Gestational Trophoblastic Disease (GTD) Part II: Gestational Trophoblastic Neoplasia (GTN) September, 2010 Dr. Mohamed El Sherbiny MD Ob.& Gyn. Senior Consultant Damietta, Egypt 1

Part II: Gestational Trophoblastic Neoplasia (GTN)

Gestational Trophoblastic Disease (GTD) 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

Gestational Trophoblastic Neoplasia (GTN) 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) II-Clinical I-Pathologic Classification I-Pathologic Classification I-Pathologic Classification I-Pathologic Classification I-Pathologic Classification I-Pathologic Classification Partial mole Complete mole Partial mole Complete mole Partial mole Complete mole Partial mole Complete mole Partial mole Complete mole Partial mole Complete mole Invasive mole Chorio carcinoma Chorio carcinoma Chorio carcinoma Chorio carcinoma Placental site trophoblastic tumour Placental site trophoblastic tumour II-Clinical Classification βhCG based: WHO, FIGO, ACOG 2004 & RCOG 2010 G.T. Neoplasia Malignant G.T.D. Persistent GTD Benign G.T.D. Metastatic Non metastatic Low risk High risk 5

Features Of Partial And Complete Hydatidiform Moles Partial mole Complete mole Karyotype Most commonly 69, XXX or - XXY 46, XX or -,XY Pathology Fetus Often present Absent Amnion, fetal RBC Usually present Villous edema Variable, focal Diffuse Trophoblastic proliferation Focal, slight-moderate Diffuse, slight-severe Clinical presentation Diagnosis Missed abortion Molar gestation Uterine size Small for dates 50% large for dates Theca lutein cysts Rare 25-30% Medical complications 10-25% Postmolar CTN 2.5-7.5% 6.8-20% Disaia &Creasman Clinical Gynecological Oncology 2007 Cunningham et al Williams Obsterics 23rd , 2010

Histopathological Classification

Invasive Mole Myometrium Villus formation preserved Trophoblast cells invade myometrium and blood vessels Villus Myometrium Myometrium invaded 8

Myometrial invasion Vesicles Invasive H. Mole Sometimes involving the peritoneum, parametrium, or vaginal vault. Originate almost always from H. mole 9

Invasive Mole anterior uterine wall 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. 12

Gestational Choriocarcinoma Sheets of anaplastic cytotrophoblast and syncytiotrophoblast cells with hemorrhage & necrosis. Myometrial &B. vessels invasion and earlymetastases No Villus formation Syncytiotrophoblast Cytotrophoblast 13

Gestational Choriocarcinoma Choriocarcinoma is evident in the fundus of the hysterectomy specimen Hemorrhagic lesions Vaginal Metastasis 14

Choriocarcinoma MRY T2 (Uterus)

Chriocarcinoma/Invasive mole 16 16

Placental Site Trophoblastic Tumour 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. Monomorphic Mononuclear Mainly cytotrophoblst 17

Placental Site Trophoblastic Tumour Intermediate cell Monomorphic Mononuclear Mainly cytotrophoblst 18

Metastatic Disease If the pelvic examination & chest X-ray are negative, it is very uncommon to have metastatic involvement of other sites 19

Metastatic Disease 1- Pulmonary (80 %) 2- Vaginal metastases (30 %) 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 %) 20

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

CT Scan: Liver metastsis 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 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 βhCG 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 βhCG 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 βhCG weekly for further 2 measurements D. Hysterectomy and then methotrexate E. CT of the brain, chest, abdomen, and pelvis C. Why? 28

Serum beta-hCG following uterine evacuation `

When Is Postmolar GTN Diagnosed ? 1-Plateau of serum βhCG level (±10%) for 4 measurements during a period of 3 weeks or longer—days 1, 7, 14, 21. or 2-Rise of serum β hCG > 10% during 3 weekly consecutive measurements or longer, during a period of 2 weeks or more—days 1, 7, 14. or 3- The serum β hCG level remains detectable for ≥ 6 months.or 4. Histological criteria for choriocarcinoma. FIGO Oncology Committee, 2002). 30

The Case Scenario1 The case has only one rise level of β hCG ,so the treatment that should be initiated is: C. Repeat βhCG weekly for further 2 measurements

Then Her ΒhCG 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 32

MRI scan of the head: Normal 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 33

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? 36

Multi-agent Chemotherapy What Is The Optimum Treatment For GTN? GTN Non metastatic GTD Metastatic Low Risk ( ≤ 6) High Risk (≥7) Multi-agent Chemotherapy Single agent Chemotherapy Methotrexate or Actinomycen D RCOG Guideline No. 38 .2010 37

FIGO Prognostic Scoring For GTN (2000( 4 2 1 FIGO SCORING >40 <40 Age (years) -- Term Abortion Mole Antecedent pregnancy ≥13 7to <13 4to <7 <4 Pregnancy to treatment Interval (months) > 100,000 10,000-100,000 1000-10,000 <1000 Pretreatment serum hCG (iu/l) ≥5 3 to<5 < 3 Largest tumour size, including uterus (cm) Liver & brain Gastro-intestinal Spleen & Kidney Lung Site of metastases >8 5-8 1-4 Number of metastases ≥2 Drugs Single drug Previous failed chemotherapy Total Score Survival : ≤ 6 = Low risk (100%) ≥7 = High risk. (95%)

Total FIGO Score : 4 = Low Risk FIGO Prognostic Scoring Fore The Case 4 2 1 FIGO SCORING >40 <40 Age (years) -- Term Abortion Mole Antecedent pregnancy ≥13 7to <13 4to <7 <4 Pregnancy to treatment Interval (months) > 100,000 10,000-100,000 1000-10,000 <1000 Pretreatment serum hCG (iu/l) ≥5 3 to<5 < 3 Largest tumour size, including uterus (cm) Liver &brain Gastro-intestinal Spleen &Kidney Lung Site of metastases >8 5-8 1-4 Number of metastases ≥2 Drugs Single drug Previous failed chemotherapy Total FIGO Score : 4 = Low Risk

FIGO Anatomic Staging Of GTN Disease confined to the uterus Stage I GTN extends outside of the uterus but is limited to the genital structures (adnexa, vagina, broad ligament) Stage II GTN extends to the lungs, with or without known genital tract involvement Stage III All other metastatic sites (brain, liver) Stage IV FIGO Anatomic Staging 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 4 2 1 FIGO SCORING >40 <40 Age (years) -- Term Abortion Mole Antecedent pregnancy ≥13 7to <13 4to <7 <4 Pregnancy to treatment Interval (months) > 100,000 10,000-100,000 1000-10,000 <1000 Pretreatment serum hCG (iu/l) ≥5 3 to<5 < 3 Largest tumour size, including uterus (cm) Liver &brain Gastro-intestinal Spleen &Kidney Lung Site of metastases >8 5-8 1-4 Number of metastases ≥2 Drugs Single drug Previous failed chemotherapy 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? Percent % I 424/424 100 II 27/27 III 130/131 99 IV 14/18 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 Secondary Uterus, ovaries, rectum, bladder or Choriocarcinoma Very rare

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 βhCG 2-Metastatic workup: Chest X ray or CT scan U/S abdomen and pelvis or CT CT or MRI scan of the head 59

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 60

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 63

FIGO Scoring System FOR The Senario Case 4 2 1 FIGO SCORING >40 <40 Age (years) -- Term Abortion Mole Antecedent pregnancy ≥13 7to <13 4to <7 <4 Pregnancy to treatment Interval (months) > 100,000 10,000-100,000 1000-10,000 <1000 Pretreatment serum hCG (iu/l) ≥5 3 to<5 < 3 Largest tumour size, including uterus (cm) Liver &brain Gastro-intestinal Spleen &Kidney Lung Site of metastases >8 5-8 1-4 Number of metastases ≥2 Drugs Single drug Previous failed chemotherapy FIGO Score :10 = High Risk :RCOG

FIGO Anatomic Staging Of GTN Disease confined to the uterus Stage I GTN extends outside of the uterus but is limited to the genital structures (adnexa, vagina, broad ligament) Stage II GTN extends to the lungs, with or without known genital tract involvement Stage III All other metastatic sites (brain, liver) Stage IV FIGO Anatomic Staging 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? 66

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 67

Why EMA-CO + Whole-brain Irradiation? The concurrent use of EMA/CO and whole- brain 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 68

GTN What Is The Optimum Treatment For GTN? Non metastatic GTD Metastatic Low Risk ( ≤ 6) High Risk (≥7) Mult-agent Chemotherapy EMA-CO Etoposide, Methotrexate, Actinomycin D, Cyclophosphamide, and Oncovin (vincristine). Single agent Chemotherapy Methotrexate or Actinomycen D RCOG Guideline No. 38 .2010 69

FIGO Oncology Committee, 2002 FIGO Staging &Treatment Of GTN Disease confined to the uterus Stage I GTN extends outside of the uterus but is limited to the genital structures (adnexa, vagina, broad ligament) Stage II GTN extends to the lungs, with or without known genital tract involvement Stage III All other metastatic sites (brain, liver) Stage IV Single Agent Chemotherapy Low Risk (score ≤ 6) High Risk (Score ≥7) Multi-agent IM.Methotrexate 10 FIGO Anatomic Staging EMA-CO BereK&NovaK’s,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 72

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