Pathogenesis and management of gestational trophoblastic disease

1. GESTATIONAL TROPHOBLASTIC DISEASEs
Dr Onesmus Byamukama
MBChB, MMED, FMAS, FPSU Fellow

2. Introduction
• Gestational trophoblastic disease (GTD) refers to a
spectrum of interrelated but histologically distinct tumors
originating from the placenta.
• There is abnormal growth and proliferation of the
trophoblasts that continue even beyond the end of
pregnancy.

4. Benign Vs Malignant
Hydatidiform Mole:
• Complete
• Partial
Gestational Trophoblastic Neoplasia (GTN):
• Invasive Mole
• Choriocarcinoma

5. Risk Factors for GTDs
Two main risk factors
1. Extremes of maternal age (<20 and >35 years)
2. Obstetric history- a history of prior unsuccessful pregnancy
• Previous spontaneous abortion doubles the risk of GTD
• History of previous GTD
• History of 1 molar pregnancy  10 fold risk
• Two molar pregnancies recurrence  16 to 28%

6. Risk factors…
Other risk factors
• Current smoking (>15 cigarettes per day)
• History of infertility, irregular menstrual cycles
• Use of oral contraceptives
• Blood type:
• A or AB are at slightly higher risk than those with type B or O

7. PATHOLOGIC
CLASSIFICATION
CLINICAL
CLASSIFICATION
Hydatidiform mole
*complete
*incomplete
Benign gestational
trophoblastic disease
Invasive mole
Malignant
trophoblastic disease
Nonmetastatic
Placental site
trophoblastic
tumor
Metastatic
Choriocarcinoma High risk Low risk
Pathologic and clinical classifications

8. HYDATIDIFORM MOLE- (MOLAR PREGNANCY)
• Hydatidiform moles are abnormal pregnancies characterized histologically
by aberrant changes within the placenta.
• Classically, the chorionic villi in these placenta show varying degrees of
trophoblast proliferation and edema of the stroma within villi.
• Hydatidiform moles are categorized as either complete hydatidiform moles
or partial hydatidiform moles
• Xsomal abnormalities play an integral role in hydatidiform mole
development.

9. Complete Moles
• Complete moles have a diploid karyotype, and 85 to 90% of cases are
46,XX.
• The chromosomes, however, in these pregnancies are entirely of paternal
origin, and thus, the diploid set is described as diandric.
• Complete moles are formed by androgenesis, in which the ovum is
fertilized by a haploid sperm that then duplicates its own chromosomes
after meiosis.

10. Cont…
• The ovum fails to contribute chromosomes.
• Most of these moles are 46,XX, but dispermic fertilization of a
single ovum, that is, simultaneous fertilization by two sperm,
can produce a 46,XY karyotype.
• Although nuclear DNA is entirely paternal, mitochondrial DNA
remains maternal..

11. Hydatidiform mole

12. Cont…
• Microscopically, complete moles display enlarged, edematous villi and
abnormal trophoblastic proliferation.
• These changes diffusely involve the entire placenta.
• Macroscopically, these changes transform the chorionic villi into clusters
of vesicles with variable dimensions.
• The name hydatidiform mole literally stems from this “bunch of grapes”
appearance.
• In these pregnancies, no fetal tissue or amnion is produced.
• As a result, this mass of placental tissue completely fills the endometrial

14. Partial Mole
• These moles differ from complete hydatidiform moles clinically, genetically,
and histologically.
• The degree and extent of trophoblastic proliferation and villous edema are
decreased compared with those of complete moles.
• Most partial moles contain fetal tissue and amnion, in addition to placental
tissues.
• Patients with partial moles typically present with signs and symptoms of an
incomplete or missed abortion.

16. Hydatidiform Mole
Clinical Manifestations:
• Vaginal bleeding (97%)
• Anemia
• Enlarged uterus (size > dates)
• Pelvic pain
• Theca lutein cysts
• Hyperemesis gravidarum
• Hyperthyroidism
• Preeclampsia <20 weeks gestation
• Vaginal passage of hydropic vesicles
• Partial mole usually presented as incomplete or missed abortion

17. Complete vs. partial mole
Partial Complete Feature
Triploid
(69,xxx or 69,
xxy)
Diploid(usually
46,xx or rarely
46,xy)
Karyotype
focal diffuse Swelling of chorionic villi
focal diffuse Trophoblastic hyperplasia
Present absent Embryonic tissue
usually<
100,000
Often > 100,000 hCG
<5% 15 - 20% Trophoblastic sequelae
Rare Up to 25% Theca lutein cysts
Rare Up to 25% Medical complications
Small for dates 50% large for dates Uterine size

18. Theca-lutein cysts
• The theca-lutein cysts develop with prolonged exposure to luteinizing
hormone (LH) or β- hCG.
• These cysts range in size rom 3 to 20 cm, and most regress with falling β-
hCG titers after molar evacuation.
• If such cysts are present, and especially if they are bilateral, the risk of
postmolar GTN is increased.

19. Hyperthyroidism
• GTD is complicated by hyperthyroidism, which may require treatment.
• This is thought to occur due to molecular mimicry between human
chorionic gonadotrophin (HCG) and thyroid-stimulating hormone (TSH)
• Both HCG and TSH have 92aa for alpha subunit but differ in the beta
subunit (HCG-145aa, and TSH 118)
• Hyperthyroidism usually resolves as the GTD is successfully treated
and correspondingly HCG levels normalise

20. Preeclampsia
• Explained by
• Abnormal trophoblastic invasion.
• Immunological theory with exaggerated antigenic sites due to
abnormal proliferation of the trophoblast
• Overproduction of the inflammatory markers which causes
endothelial damage

21. Treatment
• Suction curettage is the preferred method of evacuation
• Prostaglandins are not given to ripen the cervix
• Increase the risk of trophoblastic embolization to the pulmonary
vasculature.
• Symptomatic theca-lutein ovarian cysts are an unusual finding
and tend to regress after molar evacuation.
• Oophorectomy is not performed except when torsion leads to extensive
ovarian infarction.

22. Surgery
• Prior to surgery, patients are evaluated for associated medical
complications.
• Blood products should be available prior to the evacuation and
adequate infusion lines established.
• At the beginning of the evacuation, the cervix is dilated to admit a
10- to 12-mm plastic suction curette.
• As aspiration of molar tissues ensues, intravenous oxytocin is
given.

23. Surgery
• 10 to 20 units of oxytocin are mixed with 1 L of crystalloid and
infused at rates to achieve uterine contraction.
• A thorough, gentle curettage is performed.
• Following curettage, because of the possibility of partial mole
and its attendant fetal tissue, Rh immune globulin is given to
nonsensitized Rh D-negative women.
• Rh immune globulin, however, may be withheld if the diagnosis
of complete mole is certain

24. Post molar surveillance
• Malignant transformation into metastatic choriocarcinoma does occur
after partial mole evacuation
• Post molar surveillance with serial quantitative serum β-hCG levels
is the standard.
• Titers are monitored at least every 1 to 2 weeks until they become
undetectable. 3 consecutive undetectable levels required.
• Then levels are monitored monthly during 6 months of surveillance
for all patients with a molar gestation

25. Post molar surveillance
• Can get pregnant one year after follow-up and at birth, take the
placenta for histological evaluation
• During the follow up:
• Take history (Ask about the symptoms if they have ceased like PV
bleeding, pelvic mass, cough, hemoptysis and symptoms of
pregnancy)
• Investigations like serum β-hCG levels, CXR and Abdominal pelvic
ultra-sound scans

26. Cont..
• Women are encouraged to use effective contraception
• COC use decreases the likelihood of pregnancy
• Injectable progestins are particularly useful when poor
compliance is anticipated.
• IUDs are not inserted because of the risk of uterine perforation
in an invasive mole is present.
• Barrier methods are the best (adherence issues)

27. Prophylactic Chemotherapy
• Chemotherapy can be administered to help prevent GTN
development in high-risk patients
• Age of patient > 40 years.
• Initial levels of serum hCG > 100,000 IU/mL.
• Previous history of a molar pregnancy.
• If serum hcg doesn’t normalise within 7 to 9 weeks.
• Uterine size of > 20cm
• Theca lutein cysts
• Unilateral >10cm
• Bilateral >6cm
• Woman who is unreliable for follow up.
• Drug of choice: Single dose MTX

28. Gestational trophoblastic neoplasia

29. Introduction 1
• Gestational trophoblastic neoplasia (GTN) refers to a group of
malignant neoplasms that consist of abnormal proliferation of
trophoblastic tissue
• May follow a hydatidiform mole or a non-molar pregnancy
• GTN is comprised of the following histologic types
• Invasive mole
• Choriocarcinoma
• Placental site trophoblastic tumor (PSTT)
• Epithelioid trophoblastic tumor (ETT)

30. Introduction 2
• Invasive mole and choriocarcinoma are characterized by high
levels of hCG, while PSTT and ETT typically have low hCG
levels.
• With the use of hCG and appropriate management with highly
effective chemotherapy, most women with GTN can be cured
and their reproductive function preserved

31. Invasive Mole
• Myometrial invasion by hydatidiform mole
• Formerly known as chorioadenoma destruens
• 1 in 15,000 pregnancies
• 10-17% of hydatidiform moles will progress to
invasive moles

32. Invasive mole…
Histopathology
• Difficulty unless hysterectomy performed
• The main diagnostic feature is the presence within
the myometrium of molar villi showing trophoblastic
proliferation.
• Invasion may be of the accreta type of invasion,
increta or percreta type

33. Placental-site Trophoblastic Tumor
• This tumor consists of intermediate trophoblasts at the placental site.
• PSTT can follow any type of pregnancy but develops most commonly
following a term gestation.
• Patients have irregular bleeding months or years after the antecedent
pregnancy, and the diagnosis is made after endometrial sampling has
been performed.
• PSTT tends to infiltrate only within the uterus, disseminates late in its
course, and produces low β-hCG levels
• Metastases spread to the lungs, liver, or vagina

34. PSTT
• Hysterectomy is the primary treatment for nonmetastatic PSTT
due to its relative insensitivity to chemotherapy.
• Metastatic PSTT has a much poorer prognosis
• As a result, aggressive combination chemotherapy is indicated.
• EMA/EP regimens of etoposide,methotrexate, and dactinomycin
(actinomycin D) that alternate with etoposide and cisplatin
• Radiation, however, may also have a role.

35. Epithelioid Trophoblastic Tumor
• The preceding pregnancy event may be remote
• Epithelioid trophoblastic tumor develops from neoplastic
transformation of chorionic-type intermediate trophoblast.
• Hysterectomy is again the primary treatment due to presumed
chemoresistance
• Diagnosis is usually confirmed in advance by endometrial biopsy.

36. Gestational Choriocarcinoma
• This extremely malignant tumor contains sheets of anaplastic trophoblast
and prominent hemorrhage, necrosis, and vascular invasion.
• However, formed villous structures are characteristically absent.
• Gestational choriocarcinoma initially invades the endometrium and
myometrium but tends to develop early blood-borne systemic metastases.

37. Morphology
• Choriocarcinoma is a soft, fleshy, yellow-white tumor that
usually has large pale areas of necrosis and extensive
hemorrhage
• Histologically, it does not produce chorionic villi and consists
entirely of proliferating syncytiotrophoblasts
• Mitoses are abundant and sometimes abnormal.

39. Epidemiology
• May come from any type of pregnancy
- 25% follow abortion or tubal pregnancy
- 25% with term gestation
- 50% from hydatidiform moles
• 15% of complete moles progress to choriocarcinoma with 5 %
having metastatic disease
• Incidence 1 in 40,000 pregnancies

40. Cont..
• Vaginal bleeding is the most common symptom.
• Abnormal bleeding for more than 6 weeks following any pregnancy warrants
evaluation with β- hCG
• The diagnosis can be made in an asymptomatic woman by an incidental
positive pregnancy test.
• Choriocarcinomas following term pregnancies are associated with high-
risk features and a higher mortality rate
• Death rates range from 10 to 15 percent

41. Non-gestational choriocarcinoma
• In contrast to this gestational choriocarcinoma, primary
“nongestational” choriocarcinoma is an ovarian germ cell tumor.
• Although rare, ovarian choriocarcinoma has a histologic
appearance identical to that of gestational choriocarcinoma.
• It is in part distinguished by the lack of a preceding pregnancy

42. Diagnosis
• .

43. Assessment
• The initial evaluation may be limited to pelvic examination,
chest radiograph, and pelvic sonography.
• 40% will have micro metastases not visible on chest
radiography
• CNS involvement is rare in the absence of neurologic
symptoms or signs.
• PET may evaluate occult choriocarcinoma for relapse from

44. Metastatic GTN
• The most common sites of spread are the lungs (80 percent), vagina (30
percent), pelvis (20 percent), liver (10 percent), and brain (10 percent).
• Patients with pulmonary metastases present with cough, dyspnea,
hemoptysis, pleuritic chest pain, or signs of pulmonary hypertension.
• All patients with hepatic or cerebral metastases have concurrent
pulmonary or vaginal involvement or both.
• Attempts to excise of any metastatic disease site results in profuse
hemorrhage.

45. Treatment
• Postmolar GTN confined to the endometrial cavity and are treated primarily with
chemotherapeutic agents.
• Repeat dilatation and curettage is generally avoided to prevent morbidity and
mortality caused by:
• Uterine perforation,
• Hemorrhage,
• Infection,
• Uterine adhesions, and
• Anesthetic complications.
• If done, it reduces the number of courses in those who do require chemotherapy.

46. Approach to treatment
• Perform FIGO staging
• Assign WHO risk score
• Stabilise the patient
• Assess baseline organ function (RFTs, LFTs, CBC)
• Ascertain fertility desires
46

47. FIGO staging and WHO risk score
47

48. Chemotherapy for low-risk disease GTN
• FIGO stage I GTN
• Stage II or III GTN with a WHO risk score <7
First line therapy
• Either:
• A weekly administration of a maximum dose of 50 mg/m2
• Alternative therapy
• Methotrexate 1–1.5 mg/kg IM/IV Days 1, 3, 5, 7
• Folinic acid 0.1–0.15 mg/kg IM Days 2, 4, 6, 8
• The courses are to be repeated at interval of 7 days during therapy until
undectatable hcg levels, then an additional two to three doses are given
Second-line therapy
• Actinomycin D is for pts who fail to achieve remission to MTX
o Given in pulsed dosing (1.25mg/m2 IV every 14 days) or 5day dosing of 10-12mcg/kg every other week)
48

49. Chemotherapy for high-risk disease
GTN
High-risk GTN: Stages II and III with risk score 7 and above
• 1St line chemo: MAC
• 2nd line chemo: EMA-CO
• Salvage therapy: EMA-EP
High-risk GTN : Stage IV
• EMA-CO
• EMA-EP
49

50. Surgical Management
• Hysterectomy : Indications
o Lesions confined to the uterus in women aged >35 years, not desirous of fertility
o Placental site trophoblastic tumor, ETT, Invasive mole
o Intractable vaginal bleeding
o Localized uterine lesion resistant to chemotherapy
o Uterine perforation
• Lung resection (thoracotomy) for drug resistant pulmonary
metastases confined to one lung
• Craniotomy for control of bleeding and for solitary drug resistant
metastases in the brain
• Angiographic arterial embolization
50

51. Prevention of recurrent Disease
• Consolidation chemotherapy following negative hCG level,
should be given as follows:
oFor non-metastatic disease — one cycle
oFor good prognosis metastatic disease — two cycles
oFor poor prognosis metastatic disease — three cycles
51

52. The cell cycle

54. Brain Metastasis
• Low-risk patients with lung metastases and all high-risk patients are assumed to be at risk
of CNS disease and so undergo MRI brain scans.
• If this is negative then the patients are still considered to be at risk of occult disease and
so have a lumbar puncture
• To measure the cerebrospinal fluid (CSF) hCG : serum hCG ratio and
• To give the first dose of intrathecal MTX (12.5 mg) followed by oral folinic acid 24 h later.
• If the ratio of CSF: serum hCG is 1:60 or less
• Two further doses of intrathecal MTX are given, usually with the CO arm of EMA/CO chemotherapy.
• This completes prophylaxis for potential occult CNS disease.

55. Brain mets…
• Patients with overt CNS disease on MRI, or where the serum:
CSF hCG ratio exceeds 1:60 require more intensive therapy.
• Surgical removal of the lesion followed by chemotherapy
combined with irradiation is the treatment of choice in patients
with progressive neurological deterioration in whom
chemotherapy alone is ineffective.

56. Posttreatment- Surveillance
• Monitoring of patients with low-risk GTN consists of weekly β-hCG
measurements until the level is undetectable for 3 consecutive weeks.
• This is followed by monthly titers until the level is undetectable for 12
months.
• Patients with high-risk disease are followed or 24 months due to the
greater risk of late relapse
• During follow-up, take history, examine and investigations.
• Patients are encouraged to use effective contraception during the entire
surveillance period.

57. For Subsequent pregnancies
1. Delay pregnancy for atleast 1year after completion of treatment
2. 1st trimester ultrasound to confirm normal gestational development
3. Quantitative hCG at 6weeks
4. After delivery, examine the placenta and send to pathology for
histologic examination if any gross abnormalities are present
5. Measure serum β-hCG 6 weeks after the completion of any type of
future pregnancy to exclude choriocarcinoma
6. Send all products of conception from miscarriages and pregnancy
terminations for histology 57

58. Survival rates by stage
• Stage I 100%
• Stage II 100%
• Stage III 99%
• Stage IV 78%

59. Thank you