Philippine Society for the

Study of Trophoblastic Diseases, Inc

CLINICAL PRACTICE GUIDELINES

FOR THE
DIAGNOSIS AND MANAGEMENT OF
GESTATIONAL TROPHOBLASTIC DISEASES

November, 2011

1
 DISCLAIMER, RELEASE AND WAIVER OF RESPONSIBILITY

This is the Clinical Practice Guidelines (CPG) on Diagnosis and Management of Gestational
Trophoblastic Diseases, Second Edition, November 2011.
This is a publication of the Philippine Society for the Study of Trophoblastic Diseases, Inc.
(PSSTD).
This is the ownership of the PSSTD, its officers, and its entire membership.
The obstetrician-gynecologist, the general practitioner, the patient, the student, the allied medical
practitioner, or for that matter, any capacity of the person or individual who may read, quote, cite,
refer to, or acknowledge, any, or part, or the entirety of any topic, subject matter, diagnostic
condition or idea/s willfully release and waive all the liabilities and responsibilities of PSSTD, its
officers and general membership, as well as its Ad Hoc Committee on the Clinical Practice
Guidelines and its Editorial Staff in any or all clinical or other disputes, disagreements, conference
audits/controversies, case discussions/critiquing.
The reader is encouraged to deal with each clinical case as a distinct and unique clinical condition
which will never fit into an exact location if reference is made into any or all part/s of this CPG.
The intention and objective of CPG is to serve as a guide, to clarify, to make clear the distinction.
It is not the intention or objective of this CPG to serve as exact and precise answer, solution and
treatment for clinical conditions and situations. It is always encouraged to refer to the individual
clinical case as the one and only answer to the case in question, not this CPG.
It is hoped that with the CPG at hand, the clinician will find a handy guide that leads to a clue, to a
valuable pathway that leads 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,
2009, this CPG is meant to make each one of us a perfect image of Christ, the healer.

2
 TABLE OF CONTENTS

CONTENT PAGE NUMBER

Foreword 4
Message 5
PSSTD Officers 2011-2012 6
PSSTD General Membership 7
Ad Hoc Committee for the Clinical Practice Guidelines 8
CLINICAL PRACTICE GUIDELINES
Hydatidiform Mole 9
Gestational Trophoblastic Neoplasia 18
Placental Site Trophoblastic Tumor 24
Epithelioid Trophoblastic Tumor 29
Human Chorionic Gonadotropin 32
Appendix
Levels of Evidence and Grades of 39
Recommendations
Trophoblastic Disease Specialists by Region 40

3
FOREWORD

4
 MESSAGE

Congratulations to the officers and members of the Board of Trustees of the Philippine Society for the Study of
Trophoblastic Diseases for taking the initiative of updating the Clinical Practice Guidelines on Trophoblastic
Diseases. This will be a welcome reference for the OB-GYN practitioners in the management of their patients
with Trophoblastic Diseases. I commend the work and effort of the authors, contributors and reviewers. May
you continue to strive to improve the quality of care of patients by keeping up with recent advances in the
management, which are evidence-based.

Sylvia A. Carnero, MD
President, POGS

5
PHILIPPINE SOCIETY FOR THE STUDY OF
TROPHOBLASTIC DISEASES, INC

OFFICERS 2011-2011

MA. CARMEN H. QUEVEDO, MD

President

FILOMENA S. SAN JUAN, MD, PhD

Vice President

AGNES S. ESTRELLA, MD, MHPEd

Secretary

MARILYN D. RUARO, MD
Treasurer

ANNE MARIE C. TRINIDAD, MD

Auditor

MA. DEL CARMEN R. CASTILLO, MD

PRO

BOARD OF MEMBERS

LEOPOLDO M. ABAD III, MD

QUENNIE S. QUIÑO, MD
DIANA L. SARMIENTO, MD

6
 PHILIPPINE SOCIETY FOR THE STUDY OF
TROPHOBLASTIC DISEASES, INC

LIST OF MEMBERS
2011

Abad, Leopoldo III M. Laguimin, Ma. Lucia B.

Balete, Susan C. Lasala, Lynette L.
Bislumbre, Aileen Frances B. Llarena, Raquel T.
Burog, Honorata P. Magallanes, Maria Suyen O.
Cagayan, Ma. Stephanie Fay S. Mondragon, Laureen Honor F.
Capito, Lourdes B. Octavio-Cruz, Bernadette R.
Castillo, Ma. Del Carmen R. Oras, Celestrell May W.
Chan, Paulene Trixie C. Par, Carolyn P.
Chua, Angelica Anne A. Pastorfide, Greg B.
Cosculluela, Ma. Irene Josefa G. Quevedo, Ma. Carmen H.
Delos Santos, Rosalee T. Quiño, Queenie S.
Dy, Mary Ruth E. Quiroga, Ma. Cristina O.
Dy, Ma. Theresa G. Ruaro, Marilyn D.
Estrella, Agnes S. San Juan, Filomena S.
Evangelista, Nelia B. Sarmiento, Diana L.
Ferandez, Estrella S. Solamo, Joyce Ruth T.
Fortun, Vincent Lohengrin A. Tabio, Rowena J.
Gacoba, Ma. Cresencia R Tolentino, Criseline D.
Jacinto, Elizabeth K. Torres, Mary Carol C.
Jocson, Milagros T. Trinidad, Anne Marie C.
Lagrosa, Editha A.

7
AD HOC COMMITTEE FOR THE CLINICAL PRACTICE GUIDELINES

CHAIR AND EDITOR

Ma. Carmen H. Quevedo, MD

MANAGING EDITOR

Agnes S. Estrella, MD, MHPEd

MEMBERS

Stephanie Fay S. Cagayan, MD Elizabeth K. Jacinto, M.D.

Lourdes B. Capito, MD Milagros T. Jocson, MD
Paulene Trixie C. Chan, MD Raquel T. Llarena, MD
Ma. Bernadette O. Cruz, MD, MSc Laureen Honor F. Mondragon, MD
Estrella Sebe S. Fernandez, MD Anne Marie C. Trinidad, MD

8
 HYDATIDIFORM MOLE

Agnes S. Estrella, MD, MHPEd and Raquel T. Llarena, MD

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

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 central pathology review.6,7

The reported worldwide incidence of HM is 1-2 per 1,000 pregnancies.1 However, for reasons that are still not
understood, the incidence of molar pregnancy in Southeast Asia remains to be 7 to 10 times higher than in Europe or
North America.6Indonesia has one of the highest reported incidence rates, 1 in 77 pregnancies (1 in 57 deliveries). 8,9

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

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

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
8
HM is about 200 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 with 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
12
pregnancy. After the first HM, a 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 and those who have conceived twin
pregnancies.8,9A higher rate of HM has been observed after artificial insemination by donor compared with
normally conceived pregnancies.9

9
 4. Racial Factors
Due to differences in the geopgraphical distribution, race or ethinicity 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 Filipinos, 16.5 in
Japanese, 8.0 in Caucasians, and 7.7 in Hawaiians.13

5. Diet and Nutrition

Studies regarding the role of nutrition in the development of GTD are inconclusive. Some have cited that
11,14
decreased dietary carotene and 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 of vaginal bleeding (in 89-97% of cases),a uterine size more than the 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 insufficiency (2%).1,3,4,5,10,15

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 after
histologic examination of the curettage specimen.16

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 villous
change occurs.16This 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 reliable.1
16
Ultrasound diagnosis of PHM is less accurate and nearly 70% of 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 the gestational sac >1.5.17 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
anomalies attached to a hydropic placenta.4

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 pregnancy.18Patients 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
4
PHM less commonly 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)

10
 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 examination
irrespective of ultrasound findings.1,6,19

In the classic, fully developed complete hydatidiform mole, pathological examination shows swollen villi
often with marked circumferential villous trophoblast. Clusters of similar cyto- and syncytiotrophoblast and some
intermediate trophoblast 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 villi, there is compression
of other components of villous stroma beneath the cytotrophoblastic layer, which shows few or no blood vessels.
This hydropic change tends to be generalized.20

In partial mole, the characteristic changes affect only part of the placenta. A fetus, often with congenital
20
malformations is frequently found and excessive 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 cytotrophoblast and villous mesenchyme in the placenta of all gestations except
androgenetic complete moles.21,22

PHLDA2 is another maternally imprinted gene that is present in partial moles and absent in complete
moles and has been also shown to be useful for facilitating differentiation between the two. 23

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 CHM and PHM.24

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 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) and
urinalysis.6,18,19,24

A baseline chest x-ray (PA and Lateral) helps rule out metastatic lesions and complications from molar
pregnancy such as pulmonary hemorrhage, congestion and infection.6,18

The preoperative evaluation should also include blood typing and crossmatching, serum hCG level, and
24
electrocardiogram if appropriate.

11
 3. Surgical evacuation of molar products is the definitive management of hydatidiform
moles.(Level III, GPP)
4,6,7,18,19,24
a. Suction curettage is the preferred method to evacuate molar products regardless of uterine size.
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 little supporting evidence of such a risk.4,5,24
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. Specimen
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 U 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 and dissemination of trophoblastic cells.1,6,7,18,19 Instead, laminaria tent may be
used to dilate the cervix pre-operatively without the risk of tumor embolization.

e. Use of hysterometer for 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 expressed on trophoblast.4,6,7,,18,19,24
19
g. Routine repeat curettage after the diagnosis of a molar pregnancy is not warranted.

h. Hysterectomy with mole in-situ may be considered for patients who have completed the desired family
size or have life threatening hemorrhage.1,4,6,7, 19Removal 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-evacuation monitoring of HCG should still be
1,4,6,19
done.

i. Theca lutein cysts are best left alone during laparotomy. They regress spontaneously within 8-12 weeks
post evacuation.26

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% and 0.5-4%, respectively.1,4
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:

12
 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 trophoblastic proliferation: preeclampsia,
thyrotoxicosis, pulmonary insufficiency and disseminated intravascular coagulopathy

Randomized trials have shown that the use of chemoprophylaxis at the time of evacuation of high risk
CHM significantly decrease the development of GTN from approximately 50% to 10-15%.27-29 Therefore, women
at high risk for malignant degeneration should be identified and offered chemoprophylaxis. This should also be
3,4
administered in situations when hCG monitoring is not available or follow up is unreliable.

2. Methotrexate is the drug of choice for chemoprophylaxis. (Level III, Grade C)

Methotrexate is administered intramuscularly, and not in oral form. Actinomycin D may be given in the
presence of hypersensitivity to Methotrexate or liver toxicity. For chemoprophylaxis, only 1 course is given. The
following are the contraindications to chemoprophylaxis:

a. Hemoglobin <100mg/dl, hematocrit <0.30

b. WBC count <3 x 109
c. Absolute neutrophil count(ANC) <1.5
d. Platelet count <100
e. Any active infection
f. Presence of liver or renal dysfunction

3. Administration of chemoprophylaxis does not obviate the need for post-evacuation hCG
surveillance. (Level III, GPP)

Chemoprophylaxis does not completely eliminate the possibility of postmolar gestational trophoblastic
neoplasia. Monitoring of hCG levels remains to be the mainstay in the diagnosis of any malignant sequelae
following a molar pregnancy.

FOLLOW UP

1. After molar evacuation, all patients must have serial βhCG monitoring to detect
malignant degeneration.(Level III, GPP).

Serum ß-hCG level is measured 1 week after molar evacuation, then every 2 weeks until the level
becomes normal (<5miu/ml). After 3 consecutive biweekly normal levels, the monitoring is every month for 6
months, then at two monthly intervals for the next six months to insure that the hCG levels remain undetectable
for one year following remission. More than half of patients will have complete regression of hCG to normal within
24
two months of evacuation.

2. It is important to use a reliable contraception during the entire follow up period (Level
III, Grade C).

An essential component in the follow-up of patients who had molar disease is the use of an effective
contraception. This eliminates the potential confusion that arises in the interpretation of a rising hCG in a patient
not using a reliable form of contraception.

A low-dose combined oral contraceptive pill is the preferred method of artificial contraception because
they have the advantage of suppressing endogenous LH, which may interfere with the measurement of hCG at
24
low levels. Data from a prospective trial and other studies have shown that the use of oral contraception is safe
and does not increase the risk of gestational trophoblastic neoplasia.30,31

13
PREGNANCIES AFTER A MOLAR PREGNANCY

1. Pregnancy may be allowed after 6 months of normal serum ß-hCG level (Level III, Grade
C).
6
Persistent trophoblastic disease are diagnosed within six months of molar evacuation. Moreover, studies
have shown a negligible risk of PTD once normal hCG values are reached. 32-33 As such, it would be safe to allow
patients to get pregnant six months after achieving normal hCG levels.

2. For every succeeding pregnancy, an early ultrasound should be performed because of

the risk of another molar pregnancy. (Level III, Grade C)

Majority of women who have been treated for hydatidiform mole are in the prime of their reproductive
years, and many desire future child bearing. Studies have shown that after a molar pregnancy, the risk of another
molar pregnancy rises to 1-2%8. After 2 molar gestations, the risk for a third mole is 15-20%.12 This risk is not
decreased by a change in sexual partner,34 or the gestational age when the molar pregnancy was evacuated.35The
risk for stillbirth, prematurity, spontaneous abortion, and congenital malformation is similar to that in the general
population.12 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.
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 necessary treatment. 18

3. For each succeeding pregnancy following a molar gestation, βhCG should be monitored
at 6 weeks postpartum (Level III, GPP).

Determination of the βhCG level should be done six weeks after each succeeding pregnancy to detect
any occult gestational trophoblastic neoplasia.

4. Placenta in subsequent pregnancies should be submitted for histopathologic

examination (Level III, GPP).

Histopathologic examination of the placenta of subsequent pregnancies is done for early detection of an
occult GTN.

IN THE PRESENCE OF THE FOLLOWING, IMMEDIATE REFERRAL TO A TROPHOBLASTIC

DISEASE SPECIALIST SHOULD BE DONE:

1. High levels of ßhCG more than 4 weeks post-evacuation (serum level of 20,000mIU/ml; urine level of 30,000 mIU/ml)
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

14
 ALGORITHM FOR THE DIAGNOSIS AND MANAGEMENT OF HYDATIDIFORM MOLE

Clinical History and Pelvic Ultrasound Serum ßhCG titer

Physical Examination

HYDATIDIFORM MOLE

Completed Family Size

Total Hysterectomy + Suction Curettage

BSO

With Risk
No Risk Factor
Factor

Chemoprophylaxis Post-evacuation hCG

Monitoring
(under the supervision of
trophoblastic disease
specialist)

Spontaneous Gestational Trophoblastic

Resolution Neoplasia

REFER TO A TROPHOBLASTIC
DISEASE SPECIALIST

15
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rd
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p57kip2 immunohistochemical expression and ultrastructural findings of gestational trophoblastic disease and
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Reprod Med. 2004 Aug;49(8):630–636.
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Dec;2003(6):531-9.
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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.
16
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.

17
 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 vary. . 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 epithelioid
trophoblastic tumor.4

DEFINITION OF HISTOLOGIC TERMS

Invasive Mole (IM): a tumor or tumor-like process invading the myometrium and characterized by trophoblastic
hyperplasia and persistence of placental villous structures 5

Choriocarcinoma (ChorioCA): an epithelial malignancy of trophoblastic cells formed by the abnormal proliferation of
6
cytotrophoblasts and syncitiotrophoblasts in the absence of chorionic villi

Placental Site Trophoblastic Tumor (PSTT): a rare neoplastic proliferation of intermediate trophoblasts that invade the
myometrium at the placental site after a pregnancy 7

Epithelioid Trophoblastic Tumor (ETT): a rare trophoblastic neoplasm which is the malignant counterpart of the
intermediate trophoblasts of the chorion laeve8

DIAGNOSIS

1. The clinical presentation of GTN is more important in determining treatment and

outcome than the precise histologic diagnosis. (Level III) 5,6

Patients may present with any of the following signs and symptoms:

a. Vaginal bleeding
b. Anemia
c. Uterine enlargement
d. Acute abdomen secondary to tumor perforation
e. Infection

18
 2. One must search for signs and symptoms pertaining to the site of metastasis (GPP).
5,6,7

In the presence of a suspicious vaginal mass, biopsy should not be done as hemorrhage from the biopsy
site may ensue.

Patients may present with signs and symptoms of respiratory distress or pulmonary insufficiency
indicative of pulmonary metastasis.

Metastatic tumors may bleed and present as hemoptysis, cerebrovascular accident and intraperitoneal
bleed.

Lateralizing neurologic signs may be evidence of CNS metastasis.

DIAGNOSTIC TESTS

1. Serum β human chorionic gonadotropin (βhCG) should be obtained initially for

diagnosis and subsequently for monitoring. (Level III, Grade A) 5,10

2. Transvaginal sonography is helpful to determine the extent of disease and monitor

response to treatment. (Level III, Grade C) 9
Color flow doppler can define regions of increased vascularity representative of invasive disease and
enhanced uterine perfusion.

3. Initial evaluation should include work up for anemia, preeclampsia, electrolyte

imbalance, infections and hyperthyroidism. (Level III, GPP)11

Laboratory examinations include CBC with differential and platelet counts, blood typing, liver function test
(ALT & AST), renal function test (BUN & creatinine), thyroid function test (FT3, FT4, TSH) and urinalysis.

4. Complete metastatic work-up must establish whether the disease is locally invasive or
metastatic and whether the risk of therapeutic failure is high or low. (Level III, GPP) 5,11

The pattern of metastatic spread is hematogenous, and metastasis to the lungs is the most common,
therefore baseline Chest x-ray (PA and Lateral) helps rule out metastatic lesions 12

Systemic dissemination to the liver should be sought through ultrasound of the whole abomen.
11,13
Organ-specific computed tomography (CT) scan or magnetic resonance imaging (MRI) as needed.

MANAGEMENT

1. All patients must be staged and scored using the FIGO 2000 Anatomic Staging and
WHO Prognostic Scoring System (Tables 3 and 4). (GPP)

The FIGO anatomic staging system defines the extent of disease while the WHO prognostic scoring
13,14,15
system predicts the possible resistance of the tumor to single-agent chemotherapy.

Table 2.1 FIGO 2000 Anatomic Staging

STAGE I Disease confined to the uterus

STAGE II Disease extends to outside the uterus but
confined to the pelvic organs
STAGE III Pulmonary metastases

19
 STAGE IV Metastases to other sites

Table 2.2 WHO Prognostic Scoring System

Prognostic SCORE
Factors 0 1 2 4
Age (years) <40 ≥40
Antecedent Mole Abortion Term
Pregnancy
Pregnancy <4 4-6 7-12 >12
Interval
(Months)
Beta-hCG titer <1,000 1,000- 10,000- >100,000
(mIU/ml) <10,000 100,000
Largest tumor, <3 3 to 5 >5
in cm.
including the
uterine tumor
Site of Spleen, GI tract Liver,
metastases kidney Brain
Number of 1-4 5-8 >8
metastases
Prior Single >2 agents
chemotherapy agent

Interpretation: Low risk < 7, High risk : ≥7

2. Unlike other cancers, treatment can be started without histopathologic confirmation of

the disease.5 Chemotherapy is the principal mode of treatment. Surgery and irradiation
are adjunctive treatments. (Level III, Grade C) 5,7,16

3. Nonmetastatic and low-risk metastatic patients (Stage I, Stage II low risk & Stage III low
risk) are almost always ultimately cured using single agent chemotherapy using
methotrexate with or without folic acid rescue or dactinomycin. (Level I, Grade A) 17,18,19

4. Combination chemotherapy EMACO (Etoposide, Methotrexate, Actinomycin D,

Cyclophospahamide and Vincristine) has been the widely accepted treatment regimen
for high-risk patients (Stage II high risk, Stage III high risk & stage IV). (Level III) 22,23

5. Patients who relapse after their treatment or become resistant to drugs are given
salvage chemotherapy. (Level III) 24,25

When resistance develops with EMACO several regimens may be used. Etoposide, Methotrexate,
Actinomycin D and Cisplatin (EMACE), Carboplatin-Paclitaxel, Ifosfamide, Cyclophosphamide, Etoposide(ICE) or
Cisplatin, Vinblastine and Bleomycin (PVB) combination may be given. Salvage therapy may also be instituted by
substituting Cisplatin and Etoposide (EMA-EP). 26

6. Clean-up or consolidation therapy consists of 2 cycles for low risk and 3 cycles for high
risk, after the first normal hCG value(<5 mIU/mL). (Level III)

7. Surgery is an adjunctive treatment for appropriately selected patients in order to reduce

tumor load and decrease the number of chemotherapeutic courses. (Level III, Grade
C)16,27,28

20
 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 and
pelvis before the resection is performed. 8

Craniotomy may be indicated for decompression of brain metastasis with signs and symptoms of
8,29
increased intracranial pressure. 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 – -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. -hCG is determined monthly for the 1 st 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 1 st 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)

21
 ALGORITHM FOR THE
DIAGNOSIS AND MANAGEMENT OF
GESTATIONAL TROPHOBLASTIC NEOPLASIA

Clinical History and Serum - Radiograph and Imaging

Physical Examination hCG titer Modality

Gestational Trophoblastic Neoplasia

Referral to Trophoblastic Disease

Specialist

Stage I Stage II/III Stage IV

Low Risk High Risk

Single Agent Chemotherapy + EMACO Irradiation

Hysterectomy +Hysterectomy

REFERENCES:
1. Ngan S, Seckl MJ. Gestational trophoblastic neoplasia management: an 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 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 Dec;17(6):893-903.
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,
nd
editors. Principals and Practice of gynecologic oncology. 2 ed. Philadelphia (PA): Lippincott- 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 the New England Trophoblastic Disease Center. Gynecol Oncol 2001 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: diagnosis with doppler ultrasound.
Radiology 1987;165:445-448.

22
10. Cole LA., Kohorn EI, Kim GS. Detecting and monitoring trophoblastic disease. New perspectives on measuring
human chorionic 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 neoplasia 2000. Int J Gynecol Obstet 2002
Jun; 77(3):285-7.
15. Kohorn El, Goldstein, DP, Hancock BW, et al. Combining the staging system of the International Federation of
Gynecology and Obstetrics with the scoring system of the World Health Organization for trophoblastic neoplasia.
Report of the Working Committee of the International Society for the Study of Trophoblastic Disease and the
International Gynecologic Cancer Society. Int J Gynecol Cancer 2000: 10, 84-88.
16. Hammond CB, Weed JC Jr, Currie JL. The role of operation in the 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.
27. Lehman E, Gershenson DM, Burke TW, Levenback C, Silva EG, Morris M. Salvage surgery for chemorefractory
gestational trophoblastic disease. J Clin Oncol 1994 Dec;12(12):2737-42.
28. Suzuka K, Matsui H, Iitsuka Y, Yamazawa K, Seki K, Sekiya S. Adjuvant hysterectomy in low-risk gestational
trophoblastic disease. Obstet Gynecol 2001 Mar;97(3):431-4.
29. Evans AC Jr, Soper JT, Clarke-Pearson DL, Berchuck A, Rodriguez GC, Hammond CB. Gestational trophoblastic
disease metastatic to the central nervous system. Gynecol Oncol 1995 Nov;59(2):226-30.

23
 PLACENTAL SITE TROPHOBLASTIC TUMOR
Paulene Trixie C. Chan, MD, Agnes S. Estrella, MD, MHPEd
Estrella Sebe S. Fernandez, MD, Elizabeth K. Jacinto, MD

DEFINITION

Placental site trophoblastic tumor (PSTT) is a neoplastic proliferation of intermediate trophoblasts that invades the
1
myometrium at the implantation site. Because PSTT is rare, information on its natural history is limited.

INCIDENCE

The incidence of PSTT is reported at around 1 – 2% of trophoblastic tumors.2 Since it was first described by
Kurman et al in 1976, less than 100 cases have so far been reported in literature.2 Based on the Philippine Obstetrical
and Gynecological Society statistics, there were only 18 cases reported from 2001-2009.

PSTT affects women in the reproductive age group with a mean age at diagnosis between 31 to 33 years. 2,3 It
may arise from any form of pregnancy although term delivery is the most frequent antecedent pregnancy, followed by
abortion, hydatidiform mole and ectopic pregnancy.2

CLINICAL PRESENTATION
The clinical presentation of patients with PSTT is similar to the signs and symptoms of patients with other forms of
gestational trophoblastic disease. Symptoms may present weeks to years after the antecedent pregnancy, with irregular
vaginal bleeding following a period of amenorrhea being the most common presenting symptom. 1-5 Often, an
asymmetrical enlarged uterus may be found. Patients may also report signs and symptoms referable to the site of
metastasis.6 Other reported manifestations include nephritic syndrome, galactorrhea, polycythemia, hematuria and
2,3,5
virilization.

It has been reported that > 50% (44-69%) are diagnosed with Stage I Disease confined to the uterus while the
rest are metastatic in nature.4 The most common site of metastasis is the lung, followed by the vagina and liver.2,4 Other
reported sites are the ovaries, lymph nodes, brain, stomach, spleen, bowel, bladder, kidneys and skin.2,4

PROGNOSTIC FACTORS

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 survival rate 0f 93.5% compared to those patients with a diagnosis of FIGO III
and IV who had a survival rate 33.3%7. Moreover, only 5% of patients with early stage disease will have
recurrence of disease while 70% of stage III and 90% of stage IV patients will be diagnosed with recurrence. 4

2. Interval From The Antecedent Pregnancy

The interval from the last known antecedent pregnancy appears to be the second major prognostic factor
in PSTT. Studies have reported that an interval from the previous pregnancy of more than two years appeared to
2,8
be an independent adverse prognostic factor.

3. Mitotic count
Mitotic count is not a reliable factor in predicting the clinical course of patients with PSTT. In earlier
reports, patients who had poor outcomes had a mitotic count of more than 5 per high power field. However,
recent findings have shown that tumors with low mitotic counts also had the potential to metastasize.8

24
 4. Others
Other poor prognostic factors reported in literature include age more than 35 years, higher gravidity and
term deliveries with female fetuses. Microscopically, implication of poor prognosis include a depth of tumor
invasion and vascular space involvement.2,3,4 These however 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 below
500mIU/ml in 58%.3,6 This is explained by the predominance of intermediate trophoblasts which produce little
hCG compared to the syncythiotrophoblasts.4 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 were suggested.9

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 hypovascular type.1,3 If the plan of management is local resection, ultrasound, MRI and/or PET
scan may be used to accurately determine the size and location of the tumor and identify site of residual tumor.3

6. Histopathologic examination is very important in the diagnosis of PSTT. (Level III, GPP)
25
 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 solid, often
fleshy, and usually yellow or tan surface.11,12,13

Microscopic: PSTT is characterized by a monomorphic cell population of implantation site intermediate

11,12,13
trophoblasts that separate 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

The rarity of this disease and its variable clinical course has made the establishment of treatment
guidelines difficult.

1. The following medical complications should be promptly recognized and treated. (Level III,
GPP)
b. Anemia
c. Preeclampsia
d. Hyperthyroidism
e. Electrolyte imbalance
f. Pulmonary insufficiency
g. Disseminated intravascular coagulopathy

2. The following laboratory tests are done to determine the extent of the disease and as
prerequisites before institution of chemotherapy. (Level III, GPP)
a. CBC with platelet count
b. Blood typing
c. Liver profile (ALT, AST)
d. Renal function test (BUN, creatinine)
e. Thyroid function test (FT3, FT4, TSH)
f. Serum electrolytes
g. Urinalysis
h. Ultrasound of the Whole Abdomen and transvaginal pelvic ultrasound with color flow
Doppler
i. Chest x-ray (PA and lateral)
j. Organ-specific computed tomography (CT) scan or magnetic resonance imaging (MRI)
as needed, or in the following instances:
i. Chest CT scan with contrast is requested when baseline chest x-ray is normal.
ii. Brain CT scan with contrast is requested in a neurologically asymptomatic patient
when chest radiograph demonstrates lesion(s) at least 3 cm in diameter.

3. After a complete metastatic work-up, all patients are staged using the FIGO 2000 Staging
system.

The FIGO 2000 Staging of Gestational Trophoblastic Disease is 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 with
outcome.1,3,14

4. Unlike choriocarcinoma or invasive mole, surgery is the primary treatment for PSTT.1,2,3,4 (Level
III, GPP)
26
 a. PSTT is relatively resistant to chemotherapy. As such, surgery remains the cornerstone in management,
1,2,3,14
with total hysterectomy being the optimal therapy for both metastatic and non-metastatic disease.
Because metastasis to the ovaries is rare, these may be left behind if grossly normal, especially since
most of the patients with PSTT are less than 40 years old.4

b. Among patients who are desirous of pregnancy and with disease limited to the uterus, conservative
surgical management in the form of curettage or resection of the uterine mass by laparotomy,
laparoscopy or hysteroscopy may be performed.3,4

c. In cases when resection of the uterine mass is contemplated, an ultrasound with Doppler, MRI, and/or
6
PET scan should be performed pre-operatively to identify the size, location and vascularity of the tumor.

d. The role of pelvic and para aortic lymphadenectomy is unclear especially if surgery is done in early
disease.2,4 In a recent report, however, lymph node dissection has been recommended because of the
tendency for lymphatic spread in PSTT.15

5. Chemotherapy may be given for patients with early stage disease associated with poor
prognostic factors (interval > 2 years, volume of disease and mitotic count >5/10hpf) or
in patients with advanced stage disease.1-5, 15 (Level III, GPP)

EMACO is the most frequently used and reported primary multi-agent chemotherapy with quoted total
response rate of 71% and a complete response rate of only 38%. 14 EMA EP is given for patients resistant to, or
relapse after EMACO.2,14 Alternative salvage therapies 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 technically possible. 3 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 poor
prognostic variables.4

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 recommendations can be
1,3
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)
st
After biochemical remission, serum hCG must be done every month for the 1 6 months of follow-up,
nd
then every two months for the 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)

27
 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.
12. Shih IM, Mazur M, Kurman R. Gestational trophoblastic disease and related lesions. In Kurman RJ (Ed)
Blaustein's Pathology of the Female Genital Tract, 5th edition. Springer; 2002. Chapter 24:1193-1247.
13. Shih IM, Kurman RJ. Pathology of intermediate trophoblastic tumors and tumor-like lesions. Int J Gynecol Pathol
2001 Jan;20(1):31-47.
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 management of gestational trophoblastic
neoplasia. Am J Obstet Gynecol 2011 Jan;204(1):11-18.

28
 EPITHELIOID TROPHOBLASTIC TUMOR
Paulene Trixie C. Chan, MD, Estrella Sebe S. Fernandez, MD
Elizabeth K. Jacinto, MD

DEFINITION

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
1,2
having an epithelioid appearance.

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 years.1,2,3 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 median age of 38 years.4

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 vaginal bleeding. 1,2,4

The site of ETT lesion(s) are as follows: Uterine corpus (30%), lower uterine segment (50%),
extrauterine: lungs (20%), small bowel. Because of the tendency of ETT to grow in the lower uterine
segment and the cervix, an initial diagnosis of carcinoma of the cervix may be made and has to be
ruled out.1,2 The most common site of metastasis is the lungs. 4

4. Prognostic factors are difficult to identify because of the small number of cases and the
short period of follow-up reported.4

Studies show that histopathologic features like tumor size, extent of necrosis and cytologic atypia have no
relation to the aggressive behavior in ETT. Even high mitotic index and level of serum hCG were not shown to be
associated with malignant behavior in ETT.4

DIAGNOSIS

1. In ETT, there is elevated but generally low serum β-hCG.1,2,4 (Level III, GPP)

In a review of cases, majority of patients presented with βhCG levels below 2500IU/l (69%). There were
a small number of patients (14%) reported to have normal hCG levels below 2.0 IU/l. 4

2. Histopathologic examination is important in the diagnosis of ETT. (Level III, GPP)

29
 Gross: Solitary, discrete nodules that deeply invade the cervix and myometrium are usually seen. On cut-
surface, it is either solid or cystic. Solid areas are typically tan to brown, with varying amounts of hemorrhage and
7
necrosis.

Microscopic: In ETT, monomorphic cell population of the chorionic-type intermediate trophoblastic cells
arranged in nests and cords are seen with a predominantly nodular architecture distinguishing it from
choriocarcinoma and PSTT. The masses of cells are intimately associated with eosinophilic, fibrillar hyaline-like
material and necrotic debris. Typically, small blood vessels are located within the center of the tumor. Apoptotic
7
cells and apoptotic bodies are diffusely distributed throughout the tumor.

Immunochemistry: ETT stains diffusely positive with pLAP (placental alkaline phosphatase) and
cytokeratin and only weakly positive with hCG and hPL. It is reported to be positive also in epithelial membrane
8
antigen and inhibin. p63 which is positive in ETT is useful in differentiating ETT from PSTT.

MANAGEMENT

1. The following baseline laboratory examinations are done to determine the extent of
disease and/or for chemotherapy prerequisites. (Level III, GPP)

a. CBC with differential and platelet count

b. Blood typing
c. Transvaginal pelvic ultrasound with color flow doppler
d. Pre-treatment diluted serum β-hCG
e. Liver transaminases
f. Renal function test (BUN, creatinine)
g. Thyroid function test (FT3, FT4, TSH)
h. Urinalysis
i. Chest x-ray (PA and lateral)
j. Metastatic work-up (as outlined in the GTN section)

Other examinations (if indicated):

a. Serum electrolytes
b. 2-lead ECG

2. Epithelioid trophoblastic tumor may not be responsive to chemotherapy.

(Level III, GPP)

ETT may be considered in patients initially diagnosed to have GTN but unresponsive to chemotherapy.
1,2,3,4
Further histologic examinations are recommended in these patients. Hysterectomy and lung 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.

However, in those patients with multiple sites of metastases or associated medical conditions where
surgery cannot be performed, chemotherapy may be considered.4 There has been no recommendation as to the
type of chemotherapy because of the paucity of cases.

The effectiveness of curettage and chemotherapy for the treatment of early lesions requires further
evaluation.

FOLLOW UP

The same follow-up schedule as in PSTT is recommended for ETT patients who have
completed treatment. (Level III, GPP)

30
REFERENCES

1. 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);1393-1403.
2. Vencken PMLH, Ewing PC, Zweener RP. Epithelioid trophoblastic tumour: A case report and review of the
literature. J Clin Pathol 2006 Dec;59(12):1307-8.
3. Coulson LE, Kong C, Zaloudek C. Epithelioid trophoblastic tumor of the uterus in a postmenopausal woman: a
case report and review of literature. Am J Surg Pathol 2000 Nov; 24(11):1558-62.
4. Palmer JE, Macdonald M, Wells M, Hancock BW, Tidy JA. Epithelioid Trophoblastic Tumor: A Review of the
Literature. J Reprod Med 2008 Jul;53(7):465-475.
5. Shen DH, Khoo US, Ngan HY, Ng TY, Chau MT, Xue WC, Cheung AN. Coexisting epithelioid trophoblastic
tumor and choriocarcinoma of the uterus following a chemoresistant hydatidiform mole. Arch Pathol Lab Med
2003 Jul;127(7);e291-3.
6. Sternberg S. Diagnostic Surgical Pathology. Fourth edition. Lippincott Williams & Wilkins 2004.
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.
8. Sebire NJ, Lindsay I, Paradinas F. Pathology. In Gestational trophoblastic disease, 3rd edition, by Seckl MJ,
Berkowitz, RS, Cole LA Hancock BW. 2010:97-147.

31
 HUMAN CHORIONIC GONADOTROPIN
Lourdes B. Capito, MD and Laureen Honor F. Mondragon, MD

1. Human chorionic gonadotropin (hCG) is a glycoprotein hormone that comprises two

dissimilar subunits ( -subunit of 92 amino acids and a - subunit of 145 amino acids) with
8 sugar side chains.1
1
2. The key hCG-related molecules that are detected in serum and urine samples are:

a. regular hCG
b. hCG free -unit
c. nicked hCG
d. hCG missing the -subunit C- terminal peptide
e. hyperglycosylated hCG (hCG-H)
f. urine -core fragment (urine only)

3. It is the hCG-H, produced by stem cytotrophoblast cells, that is shown to be the autocrine
promoter of growth and malignancy in gestational trophoblastic neoplasms and persistent
mole.2-5

4. hCG-H is the principal hCG variant produced and detected in active gestational
trophoblastic neoplasms.6-8 (Table 5.1)

5. hCG free -subunit is the principal hCG form detected in PSTT and non-trophoblastic
neoplasms.1 (Table 5.1)

6. Circulating hCG from hydatidiform mole and hCG-H from GTN commonly becomes nicked
as levels diminish after therapy.9-10

When hCG values fall below 100 mIU/mL in trophoblastic diseases, nicked hCG and free -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 -
subunit or nicked hCG. It is essential to accurately monitor hCG levels until they become undetectable and
demonstrating that the immunoreactivity remains undetectable and does not rise.

7. Siemens Immulite hCG test is the only one that efficiently detects all of the hCG variant
antigens in serum samples on an equimolar. It is clearly the only appropriate test for
management of cases with gestational trophoblastic diseases. 11-13 (Table 5.2) (Level I,
Grade A)

8. Laboratories in the Philippines have different brands of hCG immunoassays. (Table 5.3)

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 disorder or history of mononucleosis. 14-17

32
 33
Table 5.1. Occurrence of hCG-related molecules in serum and urine samples.
hCG-related Normal Pregnancy Hydatidiform Mole Persistent Chorio Other
molecule GTD with malignancies
rising hCG carcinom
3-6 wk 7wks Prior to Postevacuation Post-evacuation
a pre-
to term evacuation
hCG>100 IU/L hCG<100 IU/L therapy
Regular hCG ++ +++ +++ +++ + + --
hCG-H s
+++ + + + + +++ +++
post menses
Nicked hCG -- + + + ++ + +
hCG missing -- --
-subunit C-
Free -subunit
terminal peptide + + + + +++ + +
+ +++ ++ ++ +++ ++ + +++
Urine -core
fragment (urine
only)
 34
Table 5.2. Use of common brands of hCG immunoassays to detect hCG metabolic products commonly found in individuals with gestational
trophoblastic diseases. Antigens appropriately recognized by different assays are indicated by the numeral 1. Those questionably detected
in a specific assay are indicated by 0/1. Those not detected at all are indicated with a zero.
Standard Abbott Siemens Siemens Beckman Dade Siemens Ortho Roche Tosch Wako Charin
AxSym/I Centaur ACS 180 Acces/ Dimension Immulite Vitros hCG Cross
MX Eci Elecsys A1A RIA
DXI series
series
hCG free 1 0/1 0/1 0/1 1 1 1 1 1 0/1 0/1
-subunit
HCG-H 1 1 1 1 0/1 1 1 0/1 1 1 1
Nicked hCG 1 1 1 1 1 1 1 0/1 1 0/1 1
Nicked hCG missing 0 0 0 0 1 1 0 0 0 0 0/1
BCTP
Urine -core 0 0 0 0 0 0 0 0 0 0/1
fragment
Use with caution in GTD x x x x x x x x x x
and cancer cases due
limited specificity in 1
test
Avoid use in GTD and x x x x x x
cancer cases due to very
limited sensitivity, tests
Table 5.3. Locally available hCG assays (as of March 2011)

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
Healthway Medical Clinics Roche Elecsys 2010
Manila Doctors Hospital Gamma Counter
MCU-FDT Medical Roche Elecsys 2010
National Kidney & Transplant Institute Roche Cobas e601
Philippine General Hospital Gamma Counter
Philippine General Hospital UPMC Roche Elecsys
FMAB
Polymedic (Metro Manila) Abbott Architect i1000sR
San Juan De Dios Abbott AxSym
St. Luke’s Global Siemens Advia Centaur
St. Luke’s Medical Center Siemens Advia Centaur
The Medical City Abbott AxSym
UERM Medical Center Siemens Immulite
United Doctors Medical Center Biomereiux Vidas
University of Santo Tomas Hospital Beckman Access

Cebu
Cebu Doctors Hospital Abbott Architect
Chong Hua Hospital Roche Cobas 6000

Cagayan de Oro
Capitol University Medical City Beckman Access
Northern Mindanao Regional Hospital Siemens Immulite

Davao
Davao Doctors Hospital Roche Elecsys
San Pedro Hospital TNC Mini Vidas

35
FALSE POSITIVE hCG
1. False positive results are identified by the following criteria: 14-16

a. The finding of more than 5-fold differences in serum hCG results with alternative
immunoassays.

b. The presence of hCG in serum and absence of detectable hCG or hCG related molecule
immunoreactivity in a parallel urine sample (interfering antibodies are large glycoprotein.
that do not cross the glomerular basement membrane so do not interfere with urine
measurements).

c. The observation of false positive results in other tests for molecules not normally
present in serum, such as urine b-core fragment.

d. The finding that a heterophilic antibody blocking agent (Scantibodies Inc. HBR)
prevented or limited false detection (confirmatory criterion).

e. The finding that the hCG results differ greatly when tested undiluted and diluted with
serum.

In the cases referred to the USA hCG Reference Service, false positive hCG results range from 2 to
1100 mIU/mL. In all these cases, treatment was halted even though physician’s laboratory test remained
positive. False positive results in a specific hCG assay were observed to remain false positive for 3 or more
years.

2. Transient decrease in false positive hCG values following chemotherapy or surgery may
mislead physicians by wrongly indicating presence of disease and successful therapy
of disease.1

Chemotherapy or surgery can weaken the immune system, reducing circulating antibody concentration,
leading to decreased false hCG results.

QUIESCENT GESTATIONAL TROPHOBLASTIC DISEASE

1. Quiescent Gestational Trophoblastic Disease are persistently low real hCG values in
women lacking evidence of tumor, rising hCG or any evidence of clinically active
disease.14-16,18

In the USA hCG Reference Service, Quiescent GTD is diagnosed in cases of persistent low levels of hCG
(always <250 mIU/mL) with no increasing trend continuing over a period of 3 months or longer (range: 2 months
to 9 years)

2. Total hCG and hCG-H are useful in differentiating active GTD and quiescent GTD. 14,18
(Level II, Grade A)

hCG-H was calculated as the percentage of total hCG (percent hCG-H). At the 25% cut-off, hCG-H
proportion discriminated 100% of malignancies from quiescent GTD cases.

3. It has been inferred that hCG-H is an absolute test for identifying quiescent GTD cases
which needs no chemotherapy or surgery. 14,18 (Level II, Grade A)

In monitoring patients with quiescent GTD, a single measurement showing the presence of hCG-H is
sufficient to demonstrate the presence of active disease and to initiate chemotherapy.
36
PITUITARY hCG

1. hCG production may be demonstrated in healthy non-pregnant women. This hCG has
been shown to be coming from the pituitary gland. 19

Pituitary hCG accompanies luteinizing hormone (LH) production 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 and
progesterone, as detected in serum and urine samples of postmenopausal women.

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 -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 -SUBUNIT AND PLACENTAL SITE TROPHOBLASTIC TUMOR

1. hCG free -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 : dimmers, as governed by the
law of mass action, thus leading to hCG free -subunit production. This is evident in PSTT patient urine samples
where high proportions of -core fragment are detected. Production of hCG free -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 -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 parameters (hCG level, medical history, age) that
14,15,16,18
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)
37
 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 nonpregnant subjects that has physical, immunological and biological similarities to
human chorionic gonadotropin. Proc Natl Acad Sci U S A 1976 Aug;73(8):2885-9.
20. Seki K, Matsui H, Sekiya S, Advances in the clinical laboratory detection of gestational trophoblastic disease. Clin
Chim Acta. 2004 Nov;349(1-2):1-13.
21. Snyder JA, Haymond S, Parvin CA, Gronowski AM, Grenache DG. Diagnostic considerations in the measurement
of human chorionic gonadotropin in aging women. Clin Chem 2005 Oct;51(10):1830-5.

38
 APPENDIX

LEVELS OF EVIDENCE AND GRADES OF RECOMMENDATION

LEVELS DEFINITION
I Evidence obtained rom at least one properly randomized controlled trial.
II-1 Evidence obtained from well-designed controlled trials without randomization.
II-2 Evidence obtained from well-designed cohort or case-control analytic studies,
preferably from more than one center or research group.
II-3 Evidence obtained from multiple time series with ot without the intervention.
III Opinion of respected authorities, based on clinical experience; descriptive
studies and case reports or reports of expert communities.

GRADE DEFINITION
A There is good evidence to support the recommendation of the practice in the management of
gestational trophoblastic 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.

39
 TROPHOBLASTIC DISEASE SPECIALISTS BY REGION

NATIONAL CAPITOL REGION

Abad, Leopoldo III M. Laguimin, Ma. Lucia B.
Balete, Susan C. Llarena, Raquel T.
Cagayan, Ma. Stephanie Fay S. Mondragon, Laureen Honor F.
Capito, Lourdes B. Octavio-Cruz, Bernadette R.
Castillo, Ma. Del Carmen R. Pastorfide, Greg B.
Chan, Paulene Trixie C. Quevedo, Ma. Carmen H.
Chua, Angelica Anne A. Quiroga, Ma. Cristina O.
Estrella, Agnes S. Ruaro, Marilyn D.
Ferandez, Estrella S. San Juan, Filomena S.
Jacinto, Elizabeth K. Sarmiento, Diana L.
Jocson, Milagros T. Torres, Mary Carol C.
Lagrosa, Editha A. Trinidad, Anne Marie C.
CORDILLERA ADMINISTRATIVE REGION
Oras, Celestrell May W. (Benguet)
REGION II
Par, Carolyn P. (Nueva Vizcaya)
Tolentino, Criseline D. (Cagayan Valley)
REGION III
Dy, Mary Ruth E. ( Bulacan )
REGION IV
Burog, Honorata Lalaine P. ( Batangas )
Evangelista, Nelia B. ( Cavite )
Fortun, Vincent Lohengrin ( Cavite )
Gacoba, Ma. Cresencia R. ( Laguna )
Delos Santos, Rosalee T. (Laguna, Palawan)
Solamo, Joyce Ruth T. (Rizal)
REGION V
Bislumbre, Aileen Frances ( Naga )
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 )

40