GENERAL INFORMATION
• Gestational trophoblastic diseases; It is a term used to describe a spectrum of histologically diverse diseases characterized by abnormal proliferation of placental trophoblasts.
histopathological types
Modified WHO (World Health Organization) Classification of Gestational Trophoblastic Disease
A. Molar pregnancies
Mole hydatiform (partial or complete hydatiform mole)
Invasive hydatiform mole
B. Trophoblastic Tumors Choriocarcinoma
Trophoblastic tumor arising from the placental region
Epithelioid trophoblastic tumor
• Gestational trophoblastic diseases can be histologically benign or malignant. While complete and partial mal is benign, invasive mal, choriocarcinoma, placenta! trophoblastic tumor and epithelioid trophoblastic tumors arising from the region are malignant.
• Malignant lesions can be locally invasive or metastatic and are called gestational trophoblastic neoplasia. Gestational trophoblastic neoplasms are the most treatable gynecological malignancies and are highly responsive to chemotherapy.
• Gestational trophoblastic diseases; It develops from three different cell types: cytotrophoblasts, syncytiotrophoblasts and intermediate (intermediate) trophoblasts. Except for placental site trophoblastic tumors and epithelioid trophoblastic tumors, diseases originating from villous syncytiotrophoblast and cytotrophoblast produce excessive amounts of hCG. Placental site trophoblastic tumors and epithelioid trophoblastic tumors are diseases of extravillous intermediate trophoblast origin and hCG production is low.
Characteristic markers of gestational trophoblastic diseases are Beta-HCG
Mole hydatiform
• It is the most common gestational trophoblastic disease. Molar pregnancies have a markedly different incidence in different geographic regions. The incidence of complete and partial hydatidiform moles is approximately 1:1945 and 1:695 pregnancies, respectively.
Risk factors
• advanced maternal age; The risk of complete mole increases 5-10 times over the age of 40.
• Very young maternal age
• Advanced paternal age
• History of previous molar pregnancy
• Low dietary carotene intake (a precursor of vitamin A) and a diet low in animal fat increase the risk of complete moles.
• Long-term use of oral contraceptives and a history of irregular menstruation are associated with partial mole.
• History of previous unsuccessful pregnancy; The probability of complete mole increases in patients with a history of recurrent pregnancy loss. The risk increases 2 times in those with a history of spontaneous abortion.
• Cigarette; It increases the risk of partial mole hydatiform.
• High level of education; It increases the risk of partial mole hydatiform.
Maternal age and nutritional factors are not associated with partial mole.
Complete Mole Hydatiform
• The genetic structure is only of paternal origin and is diploid. {Most often 46 XX). This genetic structure occurs in two ways:
• The haploid genome of paternal origin from a single sperm is 23X and its duplication
As a result, 46,XX structure is formed.
• The empty ovum is fertilized by two separate sperm (dyspermia) and forms a 46,XX or 46,XY karyotype.
In 90% of cases, the karyotype is 46,XX, and more rarely (10%) is 46,XY due to dyspermia.
Clinic
► Abnormal vaginal bleeding is the most common symptom (84%). Following bleeding, the molar tissue begins to be expelled as vesicles with painful contractions. Anemia due to bleeding (5%) can also be observed.
► Larger uterus for gestational age (28%).
► Preeclampsia (before 20 weeks of gestation) (27%)
► Hyperemesis gravidarum(8%)
► Hyperthyroidism (7%) occurs more in cases with high hCG levels.
► Theca lutein cysts are significantly enlarged (> 6 cm) in 50% of the cases. It is usually bilateral. Cysts develop due to the stimulus created by hCG and in parallel with the decrease in hCG level 2-4. It shows involution within a month.
► Trophoblastic embolism (2%): Typically, there is a picture of pulmonary embolism that develops within 4-6 hours following the evacuation of the mole and respiratory failure associated with it.
Diagnosis
► According to the gestational week, a significant increase in B-hCG level is observed.
► Macroscopically, it looks like a bunch of grapes.
► Ultrasound: A vesicular sonographic image (snowfall scene) is typical in a complete mole.
► Definitive diagnosis is made by histopathological examination of curettage material.
0 Diffuse trophoblastic hyperplasiaproliferation
0 Diffuse hydropic (hydatiform) swelling of chorionic villi
0 Hydropic villi are avascular
0 Embryonic or fetal tissues are not observed (due to avascularization).
0 Immunohistochemically p57 negative (as it is expressed by the maternal chromosome)
► Initially, a chest X-ray should be taken for lung metastases.
Treatment
► The uterus is evacuated by vacuum curettage. Because of the high risk of perforation, sharp curettage can be used for control purposes after vacuuming, not for emptying the uterus.
► Hysterectomy: If another pregnancy is not considered, it can be applied in elderly patients at risk of malignant development or in cases where bleeding cannot be stopped. Although the risk of metastatic disease decreases after hysterectomy, postoperative B-hCG follow-up should be continued, since it does not completely disappear.
► Theca lutein cysts are usually not treated.
Since trophoblastic cells secrete RhD, if the mother is Rh {-), anti-D Rh immunoglobulin should be administered.
Follow-up
► The same in those treated with curettage and hysterectomy:
► Absolute contraception should be provided during hCG follow-up after molar pregnancy treatment. COC or barrier method is used in patients who do not want surgical sterilization. IUD should not be used because of the risk of perforation. COCs do not increase the risk of postmolar trophoblastic disease.
► B-hCG level is monitored weekly until 3 times in a row and monthly for the following 6 months. In 70% of cases, B-hCG levels return to normal within an average of 9 weeks following uterine evacuation.
► Follow-up should be done with pelvic examination and chest X-ray.
► Risk of local uterine invasion after complete mole evacuation
While the risk of metastasis is 15%, it is 4%. This is particularly evident in high-risk groups.
High-risk criteria for invasion in malar pregnancies
Beta-HCG > 100,000 mIU/mL
overgrown uterus
Presence of bilateral theca lutein cysts larger than 6 cm
Age over 40
chemotherapy should be started in the presence of the following conditions during the follow-up period:
0 If B-hCG rises in 2 consecutive measurements or plateaus in 3 measurements
0 If B-hCG is high 15 weeks after uterine evacuation
0 If β-hCG rises again after falling to normal levels
0 If uterine size grows back to normal after
0 If bleeding occurs following uterine evacuation (suggests choriocarcinoma and invasive mole)
Partial Mole Hydatiform
• The genetic structure is of both maternal and paternal origin and is triploid. {most often 69 XXY). A diploid number of chromosomes comes from one parent, while haploid (n=23) chromosomes from the other parent: 69.XXY (58%), 69.XXX (40%), 69.XYY (2%),
Clinic
► Most of the cases present with a clinic similar to incomplete abortus or missed abortus. In these cases, the first finding is vaginal bleeding (73%). Larger-than-expected uterus (4%) and preeclampsia (3%) are rare findings. Theca lutein cyst, hyperemesis and hyperthyroidism are not observed.
► There is a fetus and it is usually lost in the first trimester and various anomalies can be seen in the fetus (syndactyly, hydrocephalus, growth retardation, etc.).
Diagnosis
► According to the gestational week, a significant increase in B-hCG level is observed. However, beta-hCG levels at the time of diagnosis are typically lower than the complete mole and usually do not exceed 100,000 mIU/ml.
► Ultrasound: Focal cystic areas in the placenta and an increase in the transverse diameter of the gestational sac are important in partial moles.
► Definitive diagnosis is made by histopathological examination of curettage material.
0 Focal trophoblastic hyperplasia/proliferation (with or without atypia)
0 Focal hydropic (hydatiform) swelling and cavitation in chorionic villi.
0 Hydropic villi are vascular.
0 Embryonic or fetal tissues are present (due to vascularization) .
0 Trophoblastic stromal inclusion and prominent villous aggregation.
0 Immunohistochemically p57 positive (as it is expressed by the maternal chromosome).
- Initially, a chest X-ray should be taken for lung metastases.
Treatment
► Same as complete mole.
Follow-up
► Absolute contraception is recommended after the procedure. Follow-up is just like a complete mole. The development of persistent non-metastatic tumors after partial mole is around 2-4%.
|
Comparison
of molar pregnancies |
||
|
|
complete mole |
Partial mole |
|
karyotype |
Diploid (46, XX) |
Triploid (69, XXY) |
|
clinical presentation |
||
|
Diagnosis |
molar pregnancy |
Missed abortion |
|
Larger-than-expected uterus |
28% |
4% |
|
vaginal bleeding |
84% |
73% |
|
hCG |
>100,000 mlU/ml |
<100,000 mlU/ml |
|
hCG persistence |
20% |
0.5% |
|
Medical complications |
||
|
preeclampsia |
27% |
3% |
|
hyperthyroidism |
7% |
no |
|
Theca lutein cyst |
50% |
no |
|
hyperemesis |
8% |
no |
|
trophoblastic embolism |
15% |
no |
|
Postmolar trophoblastic neoplasia |
diffuse hydropic |
4.6% |
|
Pathology |
||
|
Hydatiform swelling in chorionic villi |
diffuse hydropic |
focal hydropic |
|
Fetal or embryonic tissue |
no |
There is |
|
trophoblastic hyperplasia |
diffuse |
focal |
|
Trophoblastic stromal inclusion |
no |
There is |
|
Notching of chorionic villi |
no |
There is |
|
p57 immunostaining |
Negative |
Positive |
|
Genetic |
parental |
biparental |
Gestational Trophoblastic Neoplasms
• This group includes invasive moles, choriocarcinoma, placental site trophoblastic tumors, and epithelioid trophoblastic tumors.
• Gestational trophoblastic neoplasms typically develop following any form of pregnancy, but are most common following molar pregnancies.
• They can be nonmetastatic (locally invasive) or metastatic. While invasive mole and placental site trophoblastic tumors are usually nonmetastatic; Most of the metastatic diseases are seen due to choriocarcinoma.
Most metastatic gestational trophoblastic neoplasms develop following non-molar pregnancies.
Histopathological Types
invasive mole (chorioadenoma destruens)
• It is a disease in which hydropic chorionic villi penetrate the myometrium or vascular areas of the myometrium and sometimes the peritoneum, adjacent parametrium or vaginal wall.
• Almost all invasive hydatiform moles originate from a complete or partial mole.
• Bleeding is the most important finding. It may cause intraperitoneal bleeding by perforating the uterus and excessive vaginal bleeding as a result of invasion of uterine vessels. They are generally locally invasive and most of the invasive moles seen after a complete mole are nonmetastatic.
• Since the invasive mole is clinically hidden, the diagnosis is usually made from the hysterectomy specimen performed due to the complication of hemorrhage.
• Pathological diagnosis is made by demonstrating molar villi that invade the myometrium or have reached the extrauterine areas.
• Treatment indications are arranged according to hemorrhagic complications.
Trophoblastic Tumor from the Placental Region
• It is a cellular mass involving the endometrium and myometrium. The predominant cell type is intermediate trophoblasts. Although it can occur following any pregnancy, it is most commonly seen following term pregnancy.
• Abnormal vaginal bleeding is the most common symptom. Continuation of bleeding, especially following a term pregnancy, provides suspicion for a tumor developing from the placental region. Uterine enlargement often accompanies it. They tend to be limited to the uterus and metastasize in the future.
• Masses have low beta-hCG production compared to their size (usually between normal and 1000 mIU/L). High hPL levels are an important indicator.
• Tumors that are partially resistant to chemotherapy compared to others, and hysterectomy is the primary treatment for non-metastatic disease. However, systemic chemotherapy and uterine curettage can be recommended for those who want a child. Metastatic placental site trophoblastic tumors have a worse prognosis than postmolar gestational trophoblastic neoplasms, and aggressive combined chemotherapy should be given.
Epitheloid Trophoblastic Tumor
• These tumors originate from chorionic type intermediate trophoblasts. It can occur long after the previous pregnancy, and in some cases the previous pregnancy cannot even be confirmed.
• Microscopically, the placental site resembles trophoblastic tumors, but the cells are smaller and show less nuclear pleomorphism. Macroscopically, the placental site shows a nodular growth pattern rather than an infiltrative pattern of trophoblastic tumor.
• The primary treatment method is hysterectomy because they are resistant to chemotherapy. More than 1/3 of the cases present as metastatic disease and their prognosis is poor since they are resistant to multiple chemotherapy.
Gestational Choriocarcinoma
• Although most of the cases are seen after evacuation of molar pregnancy, it can also be seen after non-molar pregnancies. 2/3 of the cases seen after non-molar pregnancies are term pregnancies, and 1/3 of the cases are seen after spontaneous abortion or pregnancy termination. Elevated B-hCG values after non-molar pregnancy should be considered as choriocarcinoma until proven otherwise.
• The most common symptom is vaginal bleeding, but it can mimic many pathologies, so diagnosis delay is common. The main reason for mimicking other pathologies is metastases involving various organ systems. These foci are fragile and may cause spontaneous bleeding. Its natural course is rapid progression and death occurs within a few weeks to a few months. The cause of death is often bleeding.
|
Metastases
in gestational trophoblastic neoplasia |
|
|
1. Lungs |
80% |
|
2. Vagina (Fornix or suburethral) |
30% |
|
3. Pelvis |
20% |
|
4. Liver |
10% |
|
5. Brain |
10% |
|
6. Kidney, intestine, spleen |
5% |
|
7. Other |
<%5 |
|
8. Uncertain (persistence of BhCG after
hysterectomy) |
<%5 |
• It is a malignant tumor consisting of anaplastic cytotrophoblast, syncytiotrophoblasts and intermediate trophoblasts, characterized by hemorrhage and necrosis, with microscopically significant vascular invasion. However, chorionic villi are absent..
Staging
|
FIGO (2000)
clinical staging of gestational trophoblastic neoplasms |
|
|
stage 1 |
Patients with persistent hCG elevation with tumor
limited to the uterine corpus |
|
stage 2 |
Tumor outside the uterus but limited to the genital
organs (adnexa, vagina, lig. latum) |
|
stage 3 |
Lung metastases (with or without genital
involvement) |
|
stage 4 |
All other metastases such as brain, liver, kidney,
gastrointestinal tract |
Prognostic Risk Scoring
• World Health Organization (WHO) criteria: The World Health Organization (WHO) developed a personal risk scoring system for GTN to reliably demonstrate the potential for resistance to LT, and patients were classified as low and high risk.
• Single-agent chemotherapy is applied to the low-risk group, and combined chemotherapy (together with surgery and radiotherapy) is applied to the high-risk group.
Diagnosis
• The diagnosis of gestational trophoblastic neoplasia is made clinically by using Beta-hCG, which is an indicator of persistent trophoblastic tissue in most cases, rather than tissue diagnosis.
FIGO of Postmolar Gestational Trophoblastic Neoplasia (2000) diagnostic criteria
• A plateau (±10%) of 8-hCG level in four consecutive measurements for three weeks or longer (days 1, 7, 14, and 21)
• B-hCG in three consecutive measurements for two weeks or longer
An increase of 10% or more in the level (days 1, 7, and 14; >10% increase from day 1 to day 14)
• Elevated 8-hCG for 6 months or longer after mole evacuation
• Histological proof of choriocarcinoma
Presence of metastatic disease
Treatment
Treatment of non-metastatic (Stage 1) disease;
► If there is a desire to preserve fertility, single-agent KT is applied (methotrexate, actinomycin-D). In case of resistance to treatment, multi-agent (combined) chemotherapy is started.
► Hysterectomy can be performed and adjuvant single-agent CT is given in patients who do not have fertility problems and CT is ineffective.
► Hysterectomy is indicated in all cases of stage I placental site trophoblastic and epithelioid trophoblastic tumors that are relatively resistant to chemotherapy and the only curative treatment is hysterectomy.
Stage II and III disease treatment
► Single-agent chemotherapy in the low-risk group and combined chemotherapy in the high-risk group should be preferred as the initial regimen.
► Hysterectomy can be performed to control uterine bleeding or sepsis.
Stage IV disease treatment
► As the initial treatment, an appropriate combination of combined chemotherapy, selective radiotherapy and surgical treatment should be preferred.
► EMA-CO {Etoposide, methotrexate, actinomycind-D, cyclophosphamide, vincristine); In metastatic disease with high prognostic scores and low-risk disease resistant to single-agent chemotherapy, the EMA-CO regimen is the primary treatment of choice and is generally well tolerated.
Follow-up
Follow-up in stage I and low-risk stage 11-111 disease
► Beta-hCG level should be followed weekly until it is normal in 3 consecutive measurements, and monthly for the following 12 months. Contraception should be provided throughout the follow-up.
Follow-up in stage IV and high-risk stage 11-111 disease
► Beta-hCG level should be followed weekly until it is normal in 3 consecutive measurements, and monthly for the following 24 months. Contraception should be provided throughout the follow-up.
Prognosis
• Mol hydatiform is a completely cured disease. Cure is close to 100% in non-metastatic malignant GTD and reproductive functions continue in >90% of cases.
• There is no increased risk of any obstetric complications in subsequent pregnancies in cases with complete hydatid mole or gestational trophoblastic neoplasia treated with chemotherapy. Pregnancy outcomes are optimal for women who conceive 12 months after chemotherapy. After chemotherapy for persistent gestational trophoblastic disease, the risk of congenital anomaly did not increase, although she received chemotherapy.
The risk of hydatiform mole increases in subsequent pregnancies (1%).
In the patient who has remission after molar pregnancy, the next pregnancy most often ends with term live birth.