The first description of gestational trophoblastic disease (GTD) was by Hippocrates around 400 BC. Marchand discovered the association of this disease with pregnancy in 1895. Healthy trophoblastic tissue penetrates the endometrium, which creates a rich uterine vasculature, leading to a close connection between the fetus and the mother, which is called the placenta. Invasion is characteristic of malignant tissue, and fortunately, the malignant behavior of the healthy trophoblast is well controlled. Nevertheless, in gestational trophoblastic disease, the regulatory mechanisms become dysfunctional, resulting in highly invasive, vascular, and metastatic tumors.
GTD involves both benign and malignant entities that include hydatidiform mole (complete and partial), choriocarcinoma, invasive mole, epithelioid trophoblastic tumor (ETT), and placental site trophoblastic tumor (PSTT). The last four are known as gestational trophoblastic neoplasia (GTN); all can metastasize and can be fatal if not treated.
Trophoblast cells are the first cells to differentiate from the fertilized ovum: they supply the embryo with nutrients and eventually forming the fetal share of the placenta. The placental trophoblasts are made of cytotrophoblasts, syncytiotrophoblasts, and intermediate trophoblasts. The placental trophoblasts are the origin of molar pregnancies and gestational trophoblastic neoplasias. While the cytotrophoblasts and syncytiotrophoblasts make the hydatidiform moles and choriocarcinoma and PSTTs along with ETTs arise from intermediate trophoblasts.
In the majority of cases, a complete hydatidiform mole usually occurs when an ovum without maternal chromosomes is fertilized by one sperm that later on duplicates its DNA, which results in a 46XX androgenetic karyotype, all chromosomes are paternally derived. Approximately 10% of complete moles are 46XY, resulting from fertilization by two sperms. Even though the nuclear DNA is entirely paternal, mitochondrial DNA remains maternally derived. Some studies found that patients with the recurrent disease may have biparental molar rather than a typical androgenetic disease, which could be familial or sporadic. The mechanism by which mutations imprint abnormalities and cause gestational trophoblastic disease remains unknown.
In regards to partial hydatidiform moles, they are mainly triploid emerging from fertilization of a healthy ovum by two sperms. Diploid partial moles do not exist, which means most of the reported cases are misdiagnosed complete moles.
The risk of gestational trophoblastic neoplasia could also be related to hormonal factors, as women who had menarche after the age of 12, who have a light menstrual flow, and previously using oral contraceptives are at higher risk.
Gestational trophoblastic neoplasia is found more frequently in Asia compared to North America or Europe, which could be explained by differences in prevalence or inconsistencies between population-based and hospital-based data. Similarly, the reported prevalence of choriocarcinoma differs significantly worldwide, from 2 per 100 000 pregnancies in the United States to 202 per 100000 pregnancies in China.
The ova of older women are more prone to abnormal fertilization than an ovum of younger women. Following a molar pregnancy, the risk of an additional complete and partial mole rises to 1 to 2%. Following two molar gestations, the risk of having a third mole is 15 to 20%, and the risk is not lowered by a change of partner. Some repeat molar pregnancies are caused by familial or sporadic biparental molar disease. The prevalence of choriocarcinoma or placental-site trophoblastic tumor is less well known, as these diseases can emerge following any pregnancy.
All types of gestational trophoblastic neoplasia originate from the placenta. Hydatidiform moles and choriocarcinoma emerge from villous trophoblast, while placental-site trophoblastic tumors arise from the interstitial trophoblast. First-trimester complete moles show aberrant budding villous structure with trophoblast hyperplasia, crumpled villous blood vessels, and stromal karyorrhectic debris. On the other hand, early partial moles show patchy villous hydrops, dispersed abnormally-shaped erratic villi, patchy trophoblast hyperplasia, and trophoblastic pseudo inclusions.
Morphological differentiation of non-molar miscarriage from a partial hydatidiform mole can be complicated, as villous dysmorphism can present without the characteristic trophoblast hyperplasia that is seen in the partial mole. Furthermore, ploidy analysis shown by in-situ hybridization or flow cytometry can differentiate diploid from triploid conceptions but can not make a distinction between a complete mole and diploid non-molar miscarriage, or molar and non-molar triploidy, which indicate the need of molecular investigations.
Choriocarcinomas are malignant HCG-releasing epithelial tumors that have central necrosis and a characteristic biphasic structure. Intraplacental choriocarcinoma can also happen and is probably the one responsible for metastatic disease occurring after term pregnancies. The majority of neonatal choriocarcinoma arises from metastatic spread from intraplacental choriocarcinoma.
Placental-site trophoblastic tumors are malignant tumors, and they form uterine lesions with less hemorrhage and necrosis and lower HCG concentrations than choriocarcinoma.
Molar pregnancy could infrequently coexist with a normal pregnancy. The diagnosis is usually made through an ultrasound. Despite the high risk of spontaneous abortion, 40 to 60% of the cases result in live births. The risk of gestational trophoblastic neoplasm in coexisting molar and normal pregnancy compared to a singleton molar pregnancy increases from 15 to 20% to 27 to 46%, respectively. Pregnancy can proceed if there are no complications, and there are normal genetic and ultrasound findings.
Complete Hydatidiform Mole
46, XX (majority); 46, XY, no fetus/embryo, expanded swelling of the villi, and expanded trophoblastic hyperplasia.
Partial Hydatidiform Mole
Triploid 69, XXY; 69,XYY; 69,XXX, abnormal fetus/embryo, central swelling of the villi, central trophoblastic hyperplasia.
Diffusely penetrative growth involving endomyometrium. The tumor cells recap chorionic villous trophoblasts of different types and are arranged in biphasic to triphasic growth arrangements: sheets or cords of mononuclear tumor cells surrounded by layers of multinuclear syncytiotrophoblasts. Lymphovascular tumor thrombi are usually present.
Placental Site Trophoblastic Tumor (PSTT)
Tumor cells invade myometrium with vascular\lymphatic invasion. Focal hemorrhage and necrosis are seen in nearly half of the cases, while the transmural myometrial invasion is in 10% of the cases. Perforation could also occur.
Epithelioid Trophoblastic Tumor (ETT)
The tumor usually creates discrete nodules or cystic hemorrhagic masses, that's deeply invading the surrounding tissues. Hemorrhage, necrosis, ulceration, and fistula can be seen as well. Characteristically, ETT expresses nodular, expandable growth of approximately uniform, medium-sized tumor cells organized in nests, cords, or large sheets.
Due to the routine use of ultrasonography (US) and β-hCG levels testing, patients with complete hydatidiform mole are commonly diagnosed early in gestation. They are usually asymptomatic at the time of diagnosis. Common clinical presentations include vaginal bleeding, which usually takes place at 6 to 16 gestational weeks (46%), large for date uterine size (24%), and hyperemesis (14%).
Patients with partial hydatidiform mole are usually not diagnosed before the uterine evacuation, and histological examination of curettage specimens after incomplete or missed abortion is required for the diagnosis. As with complete hydatidiform mole, the majority of patients with partial hydatidiform mole (75%) complain of vaginal bleeding; they generally present later than those with complete hydatidiform mole. Complete hydatidiform moles are typically associated with a considerably elevated β-hCG level. Nearly half of the patients with complete hydatidiform moles have pre-evacuation β-hCG levels higher than 100000 mIU/mL. Nonetheless, such elevated β-hCG levels happen in less than 10% of patients with partial hydatidiform mole.
Ultrasound is the primary tool used for gestational trophoblastic neoplasm. Complete mole characteristically shows a uterus filled with a heterogeneous mass (it is called snowstorm), with the absence of fetal development and the presence of theca lutein ovarian cysts. Unfortunately, these findings are not visible in the first trimester.
As false negative and false positive rates are high with the use of ultrasonography, specifically in the case of partial hydatidiform mole, histological examination is necessary to reach the final diagnosis. As histological examination may not be practicable to be done after every termination, testing the level of hCG 3–4 weeks after management to make sure it returned to the normal range is highly recommended.
Post-molar GTN often expresses no symptoms or distinctive findings on ultrasonography. Hence, correlating with the hCG level is necessary to reach the diagnosis. MRI is usually not important in the routine evaluation of GTN, except in cases with atypical presentations, recurrence, or ETT\PSTT conditions.
Different treatment modalities are available for gestational trophoblastic neoplasm depending on the type and stage; these include D&C (dilation and curettage), chemotherapy, hysterectomy, or combination of these.
D & C
More commonly used in molar pregnancy where fertility is desired, nonetheless, post-D&C monitoring is essential to ensure no disease recurrence.
Some types of GTD can be well treated by chemotherapy, either single or combined. Some of the used chemotherapeutic agents include methotrexate, etoposide, actinomycin D, cyclophosphamide, cisplatin, and vincristine.
In cases of chemoresistance, severe disease, and desire to retain fertility, hysterectomy is the most common treatment option used.
Some controversial treatments have been presented in the last years, and these include:
The use of prophylactic chemotherapy instead of monitoring hCG levels until disease clearance criteria are met will decrease the use of intense chemotherapy regimens and boost the chance of complete healing.
Second D & C
The concept of this modality is to perform a second D&C after the molar pregnancy evacuation if the hCG level remains non-reassuring. However, if there is a high risk of uterine perforation or hemorrhage, a second D&C must not be performed.
Approximately 0.5-5% of women experience drug resistance GTD and, unfortunately, may die as a result. Pembrolizumab was one of the studied drugs to be used in this condition, and studies showed that it represents a valuable new approach for treating drug-resistant GTN.
Other more complex regimens have been proposed, yet they were found to be associated with more side effects, more designed RCT needs to be conducted to assess their efficacy.
The differential diagnosis will largely depend on whether the metastasis has occurred or not and if it has occurred then to which organs. Differential diagnosis of gestational trophoblastic neoplasm include:
There are three known systems to stage gestational trophoblastic diseases, these are:
The current clinical classification system that is mostly used in the United States is seen in (Table 1), which originated from the analyses of patients with metastatic gestational trophoblastic neoplasia who were treated at the NIH. The system separates the patients to those with nonmetastatic disease and those with metastatic disease, as all nonmetastatic disease patients can be cured with initial single-agent chemotherapy. On the other hand, metastatic disease patients are further subdivided according to the presence or absence of factors associated with response to initial single-agent chemotherapy. Patients with no high-risk clinical factors are likely to benefit from initial single-agent therapy and are labeled as good-prognosis metastatic GTD. Meanwhile, patients with a single high-risk clinical factor are labeled as poor-prognosis GTD. These patients are at increased risk of experiencing failure to single-agent chemotherapy and also death if treated with single-agent therapy followed by multiagent regimens.
WHO prognostic index offers precise information regarding the prognosis of the disease, yet, the clinical classification system is successful at identifying patients for whom initial single-agent chemotherapy is likely to fail, as well as, it is easy and less complicated than WHO's.
Most of the patients (about 95%) diagnosed with a hydatidiform mole who develop neoplasia have a low risk of resistance. For most of these patients, mono-chemotherapy with methotrexate or dactinomycin is the treatment of choice.
If the first-line therapy fails—usually because of resistance— it can be easily replaced with second-line or occasionally third-line chemotherapy, making the overall survival rate almost 100%.
The majority of high-risk patients with gestational trophoblastic neoplasia present with many metastases months or years following the causative pregnancy of any type. Signs and symptoms differ according to the disease's location. For example, patients with brain metastases can present with headaches, seizures, or hemiparesis. On the other hand, patients with lung metastasis can present with shortness of breath, hemoptysis, or pleuritic chest pain. Since menstrual irregularity is not universal, unfortunately, the diagnosis can be missed. The included imaging studies should be body CT, brain, and pelvic MRI along with Doppler ultrasonography. If the brain scan was normal, a lumbar puncture should be done to assess the ratio of cerebrospinal fluid to serum hCG.
Commonly reported late complications of a molar pregnancy include anemia, preeclampsia, hyperthyroidism, respiratory distress, vaginal hemorrhage, and hyperemesis, all of which are now considered rare. Pulmonary complications are less common, yet they are more life-threatening. They include pulmonary edema, pulmonary embolism, pleural effusion, and trophoblastic embolization.
All patients who have hydatidiform mole should be up for hCG surveillance and monitoring. Surveillance protocols differ from one country to another, but principles are the same. In the United Kingdom (UK), serum and urine hCG levels are measured every two weeks until the values come to normal range, then urine hCG levels are measured monthly. Patients who achieve normal hCG values within 56 days of uterine evacuation have a low risk of developing a malignant disease and are further monitored for six months from the evacuation date. If the first hCG reading was normal after 56 days, monitoring every month should continue for the next six months.
During the hCG follow-up period, patients are advised to use reliable contraception, including a combination of methods. After finishing hCG monitoring, serum or urine hCG concentrations should be measured six weeks and ten weeks after every pregnancy to ensure there is no reactivation of a previous molar disease.
Follow up following evacuation of a hydatidiform mole is vital to detect trophoblastic sequelae (invasive mole or choriocarcinoma), which occurs in nearly 15 to 20% with complete mole and 1 to 5% with partial mole.
As second D&C was one of the controversial management modalities for gestational trophoblastic neoplasia. A prospective, multicenter study was conducted in Canada, 2016 to evaluate the efficacy and safety of this procedure in 64 patients with low-risk, nonmetastatic GTN, using world health organization (WHO) risk score. The study concluded that second D&C cured 40% of the patients without complications when used as an initial treatment for low-risk, nonmetastatic GTN.
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