Gestational Trophoblastic Disease (GTD) Part II: Gestational Trophoblastic Neoplasia (GTN)

September, 2010
Dr. Mohamed El Sherbiny
MD Ob.& Gyn. Senior Consultant Damietta, Egypt

Part II: Gestational Trophoblastic Neoplasia (GTN)

Definitions Gestational Trophoblastic Disease (GTD)

It is a spectrum of trophoblastic diseases that includes: Complete molar pregnancy Partial molar pregnancies Invasive mole Choriocarcinoma Placental site trophoblastic tumour
The last 2 may follow abortion, ectopic or normal pregnancy. RCOG Guideline No. 38 .2010

Definitions Gestational Trophoblastic Neoplasia (GTN) =Malignant Gestational Trophoblastic Disease

It is a spectrum of trophoblastic diseases that develops malignant sequelae. GTN includes: Persistent post molar GTD Invasive mole Choriocarcinoma Placental site trophoblastic tumour
The last 2 may follow abortion, ectopic or normal pregnancy. Disaia &Creasman Clinical Gynecological Oncology 2007 Cunningham et al Williams Obsterics 23rd , 2010

Classifications
Gestational Trophoblastic Disease (GTD)
I-Pathologic Partial mole Classification Complete
mole Invasive Chorio mole carcinoma
Placental site trophoblastic tumour

II-Clinical Classification
hCG based: WHO, FIGO, ACOG 2004 & RCOG 2010

Benign G.T.D.

G.T. Neoplasia Malignant G.T.D.

Non metastatic

Metastatic

Low risk

High risk

Features Of Partial And Complete Hydatidiform Moles

Feature Karyotype Pathology
Fetus Amnion, fetal RBC Villous edema Trophoblastic proliferation

Partial mole
Most commonly 69, XXX or - XXY

Complete mole
Most commonly 46, XX or -,XY

Often present Usually present Variable, focal Focal, slight-moderate Missed abortion Small for dates Rare Rare 2.5-7.5%

Absent Absent Diffuse Diffuse, slight-severe

Clinical presentation
Diagnosis Uterine size Theca lutein cysts Medical complications Postmolar CTN Molar gestation 50% large for dates 25-30% 10-25% 6.8-20%

Disaia &Creasman Clinical Gynecological Oncology 2007 Cunningham et al Williams Obsterics 23rd , 2010

Histopathological Classification

Invasive Mole
Villus formation preserved Trophoblast cells invade myometrium and blood vessels Villus

Myometrium

Myometrium invaded

Myometrial invasion

Vesicles

Invasive H. Mole

Sometimes involving the peritoneum, parametrium, or vaginal vault. Originate almost always from H. mole

anterior uterine wall

Invasive Mole

Molar mass

Posterior uterine wall

MRI Axial fat-

suppressed T1

A molar mass in the distended endometrial cavity with attachment to the anterior wall of the uterine body

Gestational Choriocarcinoma
Aneuploidy (not multiplication of 23 ) 1 in 30,000 pregnancies 40% after molar pregnancy: Easily Diagnosed 60% non-molar pregnancy: Difficult Diagnosis Why difficult? The main presentations are often
non-gynecologic including hemoptysis or pulmonary embolism, cerebral hemorrhage, gastrointestinal or urologic hemorrhage.

Gestational Choriocarcinoma
Sheets of anaplastic cytotrophoblast and syncytiotrophoblast cells with hemorrhage & necrosis. Myometrial &B. vessels invasion and earlymetastases No Villus formation Syncytiotrophoblast

Cytotrophoblast

Gestational Choriocarcinoma

Hemorrhagic lesions

Choriocarcinoma is evident in the fundus of the hysterectomy specimen

Vaginal Metastasis

Choriocarcinoma MRY T2 (Uterus)

Chriocarcinoma/Invasive mole

Placental Site Trophoblastic Tumour

Monomorphic Mononuclear
Mainly cytotrophoblst

Intermediate trophoblastic cells

Bleeding after termination of pregnancy or years later. It secrets HPL and very little HCG Very Rare & Usually limited to the uterus Treatment: Hysterectomy Chemotherapy as GTN usually single agent.

Placental Site Trophoblastic Tumour

Intermediate cell
Monomorphic Mononuclear Mainly cytotrophoblst

Metastatic Disease
If the pelvic examination & chest X-ray are negative, it is very uncommon to have metastatic involvement of other sites

Metastatic Disease
In 4% of patients after molar evacuation but is seen more commonly after other pregnancies Sites of metastases

1- Pulmonary (80 %) 2- Vaginal metastases (30 %) 3- Hepatic in (10 %) 4- Central nervous system (10 %)

Chest X ray: widespread metastatic lesions.

GTN Vaginal Metastasis

Cranial MRI scan: Large metastasis on the left (black arrows)

Brain MRI of a patient with a solitary brain metastasis in remission

Autopsy specimen Multiple hemorrhagic hepatic metastasis

CT Scan: Liver metastsis

Which Women Should Be Investigated For Persistent GTN After A Non-molar Pregnancy?
Any woman who develops persistent vaginal bleeding after a pregnancy event. A urine pregnancy test should be performed in all cases of persistent or irregular vaginal bleeding after a pregnancy event. Symptoms from metastatic disease, such as dyspnoea or abnormal neurology, can occur very rarely.
RCOG Guideline No. 38 .2010

Case Scenario 1

A 32-year-old Gravida 3 ,Para 2 woman. She has 2 History of suction evacuation of molar pregnancy 5 weeks ago. Her post evacuation level of hCG level was 120,550 mIU/mL and the weekly follow up has a rapid decline. She is very worried about malignant GTD (GTN), as at the last follow up, her hCG levels was unexpectedly raised from 10,900 to 12,100 mIU/mL (11%)

Which Of The Following Treatment Would Be Initiated?

A.A course of single-agent chemotherapy B. A course of combination chemotherapy C. Repeat hCG weekly for further 2 measurements D. Hysterectomy and then methotrexate E. CT of the brain, chest, abdomen, and pelvis

C.

Why?

Serum beta-hCG following uterine evacuation `

When Is Postmolar GTN Diagnosed ?

1-Plateau of serum hCG level (10%) for 4 measurements during a period of 3 weeks or longerdays 1, 7, 14, 21. or 2-Rise of serum hCG > 10% during 3 weekly consecutive measurements or longer, during a period of 2 weeks or moredays 1, 7, 14. or 3- The serum hCG level remains detectable for 6 months.or 4. Histological criteria for choriocarcinoma.
FIGO Oncology Committee, 2002).

The Case Scenario1

The case has only one rise level of hCG ,so the treatment that should be initiated is:
C. Repeat hCG weekly for further 2 measurements

Her hCG Levels Are Raised Again : 12,100 - 19.200, - 25.400 Mlu/Ml . How Can We Manage?
1-Blood investigations:CBC ,hepatic, thyroid, and renal function tests 2-Metastatic workup : Chest X ray or CT scan U/S abdomen and pelvis or CT CT or MRI scan of the head Then
FIGO Prognostics Scoring & Anatomical staging

Case Results 1-Blood investigations: CBC, hepatic, thyroid, & renal function tests: All are within normal limits. 2-Metastatic workup: Chest X ray (+) U/S abdomen: Normal Pelvic U/S: 1 uterus endometrial lining: Thickened (21mm) and hyperechogenic MRI scan of the head: Normal

Pulmonary metastases of GTN present as Solitary R pulmonary nodules

Which Of The Following Treatment Would Be Initiated ?

A. A course of actinomycin D B. A course of Methotrexate (MTR) C. A course of actinomycin D + MTR D. A course of EMA/CO chemotherapy E. Hysterectomy and then methotrexate

B.

Why?

What Is The Optimum Treatment For GTN?

GTN
Non metastatic GTD Low Risk ( 6) Metastatic High Risk (7)

Single agent Chemotherapy Methotrexate or Actinomycen D

Multi-agent Chemotherapy

RCOG Guideline No. 38 .2010

FIGO Prognostic Scoring For GTN (2000)

FIGO SCORING Age (years) Antecedent pregnancy Pregnancy to treatment Interval (months) Pretreatment serum hCG (iu/l) Largest tumour size, including uterus (cm) Site of metastases Number of metastases Previous failed chemotherapy 0 <40 Mole <4 1 >40 Abortion 4to <7 Term 7to <13 -13 2 4

<1000 <3 Lung ---

1000-10,000 3 to<5 Spleen & Kidney 1-4 --

10,000-100,000 5 Gastrointestinal 5-8 Single drug

> 100,000 -Liver & brain >8 2 Drugs

Total Score Survival : 6 = Low risk (100%) 7 = High risk. (95%)

FIGO Prognostic Scoring Fore The Case

FIGO SCORING Age (years) Antecedent pregnancy Pregnancy to treatment Interval (months) Pretreatment serum hCG (iu/l) Largest tumour size, including uterus (cm) Site of metastases Number of metastases Previous failed chemotherapy 0 <40 Mole <4 1 >40 Abortion 4to <7 Term 7to <13 -13 2 4

<1000 <3 Lung ---

1000-10,000 3 to<5 Spleen &Kidney 1-4 --

10,000-100,000 5 Gastrointestinal 5-8 Single drug

> 100,000 -Liver &brain >8 2 Drugs

Total FIGO Score : 4 = Low Risk

FIGO Anatomic Staging Of GTN

Stage I Disease confined to the uterus Stage II GTN extends outside of the uterus but is limited to the genital structures (adnexa, vagina, broad ligament) Stage III GTN extends to the lungs, with or without known genital tract involvement Stage IV All other metastatic sites (brain, liver) The FIGO GTN Description = FIGO stage: FIGO Score FIGO Oncology Committee, 2002 The scenario case FIGO GTN Discreption=: III : 4

FIGO Scoring System FOR The Senario Case

FIGO SCORING Age (years) Antecedent pregnancy Pregnancy to treatment Interval (months) Pretreatment serum hCG (iu/l) Largest tumour size, including uterus (cm) Site of metastases Number of metastases Previous failed chemotherapy 0 <40 Mole <4 1 >40 Abortion 4to <7 Term 7to <13 -13 2 4

<1000 <3 Lung ---

1000-10,000 3 to<5 Spleen &Kidney 1-4 --

10,000-100,000 5 Gastrointestinal 5-8 Single drug

> 100,000 -Liver &brain >8 2 Drugs

FIGO Score :4 = Low Risk :RCOG 2010 TTT Methotrexate

Why Methotrexate (MTX) is the first line of choice? Hysterectomy plus Chemotherapy is indicated: If the patient does not wish to preserve fertility or There is a resistance to chemotherapies The present case has 2girles and still young and desires children

Methotrexate is less toxic than actinomycin D Methotrexate or actinomycin D alone equally effective compared with a combination of the two.
Disaia &Creasman Clinical Gynecological Oncology 2007 Cunningham et al Williams Obsterics 23rd , 2010

What is the best methotrexate regimen?

MTX:1mg/kg IM D:1, 3 ,5 ,7 alternating with Folinic acid 0.1mg/kg IM D 2 , 4 , 6 , 8 followed by 6 rest days Treatment is continued, until the hCG level has returned to normal and then for a further 6 consecutive weeks.
RCOG Guideline No. 38 .2010

As any chemotherapy treatment is reevaluated if CBC, liver or kidney FT are affected or at drug resistance

The patient responds to the MTX At the last dose of chemotherapy, the patient asked: 1-When am I allowed to conceive? 2- Will chemotherapy lead to premature menopause?

1-When am I allowed to conceive? Pregnancy can be allowed after one year after completion of chemotherapy treatment. 2- Will chemotherapy lead to premature menopause?
The age at menopause is advanced by one year after single agent chemotherapy.
RCOG Guideline No. 38 .2010

What Is The Survival of GTN By FIGO Stage?

Stage I II III IV Survival 424/424 27/27 130/131 14/18 Percent % 100 100 99 78

Disaia &Creasman Clinical Gynecological Oncology 2007

Case Scenario 2

The family of a 31-year-old P3+1 woman brings her to the emergency room with altered mental status. Gynecologist is called as there was blood spots at here under wear. Upon further history taking, she is noted as:  Underwent D&C 4 months ago for secondary postpartum hemorrhage 10 weeks postnatally  Received cough expectorants at the last 3 weeks and had bloody sputum in the last 2 days

 No history of recent trauma, infections or past history of chronic medical disorders  She is lactating and the husband is using contraceptive condom  P:110/70, pulse 95/m, RR 24/m  Chest: Mild wheeze  Examination of breasts, abdomen and rectum were normal.  Pelvic examination: Small brown vascular nodule at the postero-lateral wall of the vagina

What Is The Differential Diagnosis Of This Vaginal Nodule ?

Benign: Epidermal Inclusion Cysts Premalignant: Vaginal wart or VAIN Malignant Primary Squamous cell carcinoma Adenocarcinoma Melanoma Clear Cell Adenocarcinoma
(DES-IU exposure )

Embryonal Rhabdomyosarcoma Very rare Secondary Uterus, ovaries, rectum, bladder or Choriocarcinoma

What Is The Most Likely Diagnosis?

Metastatic Vaginal Tumors Probably Choriocarcinoma

Why Metastatic Vaginal Tumors?

The non-noplastic and the primary neoplasm are not likely:
The epidermal inclusion cysts & vaginal wart or VAIN are not vascular and are usually asymptomatic Squamous cell carcinoma and adenocarcinoma are unlikely as they occur usually after the age of 50 years Melanoma can present similar to this lesion ,but melanoma is primarily postmenopausal. Sarcoma botryoides occurs usually in children. Clear cell adenocarcinoma is always associated with vaginal adenosis that not seen in this case

Main Differential Diagnosis

Epidermal inclusion cysts

Condylomata acuminata VAIN

Squamous cell carcinoma

Melanoma

Why Most Probably metastatic Choriocarcinoma?

Vaginal metastases from adenocarcinoma of other pelvic and abdominal organs are more common than primary vaginal cancers. These primary malignancy usually metastasize via direct or lymphatic spread. On the contrary, GTN metastasizes mainly hematogenously to the Lung 80%, Vagina 30%, Liver 10%, CNS 10%, spleen and kidney.

Disaia &Creasman Clinical Gynecological Oncology 2007

Why Most Probably Metastatic Choriocarcinoma?

The history of:  D&C 4 months ago for secondary postpartum hemorrhage 10 weeks postnatal may be suggestive of persistent trophoblastic disease  Receiving cough expectorants at the last 3 weeks and had bloody sputum in the last 2 days, are suggestive of lung metastasis The presentation at the emergency room with altered mental status also may suggest brain metastasis

How Can The Diagnosis Be Confirmed?

1-Quantitatve hCG 2-Metastatic workup: Chest X ray or CT scan U/S abdomen and pelvis or CT CT or MRI scan of the head

Case Results
BhCG level is 20,550 mIU/mL 2-Metastatic workup Chest X ray: Diffuse pulmonary Nodules U/S abdomen: Normal Pelvic U/S: Endometrial lining: Thickeness19mm and hyperechogenic CT scan of the head: Diffuse Pulmonary Nodules

Diffuse Pulmonary Nodules

CT Scan Head: 2 metastatic lesions

Why C-EMA-CO chemotherapy

1-Blood investigations: CBC, hepatic, thyroid, and renal function tests 2- FIGO Prognostics Scoring 3- FIGO Anatomical staging 4-Treatment 5-Serial follow up

FIGO Scoring System FOR The Senario Case

FIGO SCORING Age (years) Antecedent pregnancy Pregnancy to treatment Interval (months) Pretreatment serum hCG (iu/l) Largest tumour size, including uterus (cm) Site of metastases Number of metastases Previous failed chemotherapy 0 <40 Mole <4 1 >40 Abortion 4to <7 Term 7to <13 -13 2 4

<1000 <3 Lung ---

1000-10,000 3 to<5 Spleen &Kidney 1-4 --

10,000-100,000 5 Gastrointestinal 5-8 Single drug

> 100,000 -Liver &brain >8 2 Drugs

FIGO Score :10 = High Risk :RCOG

FIGO Anatomic Staging Of GTN

Stage I Disease confined to the uterus Stage II GTN extends outside of the uterus but is limited to the genital structures (adnexa, vagina, broad ligament) Stage III GTN extends to the lungs, with or without known genital tract involvement Stage IV All other metastatic sites (brain, liver) The FIGO GTN Description = FIGO stage: FIGO Score FIGO Oncology Committee, 2002 The scenario case FIGO GTN Description =: IV : 10

Which Of The Following Treatment Would Be Offered ?

A- Carboplatin and paclitaxel then irradiation B-EMA/CO then surgical resection of brain lesion C. EMA/CO, along with whole-brain irradiation D. Whole brain irradiation only. E. Methotrexate 15 mg intrathecal injection

C.

Why?

Why EMA/CO + Whole-brain Irradiation?

A Carboplatin and paclitaxel is the recommended adjuvant therapy for ovarian cancer and not for GTN The corner stone of management is combination chemotherapy (EMA/CO). The hole-brain irradiation (3,000 cGy in 10 fractions) has very effective hemostatic and tumoricidal role for this highly vascular lesion.
Disaia &Creasman Clinical Gynecological Oncology 2007 RCOG Guideline No. 38 .2010

Why EMA-CO + Whole-brain Irradiation?

The concurrent use of EMA/CO and wholebrain irradiation will lessen the risk of : Spontaneous cerebral hemorrhage Cerebral hemorrhage at emergency craniotomy (if the patient displays rapidly deteriorating signs) Methotrexate 15 mg intrathecal injection may be given instead of brain irradiation adjuvant to EMA/CO regimen.
Berek & Novak's Gynecology, 14th Edit.2007 Disaia &Creasman Clinical Gynecological Oncology 2007 Schorag et al ,Williams Gynecology 2007

What Is The Optimum Treatment For GTN?

GTN
Non metastatic GTD Low Risk ( 6) Metastatic High Risk (7)

Single agent Chemotherapy Methotrexate or Actinomycen D

Mult-agent Chemotherapy EMA-CO Etoposide, Methotrexate, Actinomycin D, Cyclophosphamide, and Oncovin (vincristine).

RCOG Guideline No. 38 .2010

FIGO Staging &Treatment Of GTN

Stage Disease confined to the uterus I Stage GTN extends outside of the uterus II but is limited to the genital structures (adnexa, vagina, broad ligament) Stage GTN extends to the lungs, with or III without known genital tract involvement Stage IV All other metastatic sites (brain, liver)
Single Agent Chemotherapy IM.Methotrexate

Low Risk (score 6) High Risk (Score 7)

10

Multi-agent Chemotherapy EMA-CO BereK&NovaKs,14th Edit. 2007 FIGO Oncology Committee, 2002 Case Scenario EMA-CO: Etoposide, Methotrexate, Actinomycin D, Cyclophosphamide, and Oncovin (vincristine).

Surveillance During And After Therapy Of GTN

Monitor serum quantitative hCG levels every week during chemotherapy: 1. Response: >10% decline in hCG at one cycle 2. Plateau: 10% change in hCG at one cycle 3. Resistance: >10% rise in hCG at one cycle or Plateau for two cycles of chemotherapy  Evaluate for new metastases  Consider alternative chemotherapy  Consider extirpation of drug-resistant sites of disease
Disaia &Creasman Clinical Gynecological Oncology 2007

Chemotherapy Should Not Be Repeated Unless

WBC > 3000/cu mm Polymorph > 1500 cu mm Platelets > 100,000 cu mm BUN, SGOT, SGPT are normal No febrile course No oral or GIT ulceration

Surveillance During and After Therapy of GTN

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

RCOG Guideline No. 38 .2010

Surveillance During and After Therapy of GTN

Remission: 3 consecutive normal weekly hCG values Surveillance after remission: 1. hCG values every 2 week 3 months 2. hCG values every month to complete one year of follow-up 3. hCG values every 6 12 months indefinitely; at least 3 5 years Disaia &Creasman Clinical
Gynecological Oncology 2007

Thank You

Egypt