shih IM, Mazur M, Kurman R. Gestational Trophoblastic Disease and
Related Lesions. In: Kurman RJ (ed). Blaustein’s Pathology of the
Female Genital Tract. Fifth ed. Springer; 2002. Chapter 24, p1193-1247. 6. Circulating hCG from hydatidiform mole and hCG-H
8. Sebire NJ, Lindsay I, Paradinas F. Pathology. In Gestational from GTN commonly becomes nicked as levels diminish
trophoblastic disease, 3rd edition, by Seckl MJ, Berkowitz, RS, Cole LA after therapy.9-10
Hancock BW. 2010:97-147.
 When hCG values fall below 100 mIU/mL in trophoblastic

(urine only)
Urine b-core fragment

Free b-subunit
peptide
b-subunit C-terminal
hCG missing

Nicked hCG

hCG-H

Regular hCG

hCG-related molecule

Table 5.1. Occurrence of hCG-related molecules in serum and urine samples.

diseases, nicked hCG and free β-subunit often become the major or even
sole sources of hCG immunoreactivity in serum.

There have been reported cases in which recurrence of invasive

disease has been completely missed by use of an assay that does not detect
nicked hCG. False negative results also occurred in assays that do not
detect free β-subunit or nicked hCG. It is essential to accurately monitor hCG

menses

3-6 wks
levels until they become undetectable and demonstrating that the

+++

post
++

Pregnancy
--

--
+

Normal
immunoreactivity remains undetectable and does not rise.

7. Siemens Immulite hCG test is the only one that

term
+++

+++

s to
7wk
--
+

+
efficiently detects all of the hCG variant antigens in
serum samples on an equimolar. It is clearly the only

evacua
Prior to
+++
appropriate test for management of cases with

tion
++

+
±
gestational trophoblastic diseases.11-13 (Table 5.2) (Level
I, Grade A)

Postevacuation
hCG>100 IU/L

Hydatidiform Mole
+++
8. Laboratories in the Philippines have different brands of

++

+
±
hCG immunoassays. (Table 5.3)

hCG<100 IU/L
evacuation
Post-
9. False positive hCG is caused by interfering antibodies

+++

+++

++

+
±
which include human anti-animal antibodies gained
from exposure to animals and human heterophilic
antibodies gained from immunoglobulin A deficiency

rising hCG

Persistent
disorder or history of mononucleosis.14-17

GTD with
+++
++

+
±

carcinoma
therapy

Chorio
+++

pre-
+

+
±

malignancies
Other
+++

--
±

±
 Table 5.3. Locally available hCG assays (as of March 2011)

limited sensitivity, ≥ tests

cancer cases due to very
Avoid use in GTD and

test
limited specificity in ≥1
and cancer cases due
Use with caution in GTD

Urine β-core

BCTP
Nicked hCG missing

Nicked hCG

HCG-H

hCG free

Standard

in a specific assay are indicated by 0/1. Those not detected at all are indicated with a zero.
trophoblastic diseases. Antigens appropriately recognized by different assays are indicated by the numeral 1. Those questionably detected
Table 5.2. Use of common brands of hCG immunoassays to detect hCG metabolic products commonly found in individuals with gestational
fragment

β-subunit
LABORATORY hCG ASSAY
Metro Manila
Asia Pacific Laboratory Chemiluminescence
Asian Hospital & Medical Center Beckman DXI
Cardinal Santos Medical Center Vidas
Chinese General Hospital Roche Elecsys 2010

m/IMX
AxSy
Abbott
Healthway Medical Clinics Roche Elecsys 2010

1
x

Manila Doctors Hospital Gamma Counter

MCU-FDT Medical Roche Elecsys 2010

ur
Centa
ns
Sieme
National Kidney & Transplant Institute Roche Cobas e601

0/1
0

1
x

Philippine General Hospital Gamma Counter

Philippine General Hospital UPMC Roche Elecsys

180
ACS
ns
Sieme
FMAB

0/1
0

1
x

Polymedic (Metro Manila) Abbott Architect i1000sR

San Juan De Dios Abbott AxSym
St. Luke’s Global Siemens Advia Centaur

DXI
Acces/
an
Beckm
St. Luke’s Medical Center Siemens Advia Centaur

0/1
0

1
x

The Medical City Abbott AxSym

UERM Medical Center Siemens Immulite

on
Dimensi
Dade
United Doctors Medical Center Biomereiux Vidas
0/1

University of Santo Tomas Hospital Beckman Access

0

1
x

Cebu
Cebu Doctors Hospital Abbott Architect
Chong Hua Hospital Roche Cobas 6000
e
Immulit
s
Siemen
Cagayan de Oro
1

Capitol University Medical City Beckman Access

Northern Mindanao Regional Hospital Siemens Immulite
Eci
Vitros
Ortho

Davao
0

1
x

Davao Doctors Hospital Roche Elecsys

San Pedro Hospital TNC Mini Vidas
series
s
Elecsy
Roche
0/1

0/1
0

1
x

serie

h
Tosc
A1A
0

1
x

β
hCG
o
Wak
0/1

0/1
0

1
x

RIA
Cross
Charin
0/1

0/1

0/1
1

1
x

x
FALSE POSITIVE hCG QUIESCENT GESTATIONAL TROPHOBLASTIC DISEASE

1. False positive results are identified by the following 1. Quiescent Gestational Trophoblastic Disease are
criteria:14-16 persistently low real hCG values in women lacking
evidence of tumor, rising hCG or any evidence of
a. The finding of more than 5-fold differences in clinically active disease.14-16,18
serum hCG results with alternative immunoassays.
In the USA hCG Reference Service, Quiescent GTD is
b. The presence of hCG in serum and absence of diagnosed in cases of persistent low levels of hCG (always <250
detectable hCG or hCG related molecule mIU/mL) with no increasing trend continuing over a period of 3 months or
immunoreactivity in a parallel urine sample (interfering longer (range: 2 months to 9 years)
antibodies are large glycoprotein. that do not cross the
glomerular basement membrane so do not interfere 2. Total hCG and hCG-H are useful in differentiating active
with urine measurements). GTD and quiescent GTD.14,18 (Level II, Grade A)
c. The observation of false positive results in other hCG-H was calculated as the percentage of total hCG (percent
tests for molecules not normally present in serum, hCG-H). At the 25% cut-off, hCG-H proportion discriminated 100% of
such as urine b-core fragment. malignancies from quiescent GTD cases.

d. The finding that a heterophilic antibody blocking 3. It has been inferred that hCG-H is an absolute test for
agent (Scantibodies Inc. HBR) prevented or limited identifying quiescent GTD cases which needs no
false detection (confirmatory criterion). chemotherapy or surgery.14,18 (Level II, Grade A)
e. The finding that the hCG results differ greatly when
In monitoring patients with quiescent GTD, a single
tested undiluted and diluted with serum.
measurement showing the presence of hCG-H is sufficient to
demonstrate the presence of active disease and to initiate
In the cases referred to the USA hCG Reference Service,
chemotherapy.
false positive hCG results range from 2 to 1100 mIU/mL. In all these
cases, treatment was halted even though physician’s laboratory test
PITUITARY hCG
remained positive. False positive results in a specific hCG assay
were observed to remain false positive for 3 or more years.
1. hCG production may be demonstrated in healthy non-
2. Transient decrease in false positive hCG values pregnant women. This hCG has been shown to be
following chemotherapy or surgery may mislead coming from the pituitary gland.19
physicians by wrongly indicating presence of disease
Pituitary hCG accompanies luteinizing hormone (LH) production
and successful therapy of disease.1
at the time of mid-cycle pre-ovulatory surge. Pituitary hCG may also be
normally present alongside LH due to lack of suppression by estrogen
Chemotherapy or surgery can weaken the immune system,
and progesterone, as detected in serum and urine samples of
reducing circulating antibody concentration, leading to decreased false
postmenopausal women.
hCG results.
2. The detection of hCG in postmenopausal women may
create an erroneous assumption of malignant disease,
and lead to unnecessary and expensive invasive testing
or toxic treatments resulting in poor patient outcomes.1
(Level II, Grade A)
In the USA hCG Reference Service, all cases of perimenopausal
and postmenopausal women with measurable hCG tested negative to
hCG-H. PSTT and non-trophoblastic neoplasm were excluded by
showing the absence of hCG free β-subunit. Serum LH and FSH
confirmed menopausal status (>15 mIU/mL and >20 mIU/mL).
3. Treatment with high estrogen contraceptive pill for 3
weeks or longer would suppress hCG production and
confirmed that the source of the persistent low levels of
hCG were menopause and normal pituitary gland
function. (Level II, Grade A)
FREE β-SUBUNIT AND PLACENTAL SITE TROPHOBLASTIC
TUMOR
1. hCG free β-subunit measurements have been found to
discriminate malignant PSTT clnically, from quiescent
GTD and choriocarcinoma.1
PSTT appears to produce hCG subunits in insufficient
concentrations α:β dimmers, as governed by the law of mass action, thus
leading to hCG free β-subunit production. This is evident in PSTT patient
urine samples where high proportions of β-core fragment are detected.
Production of hCG free β-subunit by non-trophoblastic malignancies has
likewise been well established. Hence, non-trophoblastic malignancies
needs to be considered in the differential diagnosis.
2. Proportions of free β-subunit are between 25%-100% in
PSTT cases, >100% in choriocarcinoma/GTN cases and
0-25% in quiescent GTD cases.1 (Level II, Grade A)
DIFFERENTIAL DIAGNOSIS IN WOMEN PRESENTING WITH
PERSISTENT LOW LEVELS OF HCG
The differential diagnosis of different disorders in women presenting
with persistent low levels of hCG is the one of the most common issues in
the management of GTD.
Several diagnoses are considered together with essential
14,15,16,18
parameters (hCG level, medical history, age) that define the disease.
1. False positive hCG (range 0.5-1100 mIU/mL hCG)
2. Quiescent GTD (range 0.5-231 mIU/mL hCG, need history of
spontaneous abortion, ectopic pregnancy or gestational trophoblastic
disease)
3. Pituitary hCG (range 0.5-32 mIU/mL, history of oophorectomy,
amenorrhea, or age of 40 or greater)
4. Choriocarcinoma/Gestational Trophoblastic Neoplasm (range 0.5 –
3,000,000 mIU/mL, history of pregnancy, spontaneous abortion, ectopic
pregnancy or gestational trophoblastic disease, hCG levels should be
inclining)
5. PSTT (range 0.77 – 236 mIU/mL)
6. Non-trophoblastic neoplasm (0-474 mIU/mL hCG (71)
REFERENCES
1. Cole LA. Structurally related molecules of human chorionic
gonadotropin (hCG) in Gestational Trophoblastic Diseases. Reprod Biol
Endocrinol. 2010;8:102.
2. Cole LA, Dai D, Leslie KK, Butler SA, Kohorn EI. Gestational
trophoblastic diseases: 1. Pathophysiology of hyperglycosylated hCG-
regulated neoplasia. Gynecol Oncol 2006 Aug;102(2):144-9.
3. Cole LA, Khanlian SA, Riley JM, Butler SA. Hyperglycosylated hCG
(hCG-H) in gestational implantation, and in choriocarcinoma and
testicular germ cell malignancy tumorigenesis. J Reprod Med 2006
Nov;51(11):919-29.
 4. Lei ZM, Taylor DD, Gercel-Taylor C, Rao CV. Human chorionic
gonadotropin promotes tumorigenesis of choriocarcinoma JAR cells.
Troph Res. 1999;13:147-59.
5. Hamade L, Nakabayashi K, Sato A, Kiyoshi K, Takamatsu Y, Laoag-
Fernandez, JB, Ohara N, Maruo T. Transfection of antisense chorionic
gonadotropin ß gene into choriocarcinoma cells suppresses the cell
proliferation and induces apoptosis. J Clin Endocrinol Metab 2005
Aug;90(8):4873-9.
6. Elliott M, Kardana A, Lustbader JW, Cole LA. Carbohydrate and peptide
structure of the α- and ß-subunits of human Chorionic Gonadotropin from
normal and aberrant pregnancy and choriocarcinoma. Endocrine J, 1997
Aug;7(1):15-32.
7. Kobata A, Takeuchi M. Structure, pathology and function of the N-linked
sugar chains of hCG. Biochim Biophys Acta 1999 Oct 8;1455(2-3):315-
26.
8. Valmu L, Alfthan H, Hotakainen K, Birken S, Stenman UH. Site-specific
glycan analysis of human chorionic gonadotropin ß-subunit from
malignancies and pregnancy by liquid chromatography-electrospray
mass spectrometry. Glycobiology. 2006 Dec;16(12):1207-18.
9. Kovalevskaya G, Genbacev O, Fisher SJ, Caceres E, O’Connor JF.
Trophoblast origin of hCG isoforms: cytotrophoblasts are the primary
source of choriocarcinoma- like hCG. Mol Cell Endocrinol 2002
Aug;194(1-2):147-55.
10. Cole LA, Kardana A, Andrade-Gordon P Gawinowicz MA, Morris JC,
Bergert ER. The heterogeneity of hCG: III. The occurrence, biological
and immunological activities of nicked hCG. Endocrinology 1991
Sep;129(3);1559-67.
11. Cole LA, Shahabi S, Butler SA, Michell H, Newlands ES, Behrman HR,
Verrill HL. Utility of commonly used commercial hCG immunoassays in
the diagnosis and management of trophoblastic diseases. Clin Chem,
2001 Feb;47(2): 308-15.
12. Cole LA, Kohorn EI. The need for an hCG assay that appropriately
detects trophoblastic diseases and other hCG- producing cancers. J
Reprod Med 2006 Oct;51(10):793-811
13. Cole LA ,Sutton JM, Higgins TN. Higgins, Cembrowski GS. Between-
Method Variation in hCG Test Results, Clin Chem 2004 May; 50:874-82.
14. Cole LA, Khanlian SA, Giddings A, Butler SA, Muller CY, Hammond C,
Kohorn E. Gestational trophoblastic diseases: 4. Presentation with
persistent low positive human chorionic gonadotropin test results.
Gynecol Oncol 2006 Aug;102(2):165-72.
15. Cole LA, Khanlian SA Inappropriate management of women with
persistent low hCG results. J Reprod Med 2004 49(6):423-32.
16. Cole LA, Kohorn E, Smith HO. Gestational trophoblastic diseases:
Management of cases with persistent low human chorionic gonadotropin
results. Obstet Gynecol Clin North Am 2005 Dec:32(4):615-26.
17. Knight AK, Bingemann T, Cole L, Cunningham- Rundles C. Frequent
false positive beta human chorionic gonadotropin in Immunoglobulin A
deficiency. Clin Exper Immunol 2005 Aug;141(2):333-7.
18. Cole LA, Butler SA, Khanlian SA, Giddings A, Muller CY, Seckl MJ,
Kohorn EI. Gestational trophoblastic diseases: 2. Hyperglycosylated
hCG as a reliable marker of active neoplasia. Gynecol Oncol 2006
Aug;102(2):151-9.
19. Chen HC, Hodgen GD, Matsuura S, Lin LJ, Gross E, Reichert LE Jr,
Birken S, Canfield RE, Ross GT. Evidence for a gonadotropin from
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 APPENDIX A APPENDIX B
LEVELS OF EVIDENCE AND GRADES OF
RECOMMENDATION
CLINICAL FEATURES PF PSTT, ETT AND
LEVELS DEFINITION CHORIOCARCINOMA
I Evidence obtained room at least one properly randomized
controlled trial.
Feature PSTT ETT Choriocarcinoma
II-1 Evidence obtained from well-designed controlled trials without Clinical Missed Abortion Abnormal vaginal Persistent GTD
randomization. Presentation bleeding after hydatidiform
II-2 Evidence obtained from well-designed cohort or case-control mole
analytic studies, preferably from more than one center or Last known Variable, can be Variable, can be Months
research group. pregnancy or remote remote
GTD
II-3 Evidence obtained from multiple time series with or without the History of mole 5%-8% 14% 50%
intervention. Serum bHCG Low (<2,000 Low (<2,000 High (>10,000
III Opinion of respected authorities, based on clinical experience; mlU/ml) mlU/ml) mlU/ml)
descriptive studies and case reports or reports of expert Behavior Self-limited, Self-limited, Aggressive if
communities. persistent or persistent or untreated
aggressive aggressive
Response to Variable Variable Good
GRADE DEFINITION chemotherapy
A There is good evidence to support the recommendation of the Treatment Surgery Surgery Chemotherapy
practice in the management of gestational trophoblastic (hysterectomy) (hysterectomy)
diseases.
B There is fair evidence to support the recommendation of the
practice in the management of gestational trophoblastic
diseases.
C There is insufficient evidence to recommend for or against the
inclusion of the practice in the management of gestational
trophoblastic diseases.
D There is fair evidence to support the recommendation that the
practice be excluded in the management of gestational
trophoblastic diseases.
E There is good evidence to support the recommendation that
the practice be excluded in the management of gestational
trophoblastic diseases.
GPP A good practice point (GPP) is a recommendation for the best
practice based on the experience of the taskforce.
 APPENDIX C APPENDIX D
PATHOLOGIC FEATURES PF PSTT, ETT AND TROPHOBLASTIC DISEASE SPECIALISTS BY REGION
CHORIOCARCINOMA
NATIONAL CAPITOL REGION
Abad, Leopoldo III M. Laguimin, Ma. Lucia B.
Feature PSTT ETT Choriocarcinoma
Balete, Susan C. Llarena, Raquel T.
Cellular Monomorphic; Monomorphic; Dimorphic;
Cagayan, Ma. Stephanie Fay S. Mondragon, Laureen Honor F.
population implantation site Chorionic-type Primitive
Capito, Lourdes B. Octavio-Cruz, Bernadette R.
intermediate intermediate previllous-type
Castillo, Ma. Del Carmen R. Pastorfide, Greg B.
trophoblastic trophoblastic trophoblastic
Chan, Paulene Trixie C. Quevedo, Ma. Carmen H.
Cell size and Large and Small round and Irregular, highly
Chua, Angelica Anne A. Quiroga, Ma. Cristina O.
shape pleiomorphic uniform variable
Estrella, Agnes S. Ruaro, Marilyn D.
Cytoplasm Abundant and Eosinophilic or Eosinophilic or Ferandez, Estrella S. San Juan, Filomena S.
eosinophilic clear purple Jacinto, Elizabeth K. Sarmiento, Diana L.
Growth pattern Infiltrating single Epitheloid nests Dimorphic, Jocson, Milagros T. Torres, Mary Carol C.
cells or or cords or solid mononucleate Lagrosa, Editha A. Trinidad, Anne Marie C.
confluent sheets masses trophoblast and CORDILLERA ADMINISTRATIVE REGION
syncytiotrophoblast Oras, Celestrell May W. (Benguet)
Margin Infiltrating Circumscribed; Circumscribed; REGION II
expansile expansile Par, Carolyn P. (Nueva Vizcaya)
Hemorrhage Focal or Usually present Massive and Tolentino, Criseline D. (Cagayan Valley)
haphazard central REGION III
Cellular Usually absent Extensive Extensive Dy, Mary Ruth E. ( Bulacan )
necrosis REGION IV
Calcification Absent Usually present Absent Burog, Honorata Lalaine P. ( Batangas )
Vascular From periphery Absent From lumen to Evangelista, Nelia B. ( Cavite )
invasion to lumen periphery Fortun, Vincent Lohengrin ( Cavite )
Fibrinoid Present Present Absent Gacoba, Ma. Cresencia R. ( Laguna )
change Delos Santos, Rosalee T. (Laguna, Palawan)
Mitosis Variable; 0-6/10 Variable; 1- High; 2-22/10 HPF Solamo, Joyce Ruth T. (Rizal)
HPF 10/10 HPF REGION V
Associated Absent Absent absent Bislumbre, Aileen Frances ( Naga )
chorionic villi Tabio, Rowena J. ( Lucena )
REGION VI
Cosculluela, Ma.Irene Josefa ( Bacolod )
Dy, Ma. Theresa G. ( Iloilo )
Magallanes, Maria Suyen O. (Bacolod)
REGION X
Quiño, Quennie S. (Cagayan de Oro)
REGION XI
Lu-Lasala, Lynnette ( Davao )