trophoblastic disorders

1. TROPHOBLASTIC
DISORDER
BY: PEMA DOLKAR

2. GESTATIONAL TROPHOBLASTIC
DISEASES (GTD)
Definition : Gestational trophoblastic disease encompasses a
spectrum of proliferative abnormalities of trophoblasts
associated with pregnancy. Persistent GTD (persistent raised( ß-
hCG ) is referred as gestational trophoblastic neoplasia (GTN).

3. RISK FACTORS
Age below 15 & above 40 yrs.
Previous history of hydatidiform mole.
Previous miscarriage.
Excessive smoking.
Reduced carotene intake.

4. CLASSIFICATION
The conventional histological classification:
1) Hydatidiform mole
2) Complete
3) Partial
4) Invasive mole
5) Placental site trophoblastic tumor
6) Choriocarcinoma

5. Non metastatic disease
• Low risk (good prognosis )
• Disease is present <4 months duration
• Initial serum hCG level <40,000 mIU/mL
• Metastasis limited to lung and vagina
• No prior chemotherapy
• No preceding term delivery

6. Metastatic disease:
High risk ( poor prognosis )
Long duration of disease (>4 month)
Initial serum hCG level >40,000 mIU/mL
Brain or liver metastasis
Failure of prior chemotherapy
Following term pregnancy
WHO score > 7

7. Hydatidiform mole
Types : a. Complete
b. Partial
Definition : it is an abnormal condition of the placenta where
there are partly degenerative changes in the young chorionic villi.

8. Risk factors
 Prevalence is highest in teenage pregnancies & women over 35 yrs
of age.
 Low dietary intake of carotene
 Disturbed maternal immune. Mechanism suggested by :
Rise in gamma globulin level in absence of hepatic disease.
Incs assoc with AB blood grp which possesses no ABO antibody.

9.  Cytogenic abnormalities: complete mole have 46XX
karyotype(85%), molar chromosome are derived from father.
 Higher the ratio of paternal:maternal chromosomes, complt –
2:0 & partial – 2:1
 History of prior hydatidiform mole increase of recurrence.

10. Pathology of hydatidiform mole
Death of ovum or failure of the embryo to grow essential to develop CHM.
The secretion from the hyperplastic cells & transferred substances from the maternal blood
accumulate in the stroma of the villi which are devoid of the bld vessel.
Distension of villi to form small vesicles.
Vesicle fluid is interstitial fluid & is almost similar toascitic or edema fluis but rich in hCG.

11. Naked eye appearance: The mass filling the uterus is made of
multiple chains and clusters of cysts of varying sizes. There is no
trace of embryo or the amniotic sac. Hemorrhage, if occurs,
takes place in the decidual space.
Microscopic appearance : The basic findings are
(1) There is marked proliferation of the syncytial and
cytotrophoblastic epithelium.
(2) Marked thinning of the stromal tissue due to hydropic
degeneration.

12. (3) There is absence of blood vessels in the villi which seems
primary rather than due to pressure atrophy.
(4) The villous pattern is distinctly maintained.
Ovarian changes: Bilateral lutein cysts are present in about
50%. These are due to excessive production of chorionic
gonadotropin and they are also observed in multiple pregnancy.
These regress spontaneously within 2 months after expulsion of
mole. The contained fluid is rich in chorionic gonadotropin. It
also contains estrogen and progesterone.

13. SYMPTOMS
Vaginal bleeding
Varying degree of lower abd pain may be due to over stretching
of the uterus, concealed hemorrhage, infection, uterine
contraction to expel out the content.
Constitutional symptoms:
a)sick without any reason

14. b) Hyperemesis
c) Breathlessness due to pulmonary embolization of the trophoblastic cells
d) thyrotoxin features of tremors
Expulsion of grape like vesicles per vagina is diagnostic of mole.
History of quickening is absent.

15. SIGN
Pallor out of proportion to the visible blood loss & concealed
hemorrhage.
Features of pre-eclampsia may be due to over distension of the
uterus or due hyperactivity of trophoblastic cells.

16. Per abdomen:
The size of the uterus is more than expected for the period of
amnenorrhoea in 70%, POA 20%,
Undue enlargement is due to exacerbation growth of the vesicles &
concealed haemorrhage.
Uterus is firm elastic due to absence of amniotic fluid.
Fetal part are not felt, nor any fetal movement.
Absence of fetal heart sound cannot even detected by Doppler.

17. Vaginal examination :
Internal ballotment cannot elicit.
Unilateral or bilateral enlargement of the ovary. It may not be
palpated due to enlarged uterus.
Finding of vesicles in the vaginal discharge.
If the cevicle os is open, instead of membrane blood clot or
vesicles may be felt.

18. INVESTIGATIONS
Full blood count, ABO and Rh grouping.
Hepatic, renal and thyroid function tests
Sonography : “snowstorm” appearance.
Quantitative estimation of chorionic gonadotropin: high hCG
titer in urine up to 1 in 200 to 1 in 500 beyond 100 days of
POG. Rapid increase is very much suggest molar pregnancies.
hCG>100,000mIU/ml.

19. Plain Xray abdomen: in the uterus size is more than 16 weeks,
a negative fetal shadow may be of help.
X ray chest for evidence of pulmonary embolization even in
the benign mole.
CT and MRI : routine CT and MRI is nor recommended.
Definitive diagnosis is made by histological examination of the
product of the concept.

20. DIFFERENTIAL DIAGNOSIS
 Threatened abortion
 Fibroid or ovarian tumor with pregnanncy.
 Multiple pregnancy

21. COMPLIATIONS
Immediate :
1. Haemorrhage and shock : The causes of haemorrhage are
Separation of the vesicles from its attachment to the decidua.
Massive intraperitoneal haemorrhage
During evacuation of the mole due
Atonic uterus
Uterine injury

22. 2. Sepsis : As there are no protective membranes, the vaginal
organisms can creep up into the uterine cavity,Presence of
degenerated vesicles, sloughing decidua and old blood favors nidation
of bacterial growth, Increased operative interference.
3. Perforation mole: Which may produce intraperitoneal
haemorrhage.
4. Pre-eclampsia with convulsion in rare accasion.
5. Acute pulmonary insufficiency due to pulmonary embolization
6. Coagulation failure due to pulmonary embolization of
trophoblastic cells.

23. MANAGEMENT
Principles :
1) Suction and evacuation of uterus as early as the diagnosis is
made.
2) Supportive therapy: correction of anemia & infection
3) Counselling for regular follow up.

24. The patient are grouped into two :
Group A: The mole is in process of expulsion.
Group B: The uterus remains inert (early diagnosis with
USG)

25. 1. SUPPORTIVE THERAPY
The patient usually presents with variable amount of bleeding and
often they are anemia and associated with infection.
IV infusion with Ringer’s solution
Blood transfusion is given if the patient is anemic
Parenteral antibiotic is given if there is associated infection.
Blood is kept reserved during the evacuation as there is risk of
haemorrhage.

26. Group A: Cervix is favorable
a. Preferred method is suction and evacuation. A –ve pressure is
applied up to 200-250mmHg. Performed under Daizepam or GA.
b. Alternative : conventional dilatation of cervix followed by
evacuation.
c. Digital exploration & removal of mole & reduces blood loss but
ots routine is not recommended due to risk od embolzation.

27. Group B: Cervix is tubular and closed—
Prior slow dilatation of the cervix is done by introducing
lamanaria tent followed by suction and evacuation.
 Alternatively, vaginal misoprostol (PGE1a) 400 µg,3 hours
before surgery may be used.

28. Complications of vaginal evacuation—
Apart from the injury to the uterus, hemorrhage and shock,
there are two more rare but fatal complications—
• Acute pulmonary insufficiency due to pulmonary
embolization of the trophoblastic cells.

29. 2. Hysterectomy is indicated in: (1) Patients with age over 35.
(ii) Patient completed her family irrespective of age. (iii)
Uncontrolled hemorrhage or perforation during surgical
evacuation. Hysterectomy reduces the risk of GTN by fivefold.
3.Hysterotomy is rarely done these days. It maybe done in
cases with (i) profuse vaginal bleeding, (ii) cervix is unfavorable
for immediate vaginal evacuation and (iii) accidental perforation
of the uterus during surgical evacuation.

30. Noted:
following hysterectomy, persistent GTD is observed in 3-5%
cases. As such, it does not eliminate the necessity of follow-up.
The enlarged ovaries (theca lutein cysts) found during operation
should be left undisturbed as they will regress following removal
of mole. But, if complication arises, like torsion, rupture or
infarction, they should be removed.

31. 4. PLACE OF CURETTAGE
FOLLOWING VAGINAL EVACUATION:
• Routine curettage is not recommended.
• It is done in selected cases with persistent vaginal bleeding
(persistent GTN). Gentle curettage maybe done 5-7 days
following evacuation.
• At this time the uterine wall gets thicker, firmer and the cavity
becomes smaller so that effective curettage can be done
without risk of damaging the uterus.

32. The objective of curettage:
To remove the necrosed decidua and the attached vesicles so
as to accelerate involution and to reduce the irregular bleeding.
The materials should be sent for histology to note the degree
of trophohlastic hyperplasia and to see whether the vinous
structure is present or not.

33. FOLLOW-UP:
• Routine follow-up Is mandatory for all cases for at least 1 year.
• The occurrence of choriocarcinoma is mostly confined to this
period.
• The prime objective is to diagnose persistent trophoblastic disease
(20-30%) that is considered malignant.
• However, hCG levels following evacuation should regress to
normal within 3 months time.

34. Intervals:
• Initially, the checkup should be at an interval of one week till the serum
hCG level becomes negative.
• This usually happens by 4-8 weeks.
• Once negative within 56 days, the patient is followed up for every 1
month for 6 month.
• The Women who undergo chemotherapy should followed up for1 year
after hCG has been normal.
• The patient must not become pregnant during the cd up Period of
followup.

35. Methods employed in each visit:
(1)Enquire about relevant symptoms like irregular vaginal bleeding,
persistent cough, breathlessness or hemoptysis.
(2) Abdominovaginal examination to note:
(i) involution of the uterus
(ii) ovarian size
(iii) malignant deposit if any, in the anterior vaginal wall. The lutein
cysts usually regress within 2 months.
• Pelvic examination is done after 1 wk of molar evacuation.

36. Investigations:
• Detection of hCG in urine or serum—Urine or serum assays
are carried out at every visit.
• Chest X-ray: If the pre evacuation chest radiograph shows
metastasis, it should be repeated at 4 weeks interval, until remission
is confirmed. It is then repeated at 3 months interval during the
rest of the follow-up period. When pre-evacuation chest X-ray is
normal, it is repeated only when the hCG titer plateaus or rises.

37. 6.PROPHYLACTIC CHEMOTHERAPY:
The drugs used are toxic. These drugs in young females increase the risk of
premature ovarian failure and menopause. So it is not appropriate to treat
all patients as a routine prophylactically.
However, it is used with advantages in the following circumstances:
• If the hCG level fails to become normal by the stipulated time (10-12
weeks) or there is reelevation at 4-8 weeks.
• Rising 0-hCG level after reaching normal levels.

38. • Post evacuation hemorrhage (presence of trophoblastic activity).
• Where follow-up facilities are not adequate.
• Evidences of metastases irrespective of the level of hCG.
• In cases, where the malignant sequelae is higher as judged by the
risk factors and where proper follow-up facilities are not available.

39. Regimes:
• Methotrexate, I mg/kg/day IV or 1M is given on days 1, 3, 5 and 7
with folinic acid 0.1 mg/kg IM on days 2, 4, 6 and 8. It is to be
repeated every 7 days.
• A total three courses are given. ß-hCG level should decrease by at
least 15%, 4-7 days after methotrexate.
• Alternatively, intravenous actinomycin D 12 µg/kg body weight
daily for 5 days may be given. It is less toxic than methotrexate.

40. 7. CONTRACEPTIVE DEVICE
The patient is traditionally advised not to be pregnant for at
least 1 yr.
A rise in hCG titer might cause confusion btw a fresh
pregnancy or persistent GTD.
Thus pt desire may be pregnant after min 6 months, following
the –ve hCG titer.

41. Use of contraception:
• IUD is contraindicated, because of its frequent association of
irregular bleeding—a feature often coexists with choriocarcinoma.
• Combined oral pills can be used after the hCG value has become
normal.
• Injection DMPA can be used safely.
• Barrier method of contraception can also be used. Surgical
sterilization is another alternative when she has completed her
family.

42. PARTIAL OR INCOMPLETE MOLE
o The affection of the chorionic villi is focal. There is a fetus or at
least an amniotic sac.
oThe karyotype is triploid either 69XXY or 69XYY with one
maternal but usually two paternal haploid chromosomes.
oMicroscopic examination of the dilated chorionic villi shows
predominant hyperplasia of the syncytiotrophoblast and
presence of fetal blood vessels with fetal red blood cells.

43. oThe fetus, if present, dies in early first trimester. Rarely,
the baby may be born which is growth retarded with
multisystem abnormalities.

44. Features Complete Mole Partial mole
Embryo /fetus Absent Present
Hydropic degeneration
of villi
Pronounced and diffused Variable and focal
Trophoblast hyperplasia Diffuse Focal
Uterine size More than the date (30-
60%)
Less than the date
Theca lutein cysts Common( 25-50%) Uncommon
Karyotype 46, XX(85%), paternal in
origin
Triploid (90%),
diploid(10%)
ß-hCG High >50,000 Slight elevation <50,000
Classic clinical
symptoms
Common Rare
Risk of persistent GTN 20% <5%
Immunostaining Negative Positive

45. oThe hCG titer is not markedly raised. With wider use of
sonography, more and more cases are being revealed.
oIn partial mole, uterus is generally not large for dates and
malignant potential is very low.
oOnce the diagnosis is made and the fetus is not alive,
termination of pregnancy is to be done.
oEven if the fetus is alive, the patient should be warned about
the risks involved to the fetus if pregnancy is continued.

46. PLACENTAL SITE TROPHOBLASTIC
TUMOR (PSTT)
It is a rare histological diagnosis. Syncytiotrophoblastic cells are
generally absent. So there is persistent low level of serum or
urinary hCG. The tumor arises from the intermediate
trophoblasts of the placental bed and is composed mainly of
cytotrophoblastic cells.

47. • Patient presents with vaginal bleeding. Local invasion into the
myometrium and lymphatics occurs.
• PSTT is not responsive to chemotherapy.
• Hysterectomy is the preferred treatment.

48. PERSISTENT GESTATIONAL
TROPHOBLASTIC DISEASE
DEFINITION: Persistent GTD is defined where there is
persistence of trophoblastic activity as evidenced by clinical,
imaging, pathological and. or hormonal study following initial
treatment.

49. • A postmolar GTD may be benign or malignant. But a GTD
after non molar pregnancy is always a choriocarcinoma. Overall
incidence of persistent GTN after complete hydatidiform moles
is 15-20%.
• Approximately, 50% of the cases develop following a
hydatidiform mole, 25% following an abortion or ectopic
pregnancy and another 25% following normal pregnancy.

50. DIAGNOSIS
This state is diagnosed during postevacuation follow-up period.
The diagnostic features are:
• Continued vaginal bleeding.
• Persistent theca lutein cysts.
• Persistently soft and enlarged uterus.

51. • hCG titers either fail to become negative or remain plateau or
there is reelevation after a initial fall by 8 weeks postmolar
evacuation. Local or systemic metastases should always be
excluded (X-ray chest, CT, MRI of brain and liver).
Asymptomatic patients, with a normal chest X-ray, are unlikely
to have brain or other visceral metastasis.
• Pathologically this may be due to invasive mole,
choriocarcinoma or placental site trophoblastic tumor.

52. TREATMENT:
Patients are classified into low- or high-risk categories (WHO
Prognostic ScorinG.
• Low-risk group receives single-agent chemotherapy (usually
methotrexate).
• High-risk group receives combination chemotherapy [usually
etoposide, methotrexate, actinomycin D, cyclophosphamide and
vincristine (EMA-CO)].

53. Hysterectomy—
This is justified in women approaching 40 and/or who has
completed her family. Following hysterectomy or
chemotherapy, regular follow-up is essential.