Pathophysiology, Classification,Gestational trophoblastic neoplasia, presentation, management, WHO scoring , FIGO staging

1. GESTATIONAL TROPHOBLASTIC
NEOPLASIA

3. WHAT IS GESTATIONAL TROPHOBLASTIC
DISEASE ??
• A spectrum of diseases caused by abnormal
proliferation of trophoblastic tissue

4. WORLD HEALTH ORGANISATION (WHO)
CLASSIFICATION OF TROPHOBLASTIC
DISEASE
• Benign
• Hydatidiform mole
• Complete
• Partial
• Malignant gestational trophoblastic neoplasia
• Invasive hydatidiform mole
• Choriocarcinoma
• Placental site trophoblastic tumour
• Trophoblastic tumour, miscellaneous
• Exaggerated placental site
• Placental site nodule or plaque
• Unclassified trophoblastic lesions

5. COMPLETE HYATIDIFORM MOLE
• Mole without fetus or embryo
• Most often develops when either 1 or 2 sperm cells fertilize
an egg cell that contains no nucleus or DNA
• All the genetic material are paternal.
• Therefore, there is no fetal tissue.
• Usually diploid, with a 46,XX karyotype, and all molar
chromosomes are paternal in origin.
• About 10% have a 46,XY karyotype, which arises from
fertilization by two spermatozoa.

6. BENIGN
Hyatidiform mole(vesicular)
• The most common form of GTD
• It is made up of villi that are enlarged, edematous and
vesicular
• The swollen villi grow in clusters that look like bunches of
grapes
• Partial and complete differ in morphology, clinico-pathology
and cytogenic features

7. COMPLETE MOLE, PATHOGENESIS
Duplication 46XX
Empty ovum
23X
Diandric diploidy
Androgenesis
Paternal
chromosomes only

8. COMPLETE MOLE, PATHOGENESIS
46XX
Empty ovum
23X
Dispermic diploidy
Paternal
chromosomes only
23X 23X
23X

9. FEATURES
• Edematous chorionic villi in clusters “grape like”
• Different sizes
• Average size of 1.5cm in diameter
Microscopic features
• some enlarged villi show fluid filled space
“Central cistern pattern”
• High hCG production

10. COMPLETE MOLAR PREGNANCY

12. PARTIAL HYDATIDIFORM MOLE
• Develops when 2 sperm fertilize a normal egg.
• Dispermy, fertilization of an intact ovum by two spermatozoa
69XXX, 69XXY
• Fetus growth restricted and has multiple congenital
malformations often mixed in with the trophoblastic tissue.
• Often associated with severe hypertension
• Few enlarged villi and fewer masses of grape like villi.

13. PARTIAL MOLE, PATHOGENESIS
69XXY
Normal ovum
23X
Dispermic triploidy
Paternal extra set
23Y 23X
23Y 23X
23X

14. PARTIAL HYDATIDIFORM
MOLE

15. DIFFERENCES BETWEEN
COMPLETE AND PARTIAL

16. FEATURE OF CM/PM
FEATURE COMPLETE MOLE PARTIAL MOLE
Pathology
Fetal /embryonic tissue Absent Present
Hydatidiform swelling of
chorionic villi
Diffuse Focal
Trophoblastic hyperplasia Diffuse Focal
Scalloping of chorionic villli Absent Present
Trophoblastic stromal
inclusions
Absent Present
P57kip2 staining Negative Positive
karyotype 46 xx(90%),46 xy Triploid 69xxx,69xxy
Clinical presentation
Typical diagnosis Molar pregnancy Missed abortion
Post molar malignant
sequale
15% 0.5%

17. Feature Complete mole Partial mole
Clinical feature
Theca lutein cyst 25-30% 5-10%
Uterine size 50% large for date Small for date
Medical complication Frequent Rare
Need ofchemotherapy 15% 0.5%
HCG value Markedly increased Moderately increased

18. CLASSIFICATION OF GESTATIONAL
TROPHOBLASTIC DISEASE
WHO Classification
Malignant
neoplasms of
various types of
trophoblast
Malformations of
the chorionic villi
that are predisposed
to develop
trophoblastic
malignancies
Choriocarcinoma
Complete
Hydatidiform moles
Epithilioid trophoblastic
tumors
Placental site
trophoblastic tumor
Partial
Invasive

19. INVASIVE MOLE (CHORIOADENOMA
DESTRUENS)
• A Hyatidiform mole that has grown into the muscle
layer of the uterus.
• Invasive moles can either be complete or partial
• Complete moles become invasive much more often
than partial moles.
• Invasive moles develop in a little less than 1 out of
5 women who have had a complete mole removed.

20. INVASIVE MOLE
• Irregular vaginal bleeding
• Persistent theca lutein cyst
• Persistent / Rising HCG level after uterine evacuation
• Uterine subinvolution
C/F
• Persistent telomerase activity
• Whole chorionic villi that accompany excessive trophoblastic overgrowth & proliferation
• Tissue penitrate deep into myometrium peritoniumparametriumvaginal vault
pathogenesis
• Repeat D&C contraindicated for diag-ut perforation/infection /haemorrhage->hysterectomy
• Originate almost exclusively from complete or partial mole.

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

23. PLACENTAL-SITE TROPHOBLASTIC TUMOR
• Very rare form of GTD
• Develops where the placenta attaches to the lining of the
uterus.
• This tumor most often develops after a normal pregnancy or
abortion,
• It may also develop after a complete or partial mole is
removed.
• They do not spread to other sites in the body. But these
tumors have a tendency to invade the myometrium
• They are treated with surgery, not sensitive to drugs.

24. PLACENTAL SITE TROPHOBLASTIC TUMOR
• Irregular vaginal bleeding
• Follow term delivery(most common) /non-molar abortion/CM/PM
C/F
• Mostly diploid- biparental;
• Androgenic - CM
genetics
• Intermidiate trophoblast derived from cytotrophoblast
• Produce little of HCG
• hPL,B1 Glycoprotein,Ki61 may be elevated – diff from placental
nodules.
• Insensitive to chemotherapy
• Hysterectomy is primary treatment for non metastatic tumor
• Metastatic –poor prognosis,aggressive combination chemotherapy
microscopy

26. EPITHELIOID TROPHOBLASTIC TUMOR
(ETT)
• Extremely rare type of GTD
• Can be hard to diagnose.
• It can be found growing in the cervix, to be confused with cervical
cancer.
• ETT does not respond very well to chemotherapy the main
treatment is surgery.
• It might have already metastasized when it is diagnosed which carries
a poorer prognosis.

27. • Because they are frequently found in the cervix, they may be
confused with hyalinizing squamous cell carcinomas .
• Epithelioid trophoblastic tumours are focally immunoreactive
for placental-like alkaline phosphatase (PLAP) and hPL but
strongly and diffusely immunoreactive for E-cadherin and
epidermal growth factor receptor

28. • Because they are frequently found in the cervix, they may be
confused with hyalinizing squamous cell carcinomas .
• Epithelioid trophoblastic tumours are focally immunoreactive
for placental-like alkaline phosphatase (PLAP) and hPL but
strongly and diffusely immunoreactive for E-cadherin and
epidermal growth factor receptor

29. EPITHELOID TUMOR
• Neoplastic proliferation of intermediate trophoblast of the
chorionic leave. microscopically similar to PSTT but cells are more
small& show less pleomorphism.
• Nodular proliferation of intermediate troph- cords/nests
• Typically surrounded by areas of hyalinisation
Gross/microscopy
• H/o chemotherapy for invasive mole /choriocarcinoma.
• Represents the differentiating effect of treatment.
• Chemoresistant
• Hysterectomy is treatment of choice
.

30. CHORIOCARCINOMA
• Invades myometrium and local vasculature to disseminate
haematogenously to the lung (57-80%), vagina (30%), pelvis
(20%), brain (17%), and liver (10%)
• Half of all choriocarcinomas start off as molar pregnancies.
• About one-quarter develop in women who have a
miscarriage , intentional abortion, or tubal pregnancy .
• Another quarter (25%) develop after normal pregnancy and
delivery.

31. • Highly malignant
• Vaginal bleeding.(most common)
• Abnormal bleeding for more than 6 wks following any
pregnancyDO BhCG to exclude new pregnancy/GTN
• May arise from any type of pregnancy-
• Not alwayes due to antecedent pregnancy
Feature
• Soft ,purple,largely haemorrhagic mass.
• Early implanting blastocyst with central core of mononuclear
cytotrophoblast surroudistinct nded by rim of multinucleated
syncytotrophoblast & absence of chorionic villi
• Invades endometrium,myometrium,blood born systemic metastasis
• Extensive area of haemorrhage & necrosis.
• Absent connective tissue support Highly
metastatic/Haemorrhagic behavior
GROSS/MICROSCOPIY

32. SYMPTOMS & SIGNS
• Bleeding
• Infection
• Abdominal swelling
• Vaginal mass
• Lung symptoms
• Symptoms from other
metastases

33. DIAGNOSIS OF GTN
If following are met after initial evacuation -
• Plateau of hCG lasting for four measurements over a
period of 3 weeks
• E.g. days 1,7,14,21
• Rise in Hcg for 3 weekly consecutive measurements
• Hcg remains elevated for 6months or more
• Histological diagnosis of choriocarcinoma

34. EARLY FEATURES SUGGESTING
PERSISTENT GTD OR POST MOLAR
SYNDROME
1. Recurrent Or Persistent Vaginal Bleeding
2. Subinvoluation
3. Amenorrhea
4. Persistence of ovarian enlargement.
5. No malignancy in endometrial biopsy

35. INVESTIGATIONS
Blood related
• Serum b -hCG level is highly elevated ( > 100.000 mIU/m1)
• CBC, Blood group, LFTs & TFTs
Imaging
• Chest radiograph -metastasis
• cannon ball
• pleural effusion and consolidation
• Ultrasound
• snow storm appearance
• no identifiable fetus
• Doppler color flow of uterus
• CT-scan and MRI-metastasis
• Histopathology(if curettage done)

36. DOPPLER SCANS
choriocarcinoma
Invasive mole “snow storm”

37. CANNON BALL APPEARANCE ON
X-RAY

38. GTN Vaginal Metastasis

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

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

41. Prognosis

42. Modified WHO Prognostic Scoring System
0 1 2 4
Age <40 ≥40 – –
Antecedent pregnancy mole abortion term –
Interval months from
index pregnancy
<4 4–6 7–12 >12
Pretreatment serum hCG
(IU/L)
<103 103–104 104–105 >105
Largest tumor size
(including uterus)
<3 3–4 cm ≥5 cm –
Site of metastases lung spleen,
gastrointestin
l
liver, brain
Number of metastases – 1–4 5–8 >8
Previous failed
chemotherapy
– – single drug ≥2 drugs

43. SIGNIFICANCE OF WHO SCORING
WHO score 4 or less
• Commence treatment as soon as possible.
• A low risk of GTD can be managed with single-agent
chemotherapy using methotrexate with folinic acid.
• Other drugs include etoposide.
• If single-agent chemotherapy is used and is not working, a
more aggressive treatment is warranted to prevent the
emergence of drug resistance.

44. SIGNIFICANCE OF WHO SCORING
• Intermediate risk GTD (WHO score 5–7)
• Commence on regimen that includes combination
chemotherapy
• methotrexate and actinomycin D.
• If a complete response is not achieved on this regimen the
patient should be commenced on etoposide, methotrexate
and actinomycin D, alternating with cyclophosphamide and
vincristine (EMA-CO).

45. SIGNIFICANCE OF WHO SCORING
• High risk GTD (WHO score 8 or more)
• These patients require significant chemotherapy because
they include those with brain metastases, liver and
gastrointestinal tract metastases and they are at significant
risk from massive bleeding.
• A combination of chemotherapy, either EMA-CO or
methotrexate and folinic acid chemotherapy is indicated.

46. FIGO STAGING OF GTN
• Patients have persistently elevated hCG levels and tumor confined to the uterine corpus.
Stage I:
• Patients have metastases to the vagina and pelvis or both.
Stage II:
• Patients have pulmonary metastases with or without uterine, vaginal, or pelvic involvement.
• The diagnosis is based on a rising hCG level in the presence of pulmonary lesions on chest
radiograph.
Stage III:
• Patients have advanced disease and involvement of the brain, liver, kidneys, or gastrointestinal
tract.
• These patients are in the highest risk category, because they are most likely to be resistant to
chemotherapy.
• The histologic pattern of choriocarcinoma is usually present, and disease commonly follows a
nonmolar pregnancy.
Stage IV:

49. TREATMENT
• It is important to begin treatment as soon as possible after
GTN has been detected. The main methods of treatment are:
• Chemotherapy
• Surgery
• Radiation therapy (which is used less often)

50. STAGE 1
Initial Single agent chemo/hysterectomy with adjunctive chemo
Resistant Combination chemo
Hysterectomy with chemo
Local resection
Pelvic infusion
STAGE 2 & 3
Low risk
initial Single agent chemo
resistant Combination chemo
High risk
initial Combination chemo
resistant Second line combination chemo

51. STAGE 4
Initial Combination chemotherapy
Brain Whole head rediation
Craniotomy to manage complication
Liver Resection or embolisation to manage complication
Resistant Second line combination chemo
Hepatic arterial infusion

52. CHEMOTHERAPY
• Single agent chemotherapy
• Methotrexate followed by folinic acid rescue
• 2>cycles after hCG negative
• Cure rate of 100%
In terms of score < than 6 (low risk)
• Combination of therapeutic drugs e.g. etoposide, methotrexate, actinomycin-D,
cyclophosphamide, ncovin (EMACO)
• 3>cycles after hCG negative
• Cure rate of 70%
• Chemotherapy administered IV
• hCG measured after each cycle
Score of >7(High risk)
Depends on the FIGO scoring

53. SINGLE AGENT TREATMENT
• Excellent remission in nonmetastatic &
low risk pt
• Resistance in
Choriocarcinoma
Metastasis
S hcg >50000
• Minimal toxicity
Limited exposure
Excellent result
Actinomycin D,methoterxate

54. TECHNIQUE OF SINGLE AGENT
• HOLD CHEMO AS LONG AS HCG LEVEL FALLING
• NOT ADMINISTER AT PREDETERMINED DATE
FIRST COURSE
• B HCG LEVEL PLATEAUS FOR > 3 CONSECTIVE WK/BEGINS TO RISE
• HCG DOES NOT DECLINE BY 1 LOG WITH IN 18 D OF FIRST
TREATMENT
SECOND COURSE
• INCREASE THE DOSE OF MTX 1-1.5 MG/KG/
INADEQUATE
RESPONSE

55. COMBINATION CHEMOTHERAPY
EMA - EP
EMA-
CO
Triple
therapy

56. CHEMOTHERAPY REGIMEN
FOR LOW RISK PT
METHOTREXATE/FOLINIC
ACID
METHOTREXATE 50 MG IM REPEATED EVERY 48 HR FOR
TOTAL 4 DOSES
CALCIUM FOLINATE 15 MG ORALLY DAILY AFTER EACH INJ OF
METHOTREXATE
COURSE REPEATED EVERY 2
WK 1-15-29

57. CHEMOTHERAPY REGIMEN FOR
HIGH RISK PATIENT
EMA
DAY1 ETOPOSIDE
ACTINOMYCIN D
METHOTERATE
DAY 2 ETOPOSIDE
ACTINOMYCIN D
FOLINIC ACID
CO
DAY 8 VINCRISTINE
CYCLOPHOSPHAMIDE

58. MANAGEMENT OF DRUG RESISTANT
DISEASES
LOW RISK
• Persistent S B hCG level is
<300- actinomycin D
• >300IU/L –-> EMA - CO
HIGH RISK
• Combination of surgical
removal of drug resistant
site- uterus,lung brain)
together with
chemotherapy—EMA-EP
• High dose comb chemo with
autologous stem cell support
is still investigational

59. DURATION OF CHEMO
Cmb. Chemo given as often as toxicity permit
till pt has 3 consecutive normal hcg
2 additional course of chemo given to reduce
risk of relapse

60. FOLLOW - UP
LOW RISK
Wkly hCG until
normal 3
consecutive wks
Monthly hcg until
normal for 12
consecutive months
HIGH RISK
Wkly hcg until
normal 3
consecutive wks
Monthly hCG until
normal 24
consecutive months

61. ROLE OF SURGERY
• Secondary role
• Chemotherapy is effective in vast majority
Indications
• Hysterectomy
• disease confined to uterus
• Placental site trophoblastic tumours
• epithelioid trophoblastic tumors.
• Resection of Isolated chemotherapy-resistant nodules e.g.
thoracotomy, craniotomy
• Laparotomy for bowel or urinary tract obstruction
• Oophorectomy for torsion of ovarian cyst

62. RADIOTHERAPY
• For extensive metastases
• Brain and liver metastases
• In combination with chemotherapy