JACQUELINE MORGANAugust 2nd, 2017

GTD Hydatidiform Mole

Complete

Partial

Invasive Mole

Choriocarcinoma

Placental Site Trophoblastic Tumor

Epithelioid Trophoblastic tumor

Hydatidiform Mole Chorionic villi fluid filled and distended

Scant blood vessels

Proliferation of the cytotrophoblast and syncitiotrophoblast.

Variable degree of hyperplasia and anaplasia

Difficult pathologic interpretation in earlier gestations

P53 IHC

Hydatidiform Mole Incidence 0.6 – 1.1 per 1,000 pregnancies

Increased risk at extremes of reproductive age

Recurrence risk of 0.5 – 2.6%

Higher risk of neoplasia following recurrent molar pregnancy

Hydatidiform Mole- Diagnosis Classic presentation seen less and less

Vaginal bleeding

Uterine enlargement > dates

Hyperemesis

1st & 2nd trimester hypertension/Pre-eclampsia

Hyperthyroidism

CHF

Pulmonary edema

Bilateral ovarian masses

Hydatidiform Mole- Diagnosis Much earlier diagnosis now

U/S Vesicular pattern (Snow-storm)

Absent or abnormal fetus

hCG assay Elevated above normal levels, often > 100,000

Often diagnosed after histological review after treatment for incomplete or missed abortion

Hydatidiform Mole

How are Moles made?

Complete Molar Pregnancy 46XX or 46XY

Chromosomal DNA paternal

Absent fetus or embryo

Early and total villi swelling

Hyperplastic trophoblast +/- atypia

10-20% risk of subsequent trophoblastic neoplasia

Complete Molar Pregnancy

Complete Molar Pregnancy

Partial Molar Pregnancy 69XXY or 69XXX

Slowly progressive hydatidiform change

Not all villi affected

Functional villous blood vessels

Focal hyperplasia, minimal atypia

Abnormal fetus or embryo of membranes present

5% risk of subsequent trophoblastic neoplasia

Partial Mole

Phantom hCG Heterophile antibodies

Human antimouse antibodies

Mimic hCG by binding to tracer mouse IgG

If suspect false positive

Check urine hCG

Useful if serum HCG above threshold for urine test

Serial dilution of serum

Blocking agents added to serum

Obtain testing at national hCG testing lab

Avoid treating healthy patients with unnecessary surgery or chemotherapy

False Positive Cross reaction with other serum glycoproteins

Common alpha sub-unit with LH

FSH

TSH

Check levels

Trial of hormonal therapy for 3-4 weeks

Hydatidiform Mole- Evaluation Detailed history Physical exam CBC Coags Chemistry panel TFTs Type and Screen Serum hCG level Pelvic U/S CXR

Hydatidiform Mole- Evacuation

Suction D&C U/S guidance can be of benefit

Larger uterus

Variable amount of intrauterine tissue

Uterine wall soft

Hysterectomy If fertility not desired

Hysterotomy and medical induction of labor not recommended

Surgical Evacuation Follow UpPathologic analysis of all specimens

Serial hCG follow up

Contraception for 6 months- if no hysterectomy

Future pregnancies 6 week postpartum hCG level

Histological analysis of placenta or POC

Hydatidiform Mole- Follow Up 80% cured by evacuation alone

Repeat curettage

If continued bleeding

If U/S evidence of retained products

Rarely curative on its own

Serial hCG measurements

Serial hCG Follow Up Serum hCG levels every 2 weeks until 3 consecutive

normal tests

Testing to be performed at same lab, using same assay kit

Then monthly serum hCG levels for 6 months

Avoidance of pregnancy for 6 months

Post Molar Contraception OCPs commonly used

No effect on prognosis or recurrence risk

Added benefit of suppressing endogenous LH which can interfere with hCG monitoring

Need a reliable form of contraception

Must tailor to the individual patient

Risk Factors for Postmolar GTN Large pre-evacuation uterine size

Theca lutein cysts > 6cm

Age > 40yo

Serum hCG > 100,000

Medical complications from molar pregnancy

Previous molar pregnancy

Prophylactic Chemotherapy Single agent Methotrexate or Actinomycin D following

molar evacuation

Reduced incidence of post molar GTN from 47% to 14% amoung a population of patients with very high risk complete moles (Kim et al.)

No benefit to those without multiple high risk factors

Potential role when no follow up is available

Generally not recommended

Gestational Trophoblastic Neoplasia Invasive mole

Choriocarcinoma

Placental site trophoblastic tumor

Epithelioid trophoblastic tumor

Gestational Trophoblastic Neoplasia May follow

Known molar gestation

SAb or TAb

Term Gestation

Trophoblastic tumors can present decades post pregnancy

Gestational Trophoblastic Neoplasia- Presentation

Highly Variable

Lab only if ongoing hCG surveillance

Dependant upon site of disease Mass effect

Tumors have high propensity to bleed Hemoptysis

Hematemesis

Intracranial hemorrhage

Young female with multiple tumor masses- Check hCG level

Gestational Trophoblastic Neoplasia-Presentation

Gestational Trophoblastic Neoplasia Diagnosed by

Plateauing or rising hCG following molar pregnancy evacuation

Histopathologic diagnosis

Persistent elevation of hCG following any pregnancy event

Gestational Trophoblastic Neoplasia- Initial Assessment

History and Physical Exam

hCG level

CBC

Chemistry panel

Coags

TFTs

T&S

CXR

CT chest/abdo/pelvis

MRI brain

NCI Criteria for high risk disease

Greater than 4 months from antecedent pregnancy

Pretreatment hCG >100,000 on 24hr urine

>40,000 serum hCG

Metastasis to sites other than vagina and lung

Antecedent term gestation

Prior failed chemotherapy

GTN Staging System- FIGO Anatomic staging system, 1982

Stage I- Disease confined to uterus

Stage II- Disease extends to other genital structures

Stage III- Disease extends to lungs +/- genital disease

Stage IV- Disease involves other metastatic sites

GTN Staging System WHO, 1983

Prognostic scoring system

<7 - low risk disease

= or>7 - high risk disease

In 2000 FIGO included a modified WHO score into its anatomic staging system.

WHO GTN Staging SystemCharacteristic Score

0 1 2 4

Age < 40 = or > 40 - -

Months from pregnancy < 4 4 - 6 7 - 12 > 12

Pretreatment hCG < 1,000 1,000-10,000

10,000-100,000

>100,000

Largest tumor size < 3 cm 3 – 4 cm = or > 5 cm

-

Site of metastasis Lung Spleen, kidney

GI tract Liver, Brain

No of metastasis - 1 - 4 5 - 8 > 8

Antecedent pregnancy Mole Abortion Term -

Previous failed chemotherapy

- - Single drug Two or more drugs

Non Metastatic Disease Single agent chemotherapy only

Methotrexate (MTX) or dactinomycin

85-90% cure with primary therapy

Further 10% remission with alternate single agent therapy

Rarely require multiagent therapy

<5% require hysterectomy for persistent refractory uterine disease

Methotrexate Mechanism of action?

Excretion?

Toxicity?

Methotrexate Mechanism of action?

Inhibits dihydrofolate reductase

Depletes reduced folate

Thymadine starvation

Methotrexate

Excretion

Mainly renal excretion

Small amount excreted in bile

MethotrexateToxicity?

Hepatic

Elevated LFTs

GI

Mucositis

Hematologic

Myelosupression

Renal

Precipitation in renal tubules nephrotoxic, maintain hydration

Actinomycin D DNA intercalation

Impairs DNA transcription and RNA translation

Excreted in urine and bile

½ life 36 hours

Actinomycin D Toxicity

Myelosupression

Alopecia

N/V

Mucositis

Radiation recall

Necrosis if extravasation.

Single Agent Regimens

Drug Regimen

MTX 0.4mg/kg/day IV or IM for 5 days in 14 day cycle

Act D 10-12mcg/kg/day IV for 5 days of 14 day cycle

MTX 1.0-1.5 mg/kg IM day 1,3,5,7, alternating with folinic acid 0.1mg/kg day 2,4,6,8 in 18d cycle

MTX 100mg/m² IV push then 200mg/m² over 12h, then folinic acid 15mg q 12hr x 4 doses

Act D 1.25 mg/m² IM weekly

MTX 30 – 50 mg/m²IM weekly

Single Agent RegimensPatients (No.)

Primary Remission Rate (%)

Multiagent ChemoRx (%)

Secondary Surgery (%)

MTX 5-Day-Hammond 1980

122 87 --

MTX 5-Day-Lurain 1995

253 89 1.2 0.8

MTX-FA-Berkowitz 1986

163 90 4.9 2.2

MTX-FA-Bagshawe 1989

348 80 -- --

Weekly MTX-Homesley 1990

62* 74 4.8 3.2

Weekly MTX-Hoffman 1996

20 60 5.0 --

Act D 5 Day-Kohorn 1996

43 88

Act D Pulsed-Kohorn 1996

18 78

Single Agent Chemotherapy for Low Risk GTN

Patients (No.) Primary Remission Rate (%)

Weekly MTX 30mg/m2 107 53

Pulsed Act D 106 69

Osborne R et al., 2008

Low Risk Metastatic Disease Stage II and III, WHO score < 7 5 day MTX or Act D protocol or 8 day MTX-FA

protocol 50 – 70% remission with primary therapy Sequential single agent therapy if remission not

achieved, or toxicity to drug (30-50% of pts) If second single agent fails- Multi-agent

chemotherapy (5-15% of those on 2nd agent therapy) Hysterectomy can be used as adjunctive therapy if

childbearing complete Survival approaching 100%

High Risk Metastatic Disease FIGO IV or WHO score 7 or more

Initial multiagent chemotherapy

EMA-CO

EMA

EMA-EP

Complete response 70 – 80 %

Survival 90%

EMA-CO

Day Drug Dosing

1 Etoposide

Act D

MTX

100mg/m² IV over 30min

0.5 mg IV push

100mg/m² IV push then 200mg/m² over 12 hours

2 Etoposide

Act D

Folinic acid

100mg/m² IV over 30min

0.5 mg IV push

15mg IM or PO q 12hr x 4

8 Cyclophosphamide

Vincristine

600mg/m² IV

1.0mg/m² IV push

Resistant Disease EMA-EP

BEP

VIP

ICE

Paclitaxel doublets ( ET/PT)

+/- GCSF agents

CNS Disease 50 – 80% survival

Whole brain irradiation

3,000 cGy in 200cGy fractions

MTX in EMA-CO increased to 1gm/m² with 30mg folinic acid q12 hr x 3 days

Intrathecal & IV high dose MTX

Surgical Treatments Surgical resection of isolated known foci of chemo

resistant disease

Hysterectomy

Thoracotomy for isolated pulmonary disease

Also for symptom control

Hemorrhage

Infection

GTN Follow Up Treatment to hCG normalization, then 2 subsequent

cycles

Monthly hCG level for 12 months

Contraception during therapy and for 1 yr following

Early U/S in subsequent pregnancy

Post pregnancy histopath.

hCG level 6 weeks post subsequent pregnancy

Reproductive Impact of Chemotherapy Aside from those requiring hysterectomy

Most return to normal ovulatory function and fertility post therapy

No change in rate of abortion, still birth, prematurity or congenital anomalies in subsequent pregnancies

Increased risk of future GTN related to subsequent pregnancies

Secondary Malignancies Related to etoposide use

Risk increased for

Acute myelogenous leukemia

Colon cancer

Melanoma

Breast cancer

Placental Site Trophoblastic Tumor

Intermediate trophoblasts

Human placental lactogen (hPL) marker

Low level hCG production

Less vascular invasion and distant metastasis

More lymphatic spread

Presents often remote to nonmolar gestation

Pelvic mass

Abnormal bleeding

Placental Site Trophoblastic Tumor Chemoresistant

Hysterectomy is primary therapy

Metastatic disease

Multi-agent chemotherapy

EMA-EP

Surgical resection

Epithelioid trophoblastic tumor Presents typically with abnormal uterine

bleeding/mass

Intermediate and syncytiotrophoblastic cells

hCG elevated

Presents remote from antecedent pregnancy

Chemoresistant

Primary surgical therapy

Questions?