gestational trophoblastic diseases

1
Gestational Trophoblastic Disease (GTD).

• S.P CHUWA

2
KEY TERMS AND DEFINITIONS

• Gestational Trophoblastic Disease (GTD). The
  spectrum of diseases resulting from the abnormal
  proliferation of trophoblast associated with
  pregnancy.
• Gestational Trophoblastic Tumor (GTT). A term
  applied to gestational diseases that have
  neoplastic malignant potential, including
  invasive mole, choriocarcinoma, and
  placental-site trophoblastic tumor. It can be
  either nonmetastatic or metastatic. It is
  occasionally termed gestational trophoblastic
  neoplasia (GTN).

3

• Hydatidiform Mole. A placental abnormality
  involving swollen placental villi and
  trophoblastic hyperplasia with loss of fetal
  blood vessels. There are two types partial and
  complete.
• Complete Mole. A molar pregnancy with swelling of
  all placental villi. Fetal tissues are absent.
• Partial Mole. A molar pregnancy with some normal
  and some swollen villi plus fetal, cord, and/or
  amniotic membrane elements.

4

• Choriocarcinoma. A morphologic term applied to a
  highly malignant type of trophoblastic neoplasia
  in which both the cytotrophoblast and
  syncytiotrophoblast grow in a malignant fashion.
• Invasive Mole. A variant of hydatidiform mole in
  which the hydropic villi invade into the
  myometrium or blood vessels. It may spread to
  extrauterine sites.

5

• Placental-Site Trophoblastic Tumor. A rare type
  of GTT arising in the uterus that secretes human
  placental lactogen (HPL) and human chorionic
  gonadotrophin (hCG) and is often resistant to
  chemotherapy.
• Theca Lutein Cysts. Enlargements of the ovary
  occurring with hydatidiform moles and consisting
  of theca lutein cells. Usually they regress after
  treatment of the mole.

6

• High Risk Metastatic Gestational Trophoblastic
  Disease (GTD GTT). Patient with pretreatment
  serum ß-hCG greater than 40,000 mIU/ml or more
  than 4 months' duration of disease or previous
  chemotherapy failure and brain or liver
  metastases (vagina and lung excluded).
• Low Risk Metastatic GTD (GTT). Patients with
  metastatic disease outside the uterus, excluding
  the brain or liver serum ß-hCG less than 40,000
  mIU/ml duration of disease less than 4 months
  and no prior chemotherapy.

7
Introduction

• In a normal pregnancy Trophoblastic (just like
  malignancies) tissue normally have the ability
• - to divide rapidly,
• to invade locally, and
• occasionally to metastasize to distant sites such
  as the lung
• These activities usually cease at the end of
  pregnancy, and the trophoblast disappears
• However, in GTD, abnormal growth and development
  continue beyond the end of pregnancy

8
Hydatidiform Mole Molar Pregnancy

• Has three morphologic characteristics
• a mass of vesicles (distended villi) that appear
  as large, grapelike dilations
• a loss of fetal blood vessels, which are either
  diminished or absent from the villi and
• hyperplasia of the syncytiotrophoblast and
  cytotrophoblast.

9
EPIDEMIOLOGY

• The incidence is difficult to establish because
  of the low frequency and regional variation
• North American and European countries report
  rates of GTD as 66 to 121 per 100,000 pregnancies
• 50 of GTN arise from molar pregnancy, 25 from
  miscarriages or tubal pregnancy, and 25 from
  term or preterm pregnancy
• AT MNH January 2020 to June 2020. Total
  admission 1136. GTD 39 (3.4)
• The overall incidence of GTN following all types
  of pregnancies is estimated at 1 in 40,000
  pregnancies

10
RISK FACTORS

• Maternal age is an extremely important risk
  factor.
• The lowest rates are among those in their 20s and
  30s, with a great increase in those over age 40,
  after which the risk progressively increases with
  age.
• There is also an increase in risk among those
  under age 20, but the magnitude is not nearly so
  great as it is among older women.
• An additional risk factor is a history of prior
  hydatidiform mole, which increases the risk of
  subsequent mole by 20 to 40 times.
• Prior recurrent spontaneous abortion is also a
  risk factor

11

• Blood group A women x group O men are 10X of
  developing choriocarcinoma
• Group A women and AB women have relatively poor
  prognosis

12
Complete mole

• Only paternal chromosomes are believed to be
  present
• There are 46 chromosomes and nearly always 46,
  XX, although a few moles with 46, XY karyotype
  have been reported.
• Development appears to result from the
  fertilization of an "empty egg," one with an
  absent or inactive nucleus.
• Paternal chromosomes then duplicate to give the
  diploid number, a process known as androgenesis,
  the development of an "embryo" due only to
  chromosomes from an X-bearing sperm.
• In the rare case of complete mole with an XY
  chromosomal content, the "empty egg" appears to
  be fertilized by two haploid sperm, one X and one
  Y.

13
(No Transcript)
14
(No Transcript)
15
Incomplete, or partial, moles

• Are usually triploid and have 69 chromosomes of
  both maternal and paternal origin.
• Most common mechanism for the origin of partial
  mole is a haploid egg being fertilized by two
  sperm
• Resulting in three sets of chromosomes.
• Alternatively, triploidy could result when an
  abnormal diploid sperm fertilizes the haploid
  egg.

16

• It is also possible for an abnormal diploid egg
  to be fertilized by a haploid sperm, but this
  latter mechanism usually results in an abnormal
  conceptus with congenital abnormalities rather
  than a partial mole.
• Partial mole is often difficult to diagnose and
  may present as a missed abortion in the second
  trimester.

17
Partial moles cont.

• Partial moles are rarely associated with the
  subsequent development of GTT
• Despite rare subsequent malignancy, patients with
  partial moles need the same follow-up as those
  with complete mole.
• Although these fetuses are usually abnormal, it
  has been noted that some partial moles have
  occurred with phenotypically normal fetuses.
• In such cases the uterus is small for dates

18
Choriocarcinoma

• Malignancies that occur after or in association
  with pregnancy, although the same histologic
  tumor can develop without pregnancy as a primary
  neoplasm in the ovaries.
• The prognosis for primary gonadal
  choriocarcinomas, which also occur in testes, is
  worse than for those associated with gestation.
• The diagnosis is made histologically, and the
  term is applied to the finding of malignant
  cytotrophoblast and syncytiotrophoblast.
  Chorionic villi are absent.
• These tumors tend to be hemorrhagic and necrotic.
  The latter is common because these tumors
  frequently outgrow their blood supply.
• Metastases are common.

19

• Most but not all gestational choriocarcinomas
  develop after molar pregnancies.
• Trophoblastic tissue normally regresses within 2
  to 3 weeks after delivery, including cells that
  may have spread to the lung.
• The finding of trophoblastic cells in the uterus
  more than 3 weeks after delivery should lead one
  to consider the possibility of choriocarcinoma.

20
Placental-Site Trophoblastic Tumor (PSTT)

• PSTT is derived from the intermediate
  trophoblasts of the placental bed, with minimal
  or absent syncytiotrophoblastic tissue.
• Extremely rare
• May follow a molar pregnancy or a term normal
  pregnancy
• Arise from placental implantation site
• It tends to be locally invasive and most patients
  do not develop metastases.
• The tumor can lead to hemorrhage and uterine
  perforation
• Hysterectomy is the treatment of choice.
• The beta hcG may be normal, so its monitored by
  using human placental lactogen (HPL) instead.

21
Risk Factors for Hydatidiform Mole

• Maternal age is an extremely important risk
  factor.
• The lowest rates are among those in their 20s and
  30s, with a great increase in those over age 40,
  after which the risk progressively increases with
  age.
• There is also an increase in risk among those
  under age 20, but the magnitude is not nearly so
  great as it is among older women.
• An additional risk factor is a history of prior
  hydatidiform mole, which increases the risk of
  subsequent mole by 20 to 40 times.
• Prior recurrent spontaneous abortion is also a
  risk factor.

22

• Blood gp A women x gp O men are 10X of developing
  choriocarcinoma
• Gp A women and AB women have relatively poor
  prognosis

23
High risk mole for malignancy change

• Maternal age lt20 or gt40
• Beta hcG levels gt100,000 urinary IU/
• Tumour size gt 5cm
• Theca lutein cyst gt 6cm found in the ovary
• Blood group A/AB for the female and O for the
  male.
• Parity, size of the uterus at 28/40.

24
CLINICAL CLASSIFICATION OF GTD

• Classification of Gestational Trophoblastic
  Disease (GTD)
• Hydatidiform mole
• 1. Complete
• 2. Incomplete (Partial)
• Gestational trophoblastic tumor (GTT) (Malignant
  GTD)
• 3. Nonmetastatic
• 4. Metastatic
• Low risk
• High risk

25
Clinical features

• 1.Abnormal uterine bleeding during first semester
  in 90 of patients, with three fourth before 3rd
  month following the period of amenorrhea.
• 2.Exaggerated clinical sign of pregnancy with
  severe nausea and vomiting in 14- 32 ( 10 may
  need hospitalization)
• 3.Disproportionate uterine size ,half of pts have
  higher FH than expected GA, not always the case

26
Clinical feature cont..

• 4.Multiple theca lutein cyst with ovarian
  enlargement ( may present with rapture or
  infection) in the iliac fossa
• 5.Pre eclampsia in 1st trimester or early second
  trimester
• 6.Hyperthyroidism
• 7. Breathlessness and anemia are common
  accompaniments
• 8.Passage of grape like vesicle vaginally

27
Clinical feature cont..

• Abdominal pain-excessive uterine enlargement .
• Clinically not possible to demonstrate the
  presence of fetus, fetal parts can not be felt
  and fetal heart sounds cannot be heard
• On vaginal examination
• -Well defined, non-tender cystic swelling
  palpable in the fornix (lt5cm in diameter)

28

• Clinically the behaviors of partial and complete
  moles differ.
• Complete mole is the more common and also has a
  more serious prognosis, with increased risk for
  the subsequent development of a GTT.
• Partial moles usually present as an incomplete or
  missed abortion

29
Comparison of Complete and Partial Hydatidiform
Moles.
Complete Partial
Karyotype Diploid (46,XX or 46,XY) Triploid (69,XXX or 69,XXY)
Embryo Absent Present
Villi Hydropic Few hydropic
Trophoblasts Diffuse hyperplasia Mild focal hyperplasia
Implantation-site trophoblast Diffuse atypia Focal atypia
Fetal RBCs Absent Present
ß-hCG High (gt 50,000) Slight elevation (lt 50,000)
Frequency of classic clinical symptoms Common Rare
Risk for persistent GTT 2030 lt 5
30
COMPLETE MOLAR
31
PARTIAL MOLE
32
Investigations

• 1. Pregnancy test Urine for pregnancy positive
• 2.Hcg test Serum ßhcg level higher than
  expected for GA, Usually if gt100,000mlU/ml with
  clinical signs highly suggestive
• 3. USS- multiple echoes without the gestational
  sac or fetus
• snowstorm appearance
• 4.Histology of endometrial tissue from evacuation

33
Management of GTD
34
MANAGEMENT

• The probability of cure depends on the following
  
• Histological type (mole, invasive mole, or
  choriocarcinoma).
• Extent of spread of the disease.
• Level of the human chorionic gonadotropin (HCG)
  titer.
• Duration of disease from the initial pregnancy
  event to start of treatment.
• Specific sites of metastases.
• Nature of antecedent pregnancy.
• Extent of prior treatment.

35
MANAGEMENT OF GTD

• 1.Complete hydatidform Mole
• Clinical presentaion
• -Amenorrhea
• -Intermittent vaginal bleeding
• -Passage of vesicles per vagina
• -Pre eclampsia lt20wks(10-12)
• -/-Hyperthyroidism - Thyrotoxicosis features
• R/o
• -Pregnancy, Threatened abortion, Ectopic
  pregnancy, Polyhydramnios, Ovarian tumours,
  Multiple pregnacy

36
Management cont..

• Examination
• Uterus larger than GA
• No fetal parts
• No fetal heart sounds ( usually audible at 20/40)
• Bilateral ovarian enlargement-r/o Theca luteal
  cysts
• Signs of anemia-excessive bleeding???
• Sign of preeclampsia -BP, Proteinuria, Edema???
• Signs of hyperthyroidism Heat intorelance??

37
Management cont

• Investigations
• Hematological -Hb, RBC Morphology, WBC, Bleeding
  indices
• Serum hCGgt100,000mIU/ml pathognomonic - tittre
  proportional to tumor burden
• X-Ray will detect no fetal parts at 16 weeks
• USS-No fetus, no fetal heart sounds, Vesicles
  with snow storm appearance.
• Follow up-usually hCG levels regress disappear
  in 14wks after evacuation.

38
What to do?

• RESUSCITATION
• I.V line-wide bore canula
• Blood for x-matching in case BT is needed.
• Clear airways
• Evacuation of a mole
• Suction Curettage-method of choice
• I.V Oxytocin-limits bleeding-10units diluted in5
  Dextrose in 500ml,by 10 units every
  15-20minutes.
• Prostaglandins may be useful
• SC should be done in Oper/theatre under Gen.
  Anaest.
• Dont forget tissue for Histology
• Hysterectomy-advised for
• Menopausal pt.
• Pt with enough number of kids

39
COMPLICATIONS AFTER EVACUATION

• Severe bleeding
• Perforation of the uterus
• Change to the choriocarcinoma
• Sepsis
• Embolization
• Metastasis

40
FOLLOW UP

• 2 years follow up.
• COC pills for 2 years without conception.
• B-hCG assay every 1-2 wks until hCG disappear,
  then monthly for 1 year, then every 3 months for
  the 2nd year.
• Each visit
• -Full history (pv bleeding, taking the pills
  correctly).
• -Gyn exam (vulva, vagina, urethra, cx, uterine
  size, adnexal mass.
• -Periodical hCG. (2-3 consecutive -Ves titers-
  declare that the pt is free of choriocarcinoma.
• -CXR

41
SURVELLIANCE INDICATIONS FOR CHEMOTHERAPY

• Raised hCG level 6/12 after evacuation (even if
  falling)
• hCG plateau in 3 consecutive serum samples
• hCG gt20,000 IU/l more than 4/52 after evacuation
• Rising hCG in two consecutive serum samples
• Pulmonary, vulval or vaginal metastases unless
  the hCG level is falling
• Heavy PV bleeding or GI/intraperitoneal bleeding
• Histological evidence of choriocarcinoma
• Brain, liver, GI mets or lung metastases gt2 cm on
  CXR

42
Why Contraception?

• Highly effective.
• Does not have any pv bleeding (irregular)
• Suppress any other sources of hCG.
• Prevents pregnancy
• In the subsequent pregnancy, uss should be done
  in the 1st trimester due to propensity for
  recurrence of GTD.
• Also the histology of the subsequent abortion and
  titres of hCG.

43
2. INCOMPLETE MOLE

• Characterised by focal swelling of villous
  tissues, focal trophoblastic hyperplasia and
  fetal tissue present.
• Clinical presentation as in complete mole
• Management same as complete.

44
Gestational Trophoblastic Neoplasia
45
Prognostic Classification of GTT (Malignant GTD)

• Nonmetastatic GTT
• Metastatic GTT disease outside the uterus A.
  Good prognosis a. Short duration (lt 4 months).
• b. Serum -hCG lt 40,000 mlU/mL.
• c. No metastasis to brain or liver.
• d. No significant prior chemotherapy.B.
  Poor prognosis a. Long duration (gt 4 months).
• b. Serum -hCG gt 40,000 mlU/mL.
• c. Metastasis to brain or liver.
• d. Unsuccessful prior chemotherapy.
• e. Gestational trophoblastic neoplasia
  following term pregnancy

46
FIGO Classification System of GTT

• Stage Anatomic Location
• I Confined to corpus uteri
• II Metastases outside uterus limited to vagina or
  pelvic structures
• III Metastases to lungs
• IV Distant metastases to other sites
• Substages for each stage as follows
• No risk factors
• One risk factor
• Two risk factors
• Definition of risk factors
• Pretherapy serum hCG100,000 mIU/ml
• Disease duration gt 6 months

47
Management NONMETASTATIC AND GOOD-PROGNOSIS
METASTATIC GTT.

• Single-agent chemotherapy is started
• Methotrexate, 0.4 mg/kg body weight (maximum, 25
  mg) intravenously or intramuscularly daily for 5
  days every 2 weeks or
• Actinomycin D, 10 to 12 µg/kg intravenously daily
  for 5 days every 2 weeks
• or Methotrexate, 1 to 1.5 mg/kg intramuscularly
  or intravenously on days 1, 3, 5, and 7, followed
  by folinic acid 0.1 to 0.15 µg/kg intramuscularly
  on days 2, 4, 6, and 8 repeat every 1518 days

48
Follow-up

• Follow ß-hCG titer weekly. Switch to alternative
  drug if ß-hCG titer rises 10-fold or more, titer
  plateaus at an elevated level, or new metastasis
  appears.
• Labs weekly. Hold chemotherapy for WBC count lt
  3000 (absolute neutrophil count lt 1500)
  platelets lt 100,000 significantly elevated BUN,
  Cr, AST, ALT, or bilirubin or for significant
  side effects (severe stomatitis, gastrointestinal
  ulceration, or febrile course).
• Oral contraceptive agents or other form of birth
  control should be taken concurrently, and
  continued for at least 1 year following
  remission.

49

• Chemotherapy continued for one course after
  negative -hCG titer.
• Follow-up program ß-hCG titer weekly until 3
  consecutive normal titers monthly ß-hCG titer
  for 12 months thereafter ß-hCG titer every 2
  months for 1 additional year or every titer for 6
  months indefinitely.
• Physical examination including pelvic examination
  and chest radiography monthly until remission is
  induced at 3-month intervals for 1 year
  thereafter then at 6-month intervals
  indefinitely.

50
HIGH-RISK METASTATIC GTT.

• The treatment of poor-prognosis GTT requires
  multiple-agent chemotherapy.
• One protocol was designated MAC, consisting of
  methotrexate (0.3 mg/kg), actinomycin D (8 to 10
  µg/kg), and chlorambucil (oral, 0.2 mg/kg) or
  cyclophosphamide (3 to 5 mg/kg) given
  intravenously daily for 5 days.
• The cycle is repeated in 9 to 14 days as toxicity
  permits.

51

• In recent years effective protocols have been
  introduced using etoposide
• Currently, EMACO (etoposide, methotrexate,
  actinomycin D, cyclophosphamide, and vincristine)
  chemotherapy provides the best response rate
  (approximately 80) with the lowest side-effect
  profile.
• The cycle is repeated every 2 weeks

52
EMA/CO Regimen
Day Drug/Dosage Abbreviation
1 Etoposide 100 mg/m2 IV over 30 minutes E (etoposide)
Actinomycin D 0.5 mg IV push M (methotrexate)
Methotrexate 100 mg/m2 IV push A (actinomycin D)
Methotrexate 200 mg/m2 IV infusion in 1000 ml D5W over 12 hours
2 Etoposide 100 mg/m2 IV infusion in 250 ml NS over 30 minutes
Actinomycin D 0.5 mg IV push
Folinic acid 15 mg IM every 12 hours for 4 doses beginning 24 hours after starting methotrexate
8 Cyclophosphamide 600 mg/m2 IV C (cyclophosphamide)
Vincristine 1.0 mg/m2 IV push O (Oncovin)

53

• Cerebral metastases should be treated over a
  2-week period with radiation given in a dosage of
  3 Gy daily, 5 days a week, to a total organ dose
  of 30 Gy.
• Whole-liver irradiation is usually accomplished
  over 10 days to attain a 20-Gy whole-organ dose
  given at a rate of 2 Gy daily, 5 days a week.

54

• Chemotherapy should be continued for at least 3
  cycles after negative -hCG.
• As with nonmetastatic and low-risk disease, oral
  contraceptive pills or other form of birth
  control should be utilized if not
  contraindicated.
• The same tests must be employed to detect
  toxicity as are used when single-agent
  chemotherapy is given, but monitoring must be
  even more vigilant because of the possibility of
  combined toxicity.
• In resistant cases, adjunctive measures along
  with chemotherapy may include hysterectomy,
  resection of metastatic tumors, or irradiation of
  unresectable lesions

55
Prognosis

• Excellent for molar pregnancy
• Good for malignant non metastatic disease ,
  almost all cured
• 90 of non metastatic disease have preserved
  their reproductive capability, 1st line failure
  6.5
• For poor prognostic /high risk patient remission
  rate 75 -85, salvage rate 65
• Risk of secondary tumors especially with multiple
  drugs, myeloid leukemia and colon cancer
• Subsequent pregnancy are not at an increased risk
  of adverse outcome

56

• ANY QUESTIONS?????
• THANK YOU FOR LISTENING.