GESTATIONAL TROPHOBLASTIC DISEASES

 Is a heterogenous spectrum of diseases which is characterized as an abnormal trophoblastic

proliferation
 It can be benign, premalignant or malignant
 Can follow any gestational event – abortion, ectopic, normal pregnancy

WHO Classification of Gestational Trophoblastic Disease

Benign Trophoblastic Lesions
 Placental site nodule
 Exaggerated placental reaction
Hydatidiform Mole
 Complete hydatidiform mole
 Partial hydatidiform mole
Gestational Trophoblastic Neoplasia
 Invasive mole
 Choriocarcinoma
 Placental site trophoblastic tumor
 Epitheloid trophoblastic tumor

Placental site nodule is a rare benign lesion of the intermediate trophoblast which is thought to
represent incomplete involution of the placental implantation site.
It is important to distinguish it from other lesions like PSTT.
Exaggerated placental site reaction is exuberant infiltration of the endometrium and myometrium at
the implantation site by intermediate trophoblastic cells

Hydatidiform Mole
 Incidence varies greatly between different parts of the world
 Highest in Asia than in North America or Europe
 Incidence of PHM in the United Kingdom is 3/1000 pregnancies
 Incidence of CHM ranges from 1 to 3/1000 pregnancies
 Incidence is 2.4/1000 pregnancies (2008-2010) in the Philippines
 Ethnic groups like Native American Indians, Inuits, Hispanics and American Africans have
increased incidence of GTD

Hydatidiform Mole: Risk factors

Age
 <16 and >45 years old
 5 to 10 fold increase after age 40, rising precipitously thereafter
 Teenagers have a 1.5 to 2 fold increased risk
 Paternal age factor has inconsistent results
Reproductive history
 A past history of HM increases the risk in the future pregnancies by 5 to 40 fold that of
the general population
 Subsequent pregnancies have an approximate 1% risk, increasing to 25% when the
number of previous molar pregnancy is 2 or more.
 Risk is not affected by changing partners
Diet
 Conflicting results regarding diet as risk factor .
 Increased risk of CHM with decrease consumption of animal fat and beta-carotene.
 Higher incidence of GTD in countries where Vit A deficiency is prevalent
 Other studies failed to show decreased incidence with increasing consumption of
dietary protein or fat
Genetics
 Familial recurrent HM, a rare autosomal recessive disorder was identified on
chromosome 19q
 Affected women have a mutation of NLRP7 gene and more rarely the KHDC3L gene -
predisposed to abnormal pregnancies characterized by CHM

Hydatidiform Mole
 Complete HM completely derived from paternal origin
 Partial HM is derived from maternal and paternal chromosome

Complete mole is completely derived from paternal origin, greater than 90% having a 46 , XX genotype,
produced by fertilization of an empty ( anuclear ) ovum by a single haploid (23,X) sperm, which
duplicates in the ovum making it 46, XX
A small percentage of CHM have a 46,XY genotype produced by dyspermy wherein a 23, X sperm and a
23 Y sperm fertilize an empty ovum. Rarely are complete moles triploid or aneuploid.

The mechanism for the production of an empty ovum is unknown.

Partial HMs are derived from both maternal and paternal chromosomes producing a triploid genotype.
A haploid ovum is fertilized by 2 haploid spermatozoa with 69,XXX or 69,XXY.
Although a triploid karyotype is usually seen in PHM, not all triploid pregnancies show histologic changes
consistent with a partial mole.

Hydatidiform mole: Pathologic Features

Gross:
 Bulky “bunch of grapes”
 Semi-transparent vesicles ( 1-30mm)
 Absence of normal placental structures or fetal parts
Microscopic:
 1. Lack of fetal or embryonic tissues
 2. Hydropic (edematous) villi
 3. Diffuse trophoblastic hyperplasia
 4. Marked atypia of trophoblasts at the implantation site
 5. Absence of trophoblastic stromal inclusions

Partial mole: : Pathologic Features

Gross:
• Smaller volume of hydropic villi
• Possible presence of a fetus or fetal tissues
Microscopic:
 1. presence of fetal or embryonic tissues
 2. less diffuse, focal hydropic swelling of villi
 3. focal trophoblastic hyperplasia
 4. less trophoblastic atypia at the molar implantation site
 5. presence of trophoblastic scalloping and stromal inclusions

Feature Complete Mole Partial Mole

Fetal or embryonic tissue Absent Present

Hydatidiform swelling of chorionic villi Diffuse Focal

Trophoblastic hyperplasia Diffuse Focal

Trophoblastic stromal inclusions Absent Present

Genetic Parentage Paternal Bipaternal

Karyotype 46,XX;46,XY 69,XXY; 69,XYY

Persistent hCG 20% of cases 0.5% of cases

Hydatidiform Mole
Clinical Features
 Delayed menses
 Vaginal bleeding
 Large for date uterus
 Absent fetal movement
 Anemia secondary to occult hemorrhage
 Gestational hypertension before 20 wks
 Presence of theca lutein cysts
 Hyperemesis
 Hyperthyroidism
 Respiratory distress from trophoblastic emboli to the lungs

 The average age of diagnosis of CHM today is 9.6 weeks(17 weeks in 1960s)
 If uterine enlargement is more than 14 to 16 weeeks, 25% will have medical complications
related to high levels of HCG.
  β-hCG is homologous to Thyrotropin releasing hormone (TRH), β-hCG iso forms seen in CHM
may have greater affinity for the TSH receptor than normal β-hCG causing excessive thyroid
stimulation
 Also β-hCG is homologous to LH , claimed/appeared to be mechanism whereby ovarian
stimulation leads to the formation of theca lutein cysts in some patients

Data from New England Trophoblastic disease center has shown a changing clinical presentation over
time of HM.
Also demonstrated in china and Thailand suggesting a worldwide phenomenon.
Patients are more likely to present with minimal symptoms..

Clinical Features of PHM

 Found incidentally following histopath of products of conception from missed abortion or
therapeutic abortion
 Medical complications are rare
 Underdiagnosis is a risk for PHM

Diagnosis: Ultrasound

Features suggestive of CHM on US

 Echogenic endometrial mass in an enlarged uterus “snow storm appearance”
 Absence of fetal or embryonic tissue
 Absence of amniotic fluid
 Enlarged placenta with multiple cysts
 Ovarian Theca lutein cysts

Features suggestive of PHM on US

 Presence of fetal or embryonic tissue
 Presence of amniotic fluid
 Abnormal placenta with multiple cysts or increased echogenicity of chorionic villi
 Increased transverse diameter of GS
 Absence of theca lutein cysts

Diagnosis:
 Beta HCG Level
 HCG is produced by syncytiotrophoblast cell of the placenta
 Similar to FSH, LH and TSH except their beta subunits
 In normal pregnancy, its max amount is produced at approximately 10 weeks with levels
peaking at 100,000 IU/L and then falling thereafter

Elevated hCG outside pregnancy signifies the following:

1. GTN
2. Nongestational tumors secreting hCG
3. False positives
4. Menopause (secondary to LH elevation and cross reactivity of assays
Pre evacuation work up
 Chest x-ray
 Complete blood count, blood type with antibody screen
  β-hCG level
 Liver function test

Treatment
 Suction dilation and curettage
 Rh negative with Rh positive or Rh unknown partner should be treated with Rho(D) immune
globulin post evacuation
Hysterectomy
 Patients with HM with continued fertility not an issue, TAH with preservation of the adnexae
 Risk of developing GTN:
• 53% in >40 years old with HM;
• 60% in women older than 50
 After hysterectomy, risk of postmolar GTN is 3% to 5% = need for continuous hCG monitoring

 After surgical evacuation , locally invasive mole occurs in 15% to 20% of CHM
 Postmolar GTN rarely occurs with PHM (<5%)
 Prophylactic Chemotherapy is considered in patients where poor follow-up is anticipated post
evacuation
 Routine use of prophylactic chemotherapy is not recommended

Surveillance following Hydatidiform Mole Evacuation

 Baseline serum β-hCG should be done within 48 hours of evacuation

 Weekly until level becomes normal (<5 mIU/ml)
 Monthly β-hCG monitoring is recommended after a normal count for an additional of 6 to12
months.
 Minimum conventional period for observation is 6 months

Prognostic factors associated with the development of GTN:

 Advanced maternal age
 β-hCG level higher than 100,000 IU/L on presentation
 Uterine size large for date and bilateral ovarian enlargement (>8 cm theca lutein cyst) at time of
presentation
Ultrasound findings:
 presence of hyperechoic lesions (nodules)within the myometrium
 Increased signal intensity suggesting hypervascularization

Phantom β-Human Chorionic Gonadotropin

 False positive assay results
 Rare
 Secondary to heterophilic antibodies or proteolytic enzymes that mimic hCG
 Diagnosis: serum β-hCG is positive but a corresponding urine β-hCG samples taken at the same
time test negative

Quiescent Gestational Trophoblastic Disease

 Follows a hydatidiform mole, choriocarcinoma or spontaneous abortion
  Persistence of low levels ranging from 1 to 212 IU/L of β-hCG for 3 months or longer with no
obvious increase or decrease in the β-hCG level trend with absence of clinical or radiologic
evidence of GTN
 More common with complete moles.
 Described as premalignant= 25% progress to GTN-choriocarcinoma over a time frame from 6
months to 10 years
 Hyperglycosylated hCG (hCG-H) ,
 a marker of invasive cytotrophoblasts ,
 will detect 100% of quiescent GTD case that require no further treatment and 96% of
self-resolving HM cases that require surveillance
 differentiating these from GTN choriocarcinoma cases that require treatment.
Further validation with prospective studies is needed

Gestational Trophoblastic Neoplasia

 Invasive/Postmolar GTN
 Choriocarcinoma
 Placental Site Trophoblastic Tumors (PSTT)
 Epitheloid Trophoblastic tumor (ETT)

 Invasive Mole
◦ HMs characterized by syncytiotrophoblast or cytotrophoblast hyperplasia , with the
presence of villi extending into the myometrium
◦ Most are diploid except anaplastic tumors
 Choriocarcinoma
 Dominant histology in metastatic GTN
 May follow an HM or a normal pregnancy
 Occurs in approximately 1 to 50,000 pregnancies
 Sheets of anaplastic trophoblastic tissue containing cytotrophoblast and
syncytiotrophoblast cells without chorionic villi

 Primary Gonadal Choriocarcinoma (Nongestational)

 Ovarian germ cell tumor that can develop without pregnancy
 Occurs 1 in 369,000,000
 Very aggressive
 Secretes βhCG
 Same histologic appearance as gestational choriocarcinoma
 Absence of paternal DNA within the tumor using DNA analysis differentiates
nongestational from gestational choriocarcinoma

 Extragonadal Germ Cell Tumors

 Rare , originating from midline locations such as mediastinum and retroperitoneum
 No primary tumor in the ovaries but secrete β-hCG
 FISH(fluorescence in situ hybridization ) is used to identify single-nucleotide variants in exons
and introns on individual RNA transcripts === this would differentiate gestational
choriocarcinoma from extragonadal germ cell tumor

 PSTT (Placental site trophoblastic tumor)

 Rare
  Composed almost entirely of intermediate trophoblasts
 No syncytiotrophoblasts and cytotrophoblasts
 Infiltrative pattern, nests or sheets of cells invading between myometrial cells and fibers
 Less prone for vascular invasion, necrosis and hemorrhage compared to
choriocarcinoma
 Lymphatic spread

 Epitheloid trophoblastic tumor (ETT)

o Considered rare variant of PSTT
o Derived from intermediate trophoblasts
o Arranged in nests or sheets and form nodules in the myometrium
o Immunohistochemical staining is positive for multiple markers like cytokeratin and
inhibin A

Clinical Features of GTN

 Irregular vaginal bleeding
 Uterine subinvolution
 Theca lutein cysts
 Most GTN is identified during surveillance following evacuation on the basis of β-hCG
criteria

FIGO Criteria for Diagnosis of GTN

FIGO standardized criterion for diagnosing GTN following a HM:

 1. Four β-hCG values plateauing (+10%) over a 3-week period (days 1, 7, 14, 21)
 2. A rising β-hCG value of 10% or greater seen on 3 values measured over a 2-week
period (days 1,7,14)
 3. Persistence of detectable β-hCG for more than 6 months following evacuation of a
HM
 4. Histologic diagnosis of choriocarcinoma
 5. Evidence of metastasis (clinically or radiologically)

Clinical Features
Locally invasive GTN
 Persistent vaginal hemorrhage is the most common symptom
 Uterine perforation with intraperitoneal hemorrhage, infection secondary to tumor necrosis
may also occur
 Most would regress spontaneously following evacuation
 Chemotherapy may be initiated
Malignant GTN
 Most result from Choriocarcinoma
 PSTTs are associated with metastasis at the time of initial diagnosis in 40% of cases
◦ Lung metastasis is the most common site
ETT, about 50% present with metastasis at time of diagnosis

Classification and Staging

  In 2000, a revised FIGO-WHO prognostic scoring system was adopted
◦ Score of 6 or lower = low risk
◦ Score of 7 or greater = high risk
 Staging of the disease relates to tumor spread

WHO prognostic scoring system for GTD

Scoring

Parameter 0 1 2 4
Age (yr) <40 >40 --- ---
Antecedent pregnancy Mole Abortion Term ---
Interval from Index pregnancy <4 4 to <7 7 to <13 >13
(mo)
Pretreatment -hCG (IU/mL) <103 103–104 104–105 >105

Largest tumor size (cm; including ---- 3 to <5 cm >5 cm -----

uterus)
No. of metastasis ----- 1 to 4 5 to 8 >8
Site of metastasis Lung Spleen, kidney GI tract Brain, liver
Previous failed chemotherapy ----- ----- Single drug Two or more
drugs

The scores from the 8 risk factors are summed and incorporated into the FIGO stage, separated by a
colon (eg, stage II:4, Stage IV:9). Scores of 0-6 are considered low risk. Scores of 7 and greater are
considered high risk (see Table 2, below).  [2]

FIGO 2000 Classification of GTN

Staging Features
Stage I Disease confined to uterus
Stage II GTN extends outside uterus, but limited to genital structures (adnexa,
vagina, broad ligament)
Stage III GTN extends to lungs, with or without known genital tract involvement
Stage IV All other metastatic sites

WHO prognostic scoring is not applicable for PSTT and ETT. This 2 uses the FIGO staging I to IV.
Diagnosis of GTN
Invasive mole and choriocarcinoma
  Have high β-hCG level ranging from 100 to 100,000 mIU/ml
PSTT and ETT
 Produce low levels of β-hCG usually <1000 mIU/ml

 Ultrasound will rule out concurrent pregnancy

 Doppler ultrasound may show hypervascularity
*Chest x-ray , to rule lung metastasis

Management of Low-risk GTN (score of 6 or lower)

Following metastatic evaluation and determination of low-risk disease:

1. Initiate single-agent methotrexate or actinomycin D; consider hysterectomy if fertility is not
desired
 Monitor hematologic, renal, and hepatic indices before each cycle of chemotherapy
 Monitor β-hCG levels while on treatment
 If severe toxicity or resistance develops , consider switching to the alternative single agent

 If resistance to alternative agent develops:

2. Repeat metastatic evaluation
3. Consider hysterectomy if disease is confined to uterus
4. Multiagent therapy with EMA/CO

*Resistance is defined as 20% rise of β-hCG over 2 consecutive measurements or a β-hCG plateauing
or decreasing by less than 90% over a 3 week period.

Management of High-Risk GTN

 Prognostic score of 7 or higher
 Increased risk of treatment failure with single agent therapy

Chemotherapy Regimens for Intermediate and High-Risk Gestational Trophoblastic Disease

Drug Regimen Administration

EMA/CO (preferred regimen) –Course I (EMA)*

Day 1 Etoposide 100 mg/m2 IV over 30 min
Methotrexate 100mg/m2 IV bolus
Methotrexate 200mg/m2 IV as 12-hr continuous infusion
Actinomycin D 0.5 mgIV bolus
Day 2 Etoposide 100 mg/m2 IV over 320 min

Folinic acid 15 mg IV/IM/PO every 6 hr for 4 doses

 Actinomycin D 0.5 mg IV bolus
Course II (CO)
Day 8 Cyclophosphamide 600mg/m2 IV over 30 min
Vincristine 1 mg/m2 IV bolus(up to 2 mg)

Patients treated with the EMA/CO regimen have an increased rate of secondary malaignancy
particularly hematologic malignancies

High-Risk Sites of Metastasis

Central nervous system metastasis
 Brain metastasis has poor prognosis
 Favorable outcomes with combination chemotherapy
 Select craniotomy in some cases
 Whole brain radiotherapy
 Chemotherapy is the preferred option
Pulmonary Metastasis
 Manifests as chest pain, cyanosis , anemia and >50% lung field opacification
 Operative treatment of pulmonary metastasis for recurrent drug resistant cases is
recommended
Liver Metastasis
 Increased risk of hemorrhage with chemotherapy initiation
 Management: Chemotherapy
radiation therapy
embolization
surgical resection
Vaginal Metastasis
 High risk for hemorrhage
 Treatment: embolization or surgery

Treatment of Placental Site Trophoblastic Tumor & Epitheloid Trophoblastic Tumor

 Rare, less than 1%
 Ranging from benign to highly malignant
 Surgery is the cornerstone for the treatment of nonmetastatic PSTT and ETT
 Patients with metastatic PSTT and ETT have a poor prognosis
 Metastatic PSTT and ETT are relatively chemoresistant compared to invasive mole and
choriocarcinoma
 Surgery followed by combination chemotherapy EMA-EP or TP-TE has been recommended in
advanced disease
 International Society for the Study of Trophoblastic Diseases (ISSTD) collects all cases of PSTT
and ETT to establish the largest international data base in order to further inform on
management of those rare tumors

Surveillance following GTN

 After β-hCG remission is achieved for 3 weekly cycles, repeat testing every 2 weeks for 3 weeks,
monthly for 1 year
 Stage IV patients = monthly testing for 24 months
 Risk of relapse beyond the first year is <1%
 Patients with relapse , sustained remissions are achieved in more than 50% === β-hCG monitoring is
prolonged every 6 months up to 5 years
 Contraception is important during the post-GTN period
 OCP is the method of choice

Recurrences
 Stage I = occurs in 3 %
 Stage II = occurs in 8%
 Stage III = occurs in 4%
 Stage IV = occurs in 9%
 Mean time from the last detectable β-hCG to recurrence was 6 months
 Stages I to III, remissions were achieved with additional chemotherapy
 Stage IV patients with recurrences died of their disease
 There is no relationship between time to relapse and mortality
 Overall survival rate of patients with relapse is 78% (Ngan, 2007)
 Recurrence rate for PSTT and ETT ranges from 20 to 30%
 Only 30% will achieve long-term remission despite salvage treatment (chemo or surgery)

Pregnancy after GTN

 Normal reproductive outcome is expected after molar pregnancy or GTN
 Pregnancy outcome is similar to the general population
 There is an increased risk of subsequent molar pregnancy about 1 to 3/1000 to 1 to 2/100
pregnancies following a molar pregnancy
 Following 2 molar pregnancies, the risk in a subsequent pregnancy may be as high as 20%
 Changing partners has not been proven to change the risk

Effect of GTN to patients

Psychosocial sequelae for patients
 Sadness with sense of loss
 Low self esteem
 Sexual dysfunction
 Anxiety about future pregnancies
 50% showed psychological symptomatology suggestive of psychiatric disorder

Reference:
 Gestational Trophoblastic Diseases
 Comprehensive Gynecology , Latest Edition