GTN

Gestationa
l Dr. Ajay

Trophoblas
Dr. Santosh
Dr. P K Saha

Gestational Trophoblastic Neoplasia (GTN)

 Trophoblastic diseases, a locally proliferative with ability
to invade normal tissue, and the potential to
metastasize.
 Postmolar GTN
 Invasive Mole
 Choriocarcinoma
 Placental Trophoblastic Tumor
 Epithelioid trophoblastic tumor, a very rare subtype

Introduction

 Most curable gynecologic malignancy.

 Malignant GTD is diagnosed when there is
clinical, radiologic, pathologic, and/or hormonal evidence
of persistent gestational trophoblastic tissue.

 Most commonly, the diagnosis is made following a molar
pregnancy.

Postmolar GTN

 50-66% of cases of GTN are postmolar.

Symptoms-
 Irregular bleeding following evacuation of a H. mole.

Signs-
 An enlarged, irregular uterus
 Persistent bilateral ovarian enlargement.
 A metastatic vaginal lesion may be noted on evacuation.

Risk Factors For Postmolar GTN

 High pre-evacuation hCG levels > 1 lac
 Uterine size larger than expected by dates.
 Theca lutein cysts.
 Increasing maternal age > 40 yrs

FIGO Diagnosis Of Postmolar GTN

1. Plateaued hCG (± 10%) 4 values over 3 weeks.
2. Rising hCG of (≥ 10%) 3 values over 2 weeks.
3. Persistence of hCG beyond 6 months after mole
evacuation.
4. Histologically confirmed choriocarcinoma, invasive
mole or PSTT.
5. Metastatic disease without primary site with elevated
hCG (pregnancy has been excluded)

GTN Following Non-molar Gestations

 Postpartum GTN : 1/50000 births.

 History of irregular uterine bleeding, amenorrhea or
recent pregnancy.

 Hemoptysis, pulmonary embolism, cerebral
hemorrhage, gastrointestinal or urologic hemorrhage or
widely metastatic malignancy of an unknown primary
site.

Whom to screen for non molar GTN ?

 Woman with persistent vaginal bleeding after a
pregnancy.

 A urine pregnancy test should be performed.

 Symptoms from metastatic disease, such as dyspnoea or
abnormal neurology, can occur very rarely.
(RCOG, 2010)

 The possibility of malignant GTN should be suspected in
any woman of reproductive age who presents with
metastatic disease from an unknown primary site or
undiagnosed cerebral hemorrhage.

 Under these circumstances the diagnosis is facilitated by
a high index of suspicion coupled with serum hCG testing
and exclusion of a concurrent pregnancy, most often
without the need for tissue biopsy.

Gestational choriocarcinoma

 Gestational choriocarcinoma is a pure epithelial
malignancy, comprising both neoplastic
syncytiotrophoblast and cytotrophoblast elements
without chorionic villi.

 1:50000 deliveries.

 Gestational choriocarcinomas tend to develop early
systemic metastasis and chemotherapy is clearly
indicated when histologically diagnosed.

Route of metastasis

 GTN usually spreads by hematogenous dissemination.
 lymphatic spread uncommon

Evaluation of GTN

 Complete history and physical examination.
 Baseline hematologic, renal, and hepatic functions.
 Baseline quantitative hCG level.
 Chest X-ray or CT scan of chest if CXR is negative.
 Brain MRI or CT scan.
 CT scan of abdomen and pelvis.

(AJOG,2010)

 Approximately 45% of patients present with metastatic
disease when GTN is diagnosed.

 Some pulmonary metastases result from deportation of
trophoblast during molar evacuation and identiﬁcation of
pulmonary nodules in a post evacuation chest X-ray
might not indicate true malignant behavior.

Metastatic site % % Metastatic
Non-metastatic 54
Metastatic 46
 Lung only 81
 Vagina only 5
 Central nervous system 7
 Gastrointestinal 4
 Liver 1.5
 Kidney 0.7

Clinical Classification System For
Patients With Malignant GTN
Category Criteria
Non-metastatic GTN No evidence of metastases
Metastatic GTN Any extrauterine metastases

Good prognosis metastatic GTN No risk factors
Short duration (<4 months)
Pretherapy hCG <40,000 mIU/mL
No brain or liver metastases
No antecedent term pregnancy
No prior chemotherapy
Poor prognosis metastatic GTN Any one risk factor
Long duration (>4 months)
Pretherapy hCG >40,000 mIU/mL
Brain or liver metastases
Antecedent term pregnancy
Prior chemotherapy

FIGO score 0 1 2 4
2000
Age (years) < 40 ≥40

Antecedent Hydatidiform Abortion Term
pregnancy mole pregnancy
Interval from <4 4 - <7 7 - <13 ≥ 13
index
pregnancy
(months)
Previous failed Single drug ≥ 2 drug
chemotherapy
Pretreatment < 1000 1000 - < 10000 10000 - < ≥ 100000
hCG (mIU/mL) 100000
Largest tumor <3 3-<5 ≥5
size including
uterus (cm)
Site of Lung Spleen, kidney GIT Brain, liver
metastases
Number of 0 1-4 4-8 >8
metastases

 Chest X-ray rather than chest CT would be used to assess
the number of metastatic lesions.

 Low Risk = ≤ 6
 High Risk = ≥ 7

Treatment

 Treatment is based on classiﬁcation into risk groups
deﬁned by the stage and scoring system.

(AJOG,2010)

Treatment of low risk GTN

 Essentially all patients with this condition can be
cured, usually without the need for hysterectomy.

 Patients with nonmetastatic (stage I) and low-risk
metastatic (stages II and III, score < 7) GTN can be treated
with single-agent chemotherapy, with resulting survival
rates approaching 100%.
(AJOG,2010)

 Methotrexate is the corner stone of chemotherapy.

Monitor-
 Hematologic indices
 Renal function test
 Liver function test

 Oral methotrexate is readily absorbed via the GIT.

 Barter reported a retrospective analysis of 15 patients
treated solely with oral methotrexate 0.4mg/kg for 5 day
cycles that were repeated every 14 days.

 The primary remission rate was 87% with minimal
toxicity

 Concerns about patient compliance and the possibility of
unpredictable absorption.
(Barter, Am J Obstet Gynecol. 1987)

RCOG, 2010

 Women are treated with single-agent intramuscular
methotrexate alternating daily with folinic acid for 1
week followed by 6 rest days.

 The cure rate for women with a score ≤ 6 is almost 100%.

AJOG,2010

 Methotrexate most common side effect- stomatitis.

 Actinomycin D has a more toxic side effect proﬁle
(nausea, alopecia) than MTX and produces local tissue
injury if IV extravasation occurs.

 Actinomycin D has most often been used as secondary
therapy in the presence of MTX resistance or as primary
therapy for patients with hepatic or renal compromise
contraindicating the use of MTX.

Cochrane Review, 2012 July

 Included five moderate to high quality RCTs (517 women)

 Compared methotrexate with dactinomycin.

 Three studies compared weekly IM MTX with bi-weekly
pulsed IV DACT (393 women),
 One study compared five-day IM MTX with bi-weekly
pulsed IV DACT (75 women)
 One study compared eight-day IM MTX-folinic acid
(MTX-FA) with five-day IV DACT (49 women)

Contd..

 Dactinomycin is more likely to achieve a primary cure in
women with low-risk GTN, and less likely to result in
treatment failure, compared with MTX.

 There is limited evidence relating to side-effects,
however, the pulsed DACT regimen does not appear to
be associated with significantly more side-effects than
the low-dose MTX regimen and therefore should
compare favourably to the five and eight day MTX
regimens in this regard.

Contd..

 Review considers pulsed dactinomycin to have a better
cure rate than, and a side-effect profile at least
equivalent to, methotrexate when used for first-line
treatment of low-risk GTN.

Abrao et al. Gynecol Oncol,2008 Jan

 Comparison of single-agent methotrexate, dactinomycin
and combination regimens.

 Reviewed 108 cases with low-risk GTN who were treated
with first-line chemotherapy.

 42 patients MTX IM injection of 20 mg/m2 D1–D5

 42 patients DACT IV infusion of 12 μg/kg a day D1–D5

 24 patients both drugs with 20 mg MTX IM D1–D5 and
with 500μg DACT IV infusion D1–D5.

Contd..

Complete remission Adverse side effects
 MTX 69% 28.6%
 DACT 61.4% 19.1%
 combination 79.1% 62.5%
(p=0.7) (p=0.0003)

 The duration of the treatment and the number of
chemotherapy courses were similar among the groups .

Contd..

 Analysis indicates that single-agent chemotherapy
regimens are as effective as combination chemotherapy
for low-risk GTD.

 Dactinomycin might offer the best cost-effective
treatment option.

 Methotrexate must be considered as the regimen of
choice for low resource areas because of the feasibility of
its administration.

Maintenance chemotherapy

 Regardless of the treatment protocol
used, chemotherapy is continued until hCG values have
returned to normal and at least 1 course has been
administered after the ﬁrst normal hCG level.

 When chemotherapy is given for an additional 1–2 cycles
after the ﬁrst normal hCG value,recurrence rates are <5%

 Contraception, preferably oral contraceptives, should be
used to prevent an intercurrent pregnancy during
chemotherapy or monitoring after remission is achieved.

Role of surgery

 Early hysterectomy will shorten the duration and amount
of chemotherapy required to produce remission.

 Therefore, each patient’s desire for further childbearing
should be evaluated at the onset of treatment.

 Hysterectomy may be performed during the ﬁrst cycle of
chemotherapy.

 However, further chemotherapy after hysterectomy is
mandatory until hCG values are normal.

Risk factors for drug resistance to
single agent chemotherapy:

 Older patient age > 35yrs

 Higher hcg level > 1 lac miu/ml

 Presence of metastatic disease

 Higher figo score > 4
(AJOG,2010)

 Rate of fall of hCG levels has pateaued or values are
rising during therapy should be switched to an
alternative single agent regimen after radiographic
restaging.

 If there is appearance of new metastases or failure of the
alternative single-agent chemotherapy, the patient
should be treated with multiagent regimens.

Management
Initiate single-agent methotrexate or dactinomycin regimen

Consider hysterectomy if fertility not desired

Monitor hematologic, renal, and hepatic indices before each cycle of chemotherapy

Monitor serum hCG levels weekly during therapy

Change to alternative single-agent if resistance or severe toxicity to ﬁrst agent

If resistance to alternative agent

Repeat metastatic evaluation

Consider hysterectomy if no extrauterine metastases

Multiagent therapy (MAC or EMA/CO)

1–2 cycles of maintenance/consolidation chemotherapy

Remission: three consecutive weekly hCG values in the normal range

High-risk metastatic GTN

 Patients classiﬁed as having high-risk metastatic disease
(stage IV and stages II-III, score >6) should be treated in a
more aggressive manner with multiagent chemotherapy
± adjuvant radiation or surgery to achieve cure rates of
80-90%.
(AJOG,2010)

Regimens

 MAC- MTX, DACT and cyclophosphamide or chlorambucil -
63-71% cure rate.

 CHAMOCA - cyclophosphamide, hydroxyurea, actinomycin
D, methotrexate with folinic acid, vincristine, and doxorubicin

 In a RCT of CHAMOCA vs MAC, both the primary remission
rate (65% vs 73%) and the ultimate cure rate (70% vs 95%)
were inferior for CHAMOCA compared with MAC, and
CHAMOCA was more toxic.
(Obstet Gynecol 1989;73:357-62)

EMA/CO

 Alternating weekly chemotherapy with etoposide,
methotrexate/folinic acid, dactinomycin/cyclophosphamide
and vincristine (EMA/CO).

 complete response rates 71-78% and long-term survival rates
of 85-94%.

 The most widely used regimen.

 Toxicity- alopecia, stomatitis, emesis, Myelosuppression,
neutropenia, anemia. No treatment-related deaths or life
threatening toxicity occurred.

RCOG,2010

 Women with scores ≥ 7 are at high risk and are treated
with intravenous multi-agent chemotherapy, which
includes combinations of
methotrexate, dactinomycin, etoposide, cyclophospham
ide and vincristine.

 Treatment is continued, in all cases, until the hCG level
has returned to normal and then for a further 6
consecutive weeks.

 Cure rate for women with a score ≥ 7 is 95%.

EMA-EP

 The regimen, substituting etoposide and cisplatin for CO
in the EMA-CO protocol

 Considered the most appropriate therapy for patients
who have responded to EMA-CO but have plateauing
low hCG levels or who have developed re-elevation of
hCG levels after a complete response to EMA-CO.

 In patients who have clearly developed resistance to
methotrexate containing protocols, drug combinations
containing etoposide and platinum with bleomycin,
ifosfamide, or paclitaxel have been found to be effective.

Recurrence

 Approximately 30% of high-risk patients will fail ﬁrst-line
therapy or relapse from remission.

 Salvage therapy with platinum-containing drug
combinations, ± surgical resection of sites of persistent
tumor, will result in cure of most of these high risk
patients with resistant disease.

Role of surgery

 Primary adjuvant hysterectomy not effective in reducing
chemotherapy requirements or improving cure rates for
women with high-risk metastatic GTN.
(Hammond and colleagues)

 Hysterectomy is effective in producing remissions in
patients with chemoresistant non-metastatic or low-risk
metastatic disease.

Management summarise:

 Evaluate for high-risk metastases: brain, liver, kidney
 Stabilize medical status of patient
 Multiagent therapy with EMA/CO or MAC

 At least three cycles of maintenance chemotherapy after
hCG values normalize

Surveillance During And After
Therapy Of GTN

Contraception

 Contraception should be maintained during treatment
and for 1 year after completion of
chemotherapy, preferably using oral contraceptives.

Future Pregnancy

 Because of the 1-2% risk of a second GTD event in
subsequent pregnancies, pelvic ultrasound is
recommended in the ﬁrst trimester of a subsequent
pregnancy to conﬁrm a normal gestation, the products of
contraception or placentas from future pregnancies
should be carefully examined histopathologically, and a
serum quantitative hCG level should be determined 6
weeks after any pregnancy.

Lung Metastasis

 Radiographic evidence of tumor regression often lags
behind hCG level response to treatment and some
patients will have pulmonary nodules that persist for
months or years after completion of chemotherapy.

 Thoracotomy with pulmonary wedge resection- in highly
selected patients with drug-resistant disease may
successfully induce remission. Exclude the possibility of
active disease elsewhere.

 Prompt hCG level remission occurring within 1–2wks of
surgery- a favorable outcome.

Brain Metastasis

 8–15% of patients with metastatic GTN.
 Brain irradiation with systemic chemotherapy.

 During radiotherapy, the methotrexate infusion dose in the
EMA-CO protocol is increased to 1g/m2 and 30 mg of folinic
acid is given every 12 hours for 3 days starting 32 hours after
the infusion begins. (AJOG, 2010)

 A similar primary remission rate- high-dose systemic
methotrexate with intrathecal methotrexate infusions,
without brain irradiation.

 Craniotomy

Contd..

Surgery-
1. To control hemorrhage from metastases.
2. To remove chemoresistant disease
3. To treat other complications in order to stabilize
high-risk patients during therapy.

75–80% of women with brain metastases presenting for
primary therapy and 50% of patients overall with brain
metastases from malignant GTN will be cured.

Liver Metastasis

 Involvement of the liver constitutes a poor prognostic
factor.

 Consider selective angiographic embolization or
irradiation

 Survival rates of 40–50% for women with primary liver
involvement.

Vaginal Metastasis

 Highly vascular.

 Biopsy not recommended.

 If vaginal metastases are the only site of metastasis,
promptly respond to chemotherapy.

 Vaginal packing or selective embolization to control
active hemorrhage early in the course of treatment.

Hysterectomy

 Hysterectomy performed when there is disseminated
metastasis is unlikely to have a signiﬁcant impact on the
survival of patients with high-risk or recurrent GTN.

 Ovarian removal is not required, as GTN rarely
metastasizes to the ovaries and these tumors are not
hormonally influenced.

Myometrial Resections Combined With
Uterine Reconstruction
 Patients with non-metastatic GTN not willing for
hysterectomy.

 Salvage procedures in women with localized
chemoresistant disease.

 Evaluate for systemic metastases and the uterine lesion
using ultrasound, MRI, and hysteroscopy.

Contd..

 Intraoperative frozen sections to assess surgical margins.

 Small lesions associated with low hCG levels are more
likely to be completely excised with a conservative
myometrial resection than lesions >2–3 cm in diameter.

Invasive mole

 Invasive moles are characterized by edematous chorionic
villi with trophoblastic proliferation that invade directly
into the myometrium.

 Usually invasive moles undergo spontaneous resolution
after many months but they are treated with
chemotherapy to prevent morbidity and mortality
caused by uterine perforation, hemorrhage or infection.

PSTT
 0·2% of cases of GTD.

 PSTT is a tumor of placenta implantation site.

 Characterized by absence of villi with proliferation of
intermediate trophoblast cells.

 The syncytiotrophoblast is lacking with relatively lower
levels of hCG. hCG is not a reliable marker of tumor
volume.

 Trophoblastic cells infiltrate the myometrium, and there
is vascular invasion.

 Human placental lactogen (hPL) is present in the tumor
cells.

 Not as sensitive to simple chemotherapy as other forms
of malignant GTN.

 About 35% of PSTTs have distant metastases at
diagnosis.

Epithelioid trophoblastic tumor

 A rare variant of PSTT that simulates carcinoma.

 Originally termed atypical choriocarcinoma, it appears to be
less aggressive than choriocarcinoma and is now regarded as a
distinct entity.

 Appears to develop from neoplastic transformation of
chorionic type intermediate trophoblasts.

 Pathologically, it has a monomorphic cellular pattern of
epithelioid cells and may resemble squamous cell cancer of
the cervix when arising in the cervical canal.

 Most ETTs present many years after a full-term delivery.

 Clinical behavior from benign to malignant.

 About one-third of patients present with metastases, usually
in the lungs.

PSTT and ETT s/s-
 Almost always irregular uterine bleeding often distant from a
preceding nonmolar gestation.
 The uterus is usually symmetrically enlarged.
 Serum hCG levels are only slightly elevated.

AJOG,2010

Hysterectomy with lymph node dissection is the
recommended treatment.

Chemotherapy-
 Metastatic disease
 Nonmetastatic disease with adverse prognostic factors-
 Interval from last known pregnancy to diagnosis > 2 years.
 Deep myometrial invasion
 Tumor necrosis
 Mitotic count > 6/10 high power ﬁelds.

 Platinum-containing regimen, such as EMA-EP or a
paclitaxel/cisplatin–paclitaxel/etoposide doublet, is the
treatment of choice.

 The survival rate is approximately 100% for
nonmetastatic disease and 50-60% for metastatic
disease.

Gestational trophoblastic Pathological features Clinical features
disease

Myometrial invasion 15% metastatic-lung/vagina
Invasive mole Swollen villi Most often diagnosed
Hyperplastic trophoblast clinically, rather than
pathologically
Abnormal trophoblastic Vascular spread to distant
Choriocarcinoma hyperplasia sites–lung/brain/liver
and anaplasia Malignant disease
Absent villi
Hemorrhage, necrosis
Tumor cells inﬁltrate Extremely rare
PSTT myometrium with hCG levels less reliable
vascular/lymphatic invasion indicator
Intermediate cells/absent villi Relatively chemoresistant
Less hemorrhage and necrosis Mainly surgical treatment
Tumor cells stain positive for
hPL

Long-term Outcome Of Women Treated
For GTN

 Women who receive chemotherapy for GTN are likely to
have an earlier menopause.

 Women who require multi-agent chemotherapy which
includes etoposide should be advised that they may be at
increased risk of developing secondary cancers- acute
myeloid leukaemia, colon cancer, melanoma, breast
carcinoma.
(RCOG,2010)

GTN

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Editor's Notes