Gestational Trophoblastic Disease (GTD) Gestational Trophoblastic Neoplasia (GTN )

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Gestational Trophoblastic Neoplasia (GTN)

• Zohreh Yousefi Professor of Obstetrics and
  Gynecology,
• Fellowship of Gynecology Oncology , Ghaem
  Hospital,
• website www.zohrehyousefi.com

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• Danforth's
• Williams Obstetrics, 23e
• B erek and Hacker's Gynecologic Oncology
• Up To Dat
• GESTATIONAL TROPHOBLASTIC DISEASE
• PATHOGENESIS
• DIAGNOSIS
• MANAGEMENT
• GESTATIONAL TROPHOBLASTIC NEOPLASIA
• TREATMENT
• SUBSEQUENT PREGNANCY

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• Gestational trophoblastic disease (GTD) is term
• group of tumors with abnormal trophoblast
  proliferation
• produce human chorionic gonadotropin (hCG)

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• GTD histologically is divided into
• benign
• hydatidiform moles
• ( complete and partial)
• Malignant
• Invasive mole

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• Non -molar trophoblastic neoplasms
•  
• Choriocarcinoma
• Placental site trophoblastic tumor
• Epithelioid trophoblastic tumor

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Gestational trophoblastic neoplasia (GTN )

• Malignant forms of gestational trophoblastic
  disease
• GT N is all GTD except hydatidiform mole
•  
• Weeks or years following any type of pregnancy
• But frequently occur after a hydatidiform mole

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Hydatidiform mole

•  
• Microscopic (classic findings)
• Absence embryonic elements
• Trophoblastic proliferation
• (cytotrophoblast and
  syncytiotrophoblast)
• Stromal edema and hydropic degeneration
• Absence of blood vessels

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Macroscopic of Hydatidiform mole

• Hydropic villi Grapelike vesicles filled
  clear material
• usually 1 to 3cm diameter
• proliferation of the trophoblast

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• Hydatidiform mole
  
  Complete mole Partial mole Partial mole
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• Partial mol ( fetal tissue)
• Grossly placenta a mixture of normal and
• hydropic
  villi
• Fetus Severe growth restriction
• Multiple congenital anomalies

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Risk Factors hydatidiform mole

•  
• Strongest risk factors are
• Age and a
• history of prior hydatidiform mole
•  
• Both extremes of reproductive age
• adolescents twofold risk
• Older than 40 tenfold risk

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• history of Prior mole
• the risk of another mole
• Complete mole is 1.5 percent
• Partial mole is 2.7 percent
• Two prior molar pregnancies
• the risk is 23 percent

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• An ethnic predisposition
• Diet (Deficiencies of protein or)
• (Vitamin A deficiency)
• animal fat
• Smoking
• Increased paternal age

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Pathogenesis

• Abnormal fertilization process
• Normal ovum with a duplicated haploid sperm
• Inactive ovum chromosomes
• Karyotype 46, XX
• diploid and result from androgenesis
• Partial moles triploid karyotype
• 69, XXX, 69,XXY

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Clinical Findings

• Because universal sonography in prenatal care
  
• Typically diagnosed at a mean of 10 weeks
•  
• Vaginal bleeding
• spotting to profuse hemorrhage
• Moderate iron-deficiency anemia

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• Exaggerated early pregnancy symptoms
• Nausea and vomiting ( hyperemesis)
• Abdominal cramp

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• Abnormally enlarged and soft uterus uterine
  growth
• Theca-lutein cysts (hCG) 25 to 60
• (Torsion, infarction, rupture and hemorrhage)
  
• Releases antiangiogenic factors that activate
  endothelial damage
• Severe preeclampsia
• hypoxic trophoblastic mass

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• All hydatidiform moles secrete hCG
•  
• Thyrotrophic -like effects of hCG
• hCG acts a thyrotrophic substance
• Elevated serum free thyroxine (T4)
• (TSH) levels to be decreased
• thyroid hyper function
• thyroid storm

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Diagnosis

• Amenorrhea followed by irregular bleeding
• Spontaneous passage of molar tissue
• High values Serum ß-HCG measurement
• confirming the diagnosis
• IHC stain positively for p57

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• Sonography
• Echogenic uterine mass with
• anechoic cystic spaces
• without a fetus or amnionic sac
• The appearance as snowstorm

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Transvaginal sonogram demonstrating the snow
storm appearance.
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Mis-diagnosis

• Incomplete abortion
• missed abortion
• Cystic degeneration
• uterine leiomyoma
•  

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• which of the following symptoms will a highly
  intelligent physician assistant immediately
  consider hydatidiform mole?
• pelvic pain at night during the first trimester
• significantly elevated BP in the first trimester
• significant bloody vaginal discharge  in the
  first trimester
• nausea and vomiting in the first trimester

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• Answer is B

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Management

• Termination of Molar Pregnancy
• Evacuation and Curettage
• Hysterectomy (rarely and select cases
• no desired future
  pregnancy )
• Chest radiograph
• Initiate effective contraception
• OCP or MPA poor compliance

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• Serum hCG levels
• 48 hours of evacuation (baseline)
• Weekly until undetectable Weekly until
• normal for 3 consecutive weeks
• monthly until normal for at least 6
  consecutive months
• Median time for resolution is 9 weeks
  for complete
• 
  7 weeks for partial
• Hysterectomy reduces the incidence of
  malignant sequelae
• does not eliminate follow-up

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hCG change

• HM 84-100
  days
• Spontaneous abortion 19 days
• Normal delivery 12 days
• Ectopic pregnancy 8-9 days

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• After molar evacuation
• risk factors for malignant squeal
• 15 - 20 complete moles
• 1 - 5 partial moles
•  
• 1 5 of HM become invasion moles
• 2.5 progress into
  choriocarcinoma

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Twin Pregnancy (Normal Fetus and Coexistent
Complete Mole)

• Diagnosis is difficult
• (early pregnancy ultrasound)
• A single partial molar pregnancy with
  abnormal fetus Distinguished

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• A few cases the diagnosis is not suspected
• until examination of the placenta
• following delivery

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• Amniocentesis ( fetal karyotype )
• diploid or triploid
• If fetal karyotype is normal
• Major fetal malformations are excluded by
  ultrasound
•  
• Chest X-ray performed
• Serum hCG values
•  
• If there is no evidence of metastatic disease
• to allow the pregnancy
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Possible risk for developing

• Subsequent GTN
• Preterm delivery
• Preeclampsia
• Sever hemorrhage

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Persistent GTD

• Persistently elevated serum hCG level
• Irregular vaginal bleeding
• Persistent theca lute in cysts
• (2 to 4 months regress spontaneously)
• Uterine sub involution
• Risk factors for GTN

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Risk factors of GTN

• Older age
• ß-hCG levels gt 100,000 mIU/mL
• Large uterine size for-gestational age
• Theca-lutein cysts gt 6 cm
• Earlier recognition and evacuation of molar
  pregnancies
• not lower risk neoplasia

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Criteria for Diagnosis of Gestational
Trophoblastic Neoplasia

• Criteria for the diagnosis of postmolar GTN
• 1. Plateau or rise of serum ß-hCG level
• 2. Detectable serum ß-hCG level for
• 6 months or more
• 3. Histological criteria for choriocarcinoma
• 4-Irregular bleeding ,uterine sub involution

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Plateau of serum ß-hCG level ( 10 percent) for
four easurements during a period of 3 weeks or
longer days 1, 7, 14, 21 Rise of serum ß-hCG
level gt 10 percent during three weekly
consecutive , during a period of 2 weeks or
moredays 1, 7, 14

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Diagnosis

• Sonography Abdomino pelvic
• or trans vaginal
  sonography
• Radiograph of chest
• Chest CT scan
• Brain CT scan or
• MRI

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SPESIAL

• 1-Selective angiography of abdominal and pelvic
  or hepatic (if indicated )
• 2-Whole body PET Less commonly (occult disease
  )
• 3-Stool guaiac tests
• If positive test is or if gastrointestinal
  symptoms
• be routinely performed in persistent GTN
• 4- complete radiographic evaluation
• of the gastrointestinal tract

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GTN CLASSIFICATION

• Invasive Mole
• Almost all invasive moles arise from partial or
  complete moles
• Deep penetration into the myometrium
• or peritoneum
• Involvement of vaginal vault

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Invasive hydatidiform mole infiltrating the
myometrium
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Choriocarcinoma

• Most common follow a term pregnancy
• or miscarriage
• Rapidly growing both myometrium
• and blood
  vessels
• Blood-borne metastases

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• differentiation between
• invasive mole and choriocarcinoma
• if we see villi, it must be invasion mole
• if we cant see villi, it is choriocarcinoma
•  
•  

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Common Sites for Metastatic Gestational
Trophoblastic Tumors
Site Per cent
Lung 60-95
Vagina 40-50
Vulva/cervix 10-15
Brain 5-15
Liver 5-15
Kidney 0-5
Spleen 0-5
Gastrointestinal 0-5
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Symptoms

• Metastatic symptoms
• Profuse vaginal bleeding
• Vaginal or cervical metastasis
• (bluish nodule in vaginal)
• Abdominal pain (intra-abdominal hemorrhage)
• Cough, hemoptysis
• Headache, nausea, vomit, paralysis or coma
• Urologic hemorrhage

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Lung metastasis

• Four principal pulmunary radiologic patterns
• Snowstorm pattern (Alveolar pattern )
• Discrete rounded densities
• Plural effusion
• Embolic pattern

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Brain metastasis

• Plasma CSF /hCG level ratio is normally
• gt60 1
• In patients with CNS metastases lt60 1
• Falsely lowered plasma CSF /hCG level
• First -trimester abortions
• In the absence of lung or vaginal metastasis
• Risk of cerebral and hepatic spread
• is exceedingly low

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• Generally in GTN
• Serum hCG levels combined Clinical
  findings
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• Rather than a histological specimen
• Diagnose and treat this malignancy

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Follow-up of GTN patients ß-subunit until hCG

• Weekly until normal for 3 consecutive
  weeks
• monthly until normal for at least 3
  consecutive months
• at 1-month interval for 1 year
• at 1- month interval for 2 years in high
  stage
• at yearly interval for many years
• (increased risk of late recurrence)
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• Be careful
• hCG
• Pelvic examination
• Chest X-ray
• unusual rise of serum hCG
• Rule out Normal pregnancy
• Ectopic pregnancy
• False-Positive hCG

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• False-Positive hCG
• Quiescent GTN
• Phantom hCG
• Pituitary hCG
• Non-gynecologic tumors secreted -hCG

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Quiescent GTN

• Constant, low level of hCG lt100 IU/L
• Without evidence of a primary or metastatic
  malignancy
• Persisting for periods 3 months to 16 years
• Slow-growing
• Oral contraceptive pills
• and avoid pregnancy until
• hCG has been undetectable for six months
• 20 percent will eventually have recurrent
  active
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• H hCG assay is critical

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H CG variants

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• Hyperglycosylated hCG (H -hCG)
• hCG produced by syncytiotrophoblasts
• (H -hCG) synthesized by cytotrophoblast
• (H -hCG) absolute marker of ongoing invasion
• hCG-H is detectable gt1 ng/ml active GTN
• To discriminate quiescent disease

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Phantom hCG

•  False positive serum hCG
• Send the serum to two laboratories
• Using different commercial assays
• If negative in one or both
• false positive hCG
• Presence of hCG in serum but not urine

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• Heterothallic antibodies may results
• false-positive
• False positive are at risk for recurrent
• Risk for other false positives, such as
• CA-125 and thyroid antibodies

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Pituitary hCG

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• Secreted LH and hCG pulsatile and
  paralleled
• Higher levels of h CG in postmenopausal
• than premenopausal Cross-reactivity with
  LH
• Pituitary production hCG ranges from
• 1 to 32 mIU/mL 
• HRT or BSO or OCP after 23 weeks
  
• Suppress hCG Pituitary production

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• Staging of GTN
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• WHO Scoring System

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Staging

• International staging of WHO may be summarized as
  follows
• ? lesion localized in uterus, no metastasis
• ? lesion extends beyond uterus, but still
  confined to internal genitalias
• ? pulmonary lesion
• ? metastasis to other distant sites.

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IIa
IIb
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IIIalt3cm or locate in half lung IIIb disease
beyond IIIa
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Who Orgnaization prognostic scoring system for
gestational trophoblastic neoplasia
Prognostic factor 0 1 2 4
Age lt39 gt39 _ -
Antecedent pregnancy Hydatidiform Abortion , ectipic Term pregnancy -
Interval (months) lt4 4-6 7-12 gt12
hCG level (IU/liter) lt10 10-10 10-10 gt10
ABO blood groups (female/male) O/A B A/O AB
Largest tumor (cm) lt3 3-5 gt5 _
Site of metastasis _ Spleen, kidney Gastrointestinal tract, liver Brain
Number of metastases _ 1-3 4-8 gt8
Prior chemotherapy _ _ Single drug Multiple drugs
The total score is obtained by adding the
individual scores for each prognostic factor .
Total score lt4 , low risk 5-7 , intermediate
risk gt8 , high risk . Interval between
antecedent pregnancy and start of chemotherapy.
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• According to the FIGO staging of gestational
  trophoblastic tumors
• a lady with choriocarcinoma having
• lung metastasis will belong to which stage

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protocol for treatment of GTD

• Clinically staging( FIGO)
• WHO scoring
• Again, it is stressed that the diagnosis of
• GTN made by persistently elevated serum
• ß-hCG without confirmation by pathological
  tissue study

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Choice of treatment

• Chemotherapy ( highly sensitive )
• Surgery ( unresponsive or drug
  fails )
• Irradiation (brain and liver ) 

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• Chemotherapy are best management
• Protocols Single-agent for
• low-risk Methotrexate
• Combination for high-risk disease
  EMA-CO
• Early-stage GTN is typically cured
• Later -stage disease usually responds
• to chemotherapy
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Surgery in malignant GTN

• Hysterectomy
• Laparoscopy
• Craniotomy (brain hemorrhage)
• Thoracotomy
• (solitary nodules in drug-resistant disease )
  
• selective resection of lesion in uterus or
  liver

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Main causes of death

• Hemorrhage
• Infection
• Metastasis

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Placental Site Trophoblastic Tumor (PSST)

• PSTT or non-trophoblastic malignancy
• Uncommon tumor arises from implantation
  site-intermediate trophoblast
• Secrete (hPL) from intermediate cells
• Relatively small amounts of hCG
• hCG free ß-subunit is more than one third of hCG
  (30)

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• Typically local myometrial invasion
• Rare systemic metastases
• Treatment of ( PSST) is preferred hysterectomy
• Because resistant to chemotherapy
• For higher-risk than stage I
• combination chemotherapy given

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Epithelioid Trophoblastic Tumor

• This rare tumor
• Intermediate trophoblast -type
• Grossly a nodular fashion
• Primary treatment is hysterectomy
• Relatively resistant to chemotherapy
• Approximately a fourth this neoplasm
• will have metastatic disease,
• combination chemotherapy

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SUBSEQUENT PREGNANCY

• Pregnancy outcomes are usually normal
• May develop
  
• 1-Repeat molar gestation 2-percent
• 2-Spontaneous abortions
• 3-Congenital anomalies
• 4-Ovarian failure (chemotherapy)
• 5-Secondary tumors including
• leukemia
• colon cancer, melanoma
• and breast cancer

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After Termination of Subsequent Pregnancy

• Sonographic evaluation in early pregnancy
• pathological evaluation placenta after delivery
  
• serum ß-hCG level is measured 6 weeks
  postpartum

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Conclusion

• The possibility of metastatic GTN should be
  considered
• In any woman of the reproductive age
• Presenting with metastatic disease
• Or
• an unknown primary site of malignancy

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