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

2. Part II: Gestational Trophoblastic Neoplasia (GTN)

3. 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

4. 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

5. 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

6. 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 %
6.8-20%
Disaia &Creasman Clinical Gynecological Oncology 2007 Cunningham et al Williams Obsterics 23rd , 2010

7. Histopathological Classification

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

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

11. 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

12. 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

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

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

15. Choriocarcinoma MRY T2 (Uterus)

16. Chriocarcinoma/Invasive mole16 16

17. 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

18. Placental Site Trophoblastic Tumour
Intermediate cell
Monomorphic
Mononuclear
Mainly cytotrophoblst 18

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

20. 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

21. Chest X ray: widespread metastatic lesions.

22. GTN Vaginal Metastasis

23. Cranial MRI scan: Large metastasis on the left (black arrows)
Brain MRI of a patient with a solitary brain metastasis in remission

24. CT Scan: Liver metastsis
Autopsy specimen Multiple hemorrhagic hepatic metastasis
CT Scan: Liver metastsis

25. 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

26. Case Scenario 1

27. 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%)

28. 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

29. Serum beta-hCG following uterine evacuation `

30. 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, 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

31. 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

32. Then Her ΒhCG Levels Are Raised Again :
12, , 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

33. 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

34. Pulmonary metastases of GTN present as
Solitary R pulmonary
nodules

36. 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

37. 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 37

38. 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
,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%)

40. 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
,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

41. 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

42. FIGO Scoring System FOR The Senario Case4 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
,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 TTT Methotrexate

43. 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

44. 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
As any chemotherapy treatment is reevaluated if CBC, liver or kidney FT are affected or at drug resistance

45. 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?

46. 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

47. 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

48. Case Scenario 2

49. 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

50. 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

53. 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

54. What Is The Most Likely Diagnosis?
Metastatic Vaginal Tumors
Probably Choriocarcinoma

55. 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

56. Main Differential Diagnosis
Epidermal inclusion cysts
Condylomata acuminata VAIN
Squamous cell carcinoma
Melanoma

57. 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

58. 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

59. 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

60. 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

61. Diffuse Pulmonary
Nodules

62. CT Scan Head: 2 metastatic lesions

63. 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

64. FIGO Scoring System FOR The Senario Case4 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
,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

65. 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

66. 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

67. 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 67

68. 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

69. 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 69

70. 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).

71. 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

72. 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

73. 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

74. 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

75. Thank You
Egypt