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Persistant gestational trophoblastic tumor
Highly malignant chemo sensitive tumor occur in two categories:
A-non metastatic lesion : usually confined to uterus in form of invasive mole
and is follow [ 15%] of primary HM.
B- metastatic lesion : usually lead to distant metastasis and is follow [5%] of
primary HM.
Incidence and epidemiology :
1. Geographical distribution: similar to that of HM. west [1 :10.000- 1
:70.000 ] pregnancy, middle east [ intermediate position ], Asia [1- 250 -
1-6000].
2. Age > in old, parity > in high parity, socioeconomic > in poor.
3. Antecedent pregnancy: HM in [50% -75%], normal term pregnancy [
25%], abortion [ 25%].
4. Maternal blood group: > in group A, < in group O.
Pathology of persistent GTT:
Macroscopic appearance:
Dark hemorrhage tumor mass on uterine wall, cervix and vagina could
perforate uterine wall or invade blood vessels leading to metastases.
Microscopic appearance:
Invasive mole: trophoblastic extensive deep myometrial penetration, may
reach peritoneal covering of uterus or vagina with necrosis of muscles and
preservation of villous pattern usually lacking tendancy of widespread
metastasis.
Choriocarcinoma: completely disorganized growth with bizarre forms of
cytotrophoblasts and syncytiotrophoblast, with variable cellular anaplasia and
absence villi.
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Clinical feature of persistent GTT:
a-uterine cramps and bleeding which is the commonest complaint and is
either internal bleeding due to myometrial infiltration by tumor and lead to
perforation and hemoperitoneum, or external bleeding.
b-offensive vaginal discharge.
c-cachexia, weakness and pyrexia as disease advances.
d-not uncommon, patient has no specific complaint and she diagnosed during
surveillance after molar pregnancy when one of the indication of
chemotherapy is encountered.
d-signs and symptoms of metastatic lesion: metastasis may be local to broad
ligament and paracervical tissues or through blood stream to the lungs most
commonest site of metastasis [75%] leading to dyspnea and hemoptysis,
vagina next common site of metastasis [50%] leading to bleeding nodules, CNS
lead to seizure and CVA, liver metastasis.
Investigations of persistent GTT:
a-HCG: important in the diagnosis and clinical staging of persistent GTT HCG
should normalize [48 hours after term delivery], [2 weeks after abortion] and
[6-8 weeks after HM]. So persistent increase levels of HCG mean persistent
GTT.
b-CXR to detect lung metastasis.
c-imaging techniques U/S,CT scan, MRI. [ MRI is superior to U/S and CT scan in
evaluating abdominal and pelvic organs and CNS metastasis.
Staging of persistent GTT:
Numbers of factors identified which influence prognosis of persistent GTT in a
positive way they are as follows:
1-increasing HCG before starting treatment because it reflect larger mass.
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2- metastasis and this include :
a-Site of metastasis worst prognosis with CNS metastasis because
chemotherapy agents usually do not cross blood brain barrier, liver metastasis
associated with poor prognosis because chemotherapy rapidly detoxified in
liver.
b-Numbers of metastatic lesions the more the numbers the poor the
prognosis.
3-size of largest mass: the larger the mass the poorer the prognosis.
4-antecedent pregnancy: worst prognosis when antecedent pregnancy is term
normal pregnancy, better prognosis with abortion, best prognosis when
antecedent pregnancy is H, mole.
5-pregnancy – treatment interval: longer the interval between pregnancy and
chemotherapy the worse the prognosis.
6-previous unsuccessful chemotherapy: associated with poor prognosis due to
drug resistance may be due to impermeability of chemotherapy to tumor
mass because of scarring and fibrosis or accumulating drugs toxicity.
7-ABO group : worst prognosis in blood groups B,AB.
8-age poor prognosis if[ > 39 ]and parity >[ 3 or 4].
Each of the above mentioned prognostic variables is given a score ranging
from [ zero to 30 ] zero if absent and 30 if present.
By calculating the score of the patient : final score
+ [< 50 ]allocated as low risk G.T.T.
+ [ 55-95 ] allocated as medium risk G.T.T.
+ [ >95 ] allocated as high risk G.T.T.
So staging affect survival rate and choice of chemotherapy , this based mainly
on HCG levels and metastasis and is not a pathological classification.
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Treatment of persistent GTT:
Optimum result encountered in highly specialized centers, same policy of
treatment in invasive mole and metastatic choriocarcinoma .
Treatment modalities:
Chemotherapy= main stay of treatment.
Surgery=certain limited indication.
Radiotherapy= limited indication.
Further management and follow up.
Chemotherapy of persistent GTT:
Chemotherapy is indicated in all cases of persistent GTT. metastatic or non
metastatic forms of tumors are highly chemosensitive.
Protocol for chemotherapy agents are selected according to degree of risk of
patient [ low, medium, high ] which indicated by her pre treatment prognostic
score. Low risk category responds to single drug and medium, high risk
category require combination of drugs.
Low risk category:
Survival rate [100 %] carries best prognosis responds to single agent
chemotherapy either methotrexate or actinomycin D
Methotrexate : it is the drugs of choice in single chemotherapeutic courses
because its simplicity and low toxicity [ its low toxicity attributed to the
availability of antidote folinic acid which reduce toxicity and allow use of
higher dose.
How to give methotrexate ?
Before starting chemotherapy send for CBP, LFT, RFT and is given parentrally
[iv – im] excreted in urine so its contraindicated in renal failure, the coarse
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constitutes [8 days] , methotrexate given every other day alternating with
folinic acid.
D1=D3=D5=D7= methotrexate D2=D4=D6=D8= folinic acid.
HCG should be assessed twice weekly to ensure that it is regressing
satisfactorily, if HCG is increase or plateau which mean drugs resistance and
you need to change agent.
WBC count and platelet count sent for daily so stop chemotherapy if [WBC
count < 1000], [platelet count <50.000].
Toxicity of methotrexate may be encountered
a-myelosuppression: thrombocytopenia, granulocytopenia.
b-mucus membrane: stomatitis, oesophagitis, vaginitis, conjunctivitis.
c-skin rush, nephrotoxicity, hepatotoxicity.
When 8day course completed give [7- 14]days rest then start second course of
methotrexate in similar manner and you need [ 2-4] courses
To reach undetected level of HCG. When HCG level undetected give[ 2-3]extra
courses of methotrexate because approximately[ 100.000] trophoblast cells
may escape detected by RIA of HCG.
actinomycin D: given parenterally in courses consisting of 5 days , spaced by
[7- 14]days rest repeat courses until you reach undetectable level of HCG
followed by[ 2-3]extra courses, monitor patient condition by CBP, LFT, RFT and
is given and monitor patient response by HCG twice weekly.
Medium risk category:
Overall survival rate [ 95 %], they resist methotrexate when used as single
agent combination chemotherapy improves prognosis significantly. The
following agents are added to methotrexate.
^Actinomycin, 6 mercaptopurine, vincristine and cyclophosphamide.
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High risk category:
biggest therapeutic challenge, survival rate [40 – 65% ] they require seven
drugs combination courses include: alklating agent as chlorambucil +
methotrexate + Actinomycin D + vincristine and others, they also require
prophylactic intra thecal methotrexate on each alternating course to prevent
CNS metastasis, also these drugs combined in courses spaced by [7- 14]days
rest.
Surgical treatment of persistent GTT.
In pre chemotherapy era hysterectomy was the treatment of choice in
persistent GTT and at that time it may resulted in favorable outcome with HM
or invasive mole but was totally inadequate for metastatic choriocarcinoma.
Now we are in the era of chemotherapy,
success of chemotherapy replaced hysterectomy favorable pregnancy
outcome is possible after successful chemotherapy so is best to avoid
hysterectomy and preserve reproductive function.
Surgical treatment is indicated in the following :
a-drugs resistance focus: diagnosed when find focus with persistent increase
in HCG despite drugs combination so hysterectomy if the focus confined to
uterus or salvage surgery e.g lobectomy if the focus confined to lung or vaginal
nodules excision.
b-uterine perforation: by invasive mole lead to hemopeirtonium.
c-heavy uncontrollable uterine bleeding.
Hysterectomy with preservation of ovaries because ovarian metastasis is very
rare.
Radio therapy of persistent GTT.
persistent GTT not sensitive to radio therapy, it is of no benefit in
chemotherapy resistance tumor may be indicated in cases of brain or liver
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metastasis who develop hemorrhage into these metastatic lesions after
chemotherapy.
Further management of persistent GTT:
By quantitative assessment of HCG the aim of follow up is to diagnose
remission which define as 4 consecutive weekly -ve HCG assay. And to detect
relapse and majority of relapses occur in the first 12 months of remission,
contraception essential during treatment and during the first year of remission
by barrior methods then OCCP after normalization of HCG levels.
Follow up scheme
a-monthly HCG assay in the first year.
b-twice per a year for 5 years.
c-once per a year for 5 years.
Plus follow up previous metastatic lesion by appropriate tests
CXR for lung metastasis and MRI for pelvic, abdominal viscera and CNS.
This lecture by Dr-Nadia AL-Assady
CABOG & FIBOG