Gestational trophoblastic diseases (GTD) are a group of rare disorders associated with abnormal pregnancies. It includes benign partial and complete gravida, as well as malignant erosive and metastatic gravida, choriocarcinoma, placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT). Persistent elevation of human chorionic gonadotropin (HCG) may occur after evacuation of the gravida (15% to 20% in complete gravida and 0.1% to 5% in partial gravida), and may also progress to choriocarcinoma. Malignant GTD is also known as gestational trophoblastic neoplasm (GTN).
Staphyloma is more common in some parts of Asia, with an incidence of up to 2/1000 pregnancies. The incidence in Europe and North America is usually less than 1 in 1000 pregnancies. In recent years, the incidence of staphyloma appears to be decreasing in Asian countries, possibly associated with improvements in the economy and diet and declining birth rates. The incidence of choriocarcinoma is difficult to estimate because of its rarity and the clinical difficulty in distinguishing choriocarcinoma, which occurs in gravida, from erosive gravida because of the lack of histopathological evidence. The incidence of choriocarcinoma has been reported to be about 1/40,000 to 9/4,000 pregnancies, and the incidence has been decreasing.PSTT and ETT are rarer than choriocarcinoma.
I. Genetics and pathology
1. Staphyloma: Cytogenetics can help distinguish complete staphyloma from partial staphyloma and hydatid spontaneous abortion. Typically, complete staph is diploid with chromosome 46, XX, whose two X’s are of paternal origin; whereas partial staph is triploid with maternal and paternal origins. Hydatid spontaneous abortions usually have 46, XX or XY, from both parents. Immunohistochemical staining for the imprinted gene p57Kip2 can help show the presence of the maternal gene, while excluding complete staph. In rare cases, erosive and metastatic staph can be diagnosed by removal of the uterus or metastases.
2. Choriocarcinoma: Choriocarcinoma is a malignant tumor without the presence of villi, with abnormal syncytial trophoblasts and cytotrophoblasts, necrosis and hemorrhage. It may invade the uterus and surrounding organs, and often has distant metastasis, especially to the lung, but also to the liver, spleen, kidney, intestine and brain.
3. Placental site trophoblastic tumor: PSTT originates from maternal mononuclear intermediate trophoblast cells that invade the myometrium in the placental bed. The tumor cells have irregular nuclear membranes, deeply stained nuclei, strongly eosinophilic or double-stained cytoplasm, and no villi structure. The tumor cells reacted strongly and extensively to human placental prolactin (HPL) and only focally to HCG. It can be distinguished from benign by amplifying the placental site reaction with low Ki67 index.
4. Epithelioid trophoblastic tumor: ETT is a chorionic villous type of injury of intermediate trophoblast type. It usually shows as a free-standing, hemorrhagic, solid and cystic lesion. The lesion may be found in the fundus, the lower uterine segment, the cervix or even the broad ligament. Histologically, islands of intermediate type trophoblast cells are surrounded by extensive necrosis and combined with a vitreous stroma. The tumor is focally immunoreactive to HPL, HCG, cytokeratin and inhibin-α. It can be distinguished from PSTT by positive p63 immunostaining. ett can coexist with either choriocarcinoma or PSTT. Emerging data suggest that atypical placental site nodules (APSN) can coexist and/or precede EPT and PSTT, suggesting that at least APSN cannot be considered benign.
II. Clinical manifestations, examination and diagnosis
1. Staphyloma: The most common manifestation of staphyloma is abnormal vaginal bleeding during pregnancy. With the popularity of ultrasound, staph is usually diagnosed during early pregnancy. Therefore, the classic clinical manifestations of severe pregnancy vomiting, eclampsia, hyperthyroidism, preeclampsia, pulmonary artery trophoblastic embolism and uterine size larger than the gestational week are now uncommon. In the early stages, ultrasound may not show the typical falling snow sign of a complete gravida. Partial absence of the fetus, a cystic-appearing placenta and a deformed gestational sac may suggest early staph. Some gravid pregnancies are diagnosed only by histological examination of the cleared uterus after spontaneous abortion.
2, gestational trophoblastic neoplasm: GTN occurring after gravida is usually diagnosed by HCG monitoring and patients are usually asymptomatic. 2000 FIGO Gynecologic Oncology Committee meeting agreed on the definition of GTN occurring after gravida based on changes in HCG levels as well as histology and specific examinations.
3. HCG monitoring: When monitoring GTN, total HCG assay can detect all forms of HCG, such as β-HCG, core HCG, carboxy-terminal HCG, lack of engraved-free β, β core, and preferably high glycosylation should be applied. Patients with persistently low HCG levels should be followed up to exclude false positives due to heterophilic antibodies, as some cases may develop GTN along with increasing HCG levels.
4. Gestational trophoblastic neoplasm of non-staphylocytic origin: Only about 50% of GTNs are secondary to staphylocytosis, but GTN can also be secondary to spontaneous abortion, ectopic pregnancy or full-term pregnancy. Bleeding from metastatic sites such as the abdomen, lungs or brain may occur; neurological symptoms of pulmonary and spinal or brain metastases are present. Serum HCG monitoring is very important.
III. Treatment
1. Treatment of gravida: Clearance of gravida should be performed by an experienced gynecologist, especially if the uterine volume is greater than 16 weeks of gestation, ideally under ultrasound guidance. The risk of haemorrhage can be reduced by the use of contractions after dilation and clearance. If there is no persistent bleeding, a second evacuation is usually not necessary. There is no indication for hysterectomy unless comorbidities are present.
HCG monitoring after clearance of a gravid fetus is very important. Recent data show that GTN rarely occurs in patients with a natural return to normal HCG, so contraception is now recommended for only 6 months rather than 1 year. During the monitoring period after HCG returns to normal, termination of pregnancy is not required in case of an unplanned pregnancy. Data now also suggest that oral contraceptives are safe. The risk of recurrence after a single gravida is low (0.6% to 2%), but the chance of recurrence after consecutive gravida pregnancies is much higher. Mutations in the NLRP7 and KHDC3L genes are present in women with recurrent staph.
2. Normal pregnancy combined with gravidity: Gravidity rarely coexists with normal pregnancy and is usually diagnosed by ultrasound. Although the risk of spontaneous abortion is high, approximately 40% of patients still end up with a live birth and do not have an increased risk of GTN. If there are no complications and genetically normal, the pregnancy may be allowed to continue under close ultrasound monitoring.
3. Gestational trophoblastic neoplasm: The main treatment for GTN is chemotherapy, and the chemotherapy regimen depends on staging and grading. Table 3 shows the 2000 FIGO clinical staging and grading; Table 4 shows the FIGO (WHO) prognostic scoring system, with a score of 6 or less being considered low-risk and a score of 6 or more being considered high-risk.
4, Low-risk gestational trophoblastic neoplasms: Table 5 lists chemotherapy regimens for patients with low-risk GTN treated with methotrexate or actinomycin-D (Act-D) monotherapy regimens. 2012 Cochrane systematic review, in a study of 5 randomized controlled trials including 513 patients, showed that actinomycin D appeared to be superior to methotrexate (MTX) (RR 0.64, 95% CI 0.54 to 0.76). Methotrexate failed more often than actinomycin-D treatment (RR 3.81, 95% CI 1.64 to 8.86). If response to the first monotherapy is good and the HCG plateau remains above normal during treatment, or if toxicity prevents adequate dosing or treatment frequency, change to another monotherapy may be indicated. If there is a poor response to single agent chemotherapy, a significant increase in HCG levels, progression of metastases, or resistance to replacement single agent chemotherapy, a combination of multiagent chemotherapy should be used. Studies in the UK have shown that when HCG levels are less than 100 U/ L or 300 U/ L, switching to Act-D monotherapy will result in a good response; otherwise, multi-drug combination chemotherapy is required. 2 to 3 cycles of consolidation chemotherapy after HCG levels return to normal will reduce the chance of recurrence. The complete remission rate is close to 100%.
5. high-risk gestational trophoblastic neoplasms: multi-drug combination chemotherapy regimens are used to treat high-risk GTN. the most commonly used is EMA-CO (etoposide, methotrexate, actinomycin-D, cyclophosphamide, vincristine) (see Table 6), with a complete remission rate of about 85% and a 5-year overall survival rate of 75% to 90%. Patients with combined liver and/or brain metastases have poorer outcomes.
6. Very high-risk gestational trophoblastic tumors and salvage therapy: High-risk subgroups with scores ≥12, such as patients with combined liver, brain, or extensive metastases, respond poorly to first-line multidrug combination chemotherapy. Standard chemotherapy given to patients with combined severe disease may cause severe myelosuppression leading to bleeding, sepsis, and even multiorgan failure. This can be avoided by using a lower dose and reduced frequency regimen, such as etoposide 100 mg/m2 and cisplatin 20 mg/m2 on days 1 and 2, repeated weekly, for 1 to 3 weeks of treatment before starting the conventional chemotherapy regimen.
Patients with combined liver or brain metastases or very high scores may have better responses and outcomes with EPEMA or other more intensive chemotherapy regimens (Table 7). These may also be used in patients with relapsed or advanced disease. High-risk patients should consolidate for 4 cycles of chemotherapy. When using the EMA-CO regimen for patients with brain metastases, increasing the methotrexate dose to 1 g/m2 will help the drug cross the blood-brain barrier, and methotrexate 12.5 mg can be given intrathecally along with CO. Some centers give whole-brain radiotherapy (200 cGy per day for a total of 3000 cGy) along with chemotherapy, or use stereotactic radiation therapy.
7. Role of surgery: Surgery also has an important role in the treatment of GTN. Uterine artery embolization is often used when uterine bleeding cannot be controlled, and hysterectomy can also be considered. There is bleeding from the liver, gastrointestinal tract, kidneys and spleen and other organs may require open abdominal hemostasis. The presence of intracerebral hemorrhage or increased intracranial pressure also requires surgery. In the presence of isolated drug-resistant tumor lesions, removal of isolated cranial or pulmonary nodules or uterus can improve survival rates.
8. Role of radiotherapy: Except for the treatment of brain metastases, radiotherapy has a limited role in the treatment of GTN, and it is controversial whether it is more effective than intrathecal methotrexate injection.
9.Treatment of PSTT and ETT: PSTT and ETT are less sensitive to chemotherapy than choriocarcinoma. Hysterectomy is the main treatment modality. If fertility preservation is desired, conservative treatment such as hysterectomy, hysteroscopic excision of the lesion and chemotherapy can be considered for those with limited lesions. EP-EMA is the most commonly used chemotherapy regimen. Recurrence more than 48 months from previous pregnancy is the most significant poor prognostic factor.
IV. Follow up
After GTN treatment, HCG should be monitored regularly for at least 12 months and contraception should be reliable. Although some patients may require psychological and psychosexual counseling, GTN cure has no impact on future fertility, pregnancy, or offspring.
V. Summary
Although the level of diagnosis and treatment of gestational trophoblastic disease in China has improved greatly, two major clinical problems still exist: overdiagnosis and non-standardized treatment. When encountering an abnormal pregnancy with unsatisfactory HCG drop after treatment, the first thing that comes to mind is the rare gestational trophoblastic disease, instead of first considering common diseases such as incomplete abortion, incomplete aspiration, placental residue, ectopic pregnancy, etc., and taking chemotherapy before the diagnosis is clear. The treatment after diagnosis is not standardized, including indications for prophylactic chemotherapy, selection of chemotherapy drug regimen, discontinuation indications, management of drug-resistant patients, indications and timing of surgery, etc. All these problems need to be taken seriously and the clinical treatment level should be improved as soon as possible.