GestationalTrophoblastic Neoplasia

Dr. Ajay

Dr. SantoshDr. 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 % % MetastaticNon-metastatic 54Metastatic 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 CriteriaNon-metastatic GTN No evidence of metastasesMetastatic GTN Any extrauterine metastases

Good prognosis metastatic GTN No risk factorsShort duration (<4 months) Pretherapy hCG <40,000 mIU/mLNo brain or liver metastasesNo antecedent term pregnancyNo prior chemotherapy

Poor prognosis metastatic GTN Any one risk factorLong duration (>4 months)Pretherapy hCG >40,000 mIU/mLBrain or liver metastasesAntecedent term pregnancyPrior chemotherapy

FIGO score 2000

0 1 2 4

Age (years) < 40 ≥40

Antecedent pregnancy

Hydatidiform mole

Abortion Term pregnancy

Interval from index pregnancy (months)

<4 4 - <7 7 - <13 ≥ 13

Previous failed

chemotherapy

Single drug ≥ 2 drug

Pretreatment hCG

(mIU/mL)

< 1000 1000 - < 10000

10000 - < 100000

≥ 100000

Largest tumor size including

uterus (cm)

< 3 3 - < 5 ≥ 5

Site of metastases

Lung Spleen, kidney

GIT Brain, liver

Number of metastases

0 1-4 4-8 >8

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

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, cyclophosphamide 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 AfterTherapy 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 disease3. 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

disease

Pathological features Clinical features

Invasive moleMyometrial invasion

Swollen villiHyperplastic trophoblast

15% metastatic-lung/vaginaMost often diagnosed clinically, rather than

pathologically

ChoriocarcinomaAbnormal trophoblastic

hyperplasiaand anaplasia

Absent villiHemorrhage, necrosis

Vascular spread to distant

sites–lung/brain/liverMalignant disease

PSTTTumor cells infiltrate

myometrium withvascular/lymphatic

invasionIntermediate

cells/absent villiLess hemorrhage and

necrosisTumor cells stain positive for hPL

Extremely rarehCG levels less reliable

indicatorRelatively

chemoresistantMainly surgical

treatment

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)

Thank you