jacqueline morgan august 2nd, 2017 - kusm-w wesley … · 2017-08-06 · chorionic villi fluid...
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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?