Gestational trophoblastic neoplasia (GTN) is group of rare diseases related to pregnancy and included in gestational trophoblastic disease (GTD) in which abnormal trophoblast cells grow in the uterus. GTN can be classified into benign and malignant lesions. Benign lesions include placental site nodule and hydatidiform moles while malignant lesions have four subtypes including invasive mole, gestational choriocarcinoma, placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT). The choriocarcinoma has 2 significant subtypes including gestational and non-gestational and they are differentiated by their different biological feature and prognosis. Signs and symptoms of GTN will appear vary from person to person and depending upon the type of the disease. They may include uterine bleeding not related to menstruation, pain or pressure in pelvis, large uterus and high blood pressure during pregnancy. The cause of this disease is unknown but the identification of the tumor based on total beta-human chorionic gonadotropin (β-hCG) in the serum. Management of GTN requires pathology review, treatment options and monitoring of hCG. Therefore, it can be treated with curettage, hysterectomy and single agent or multi agent chemotherapy. Although this group of diseases are highly susceptible to chemotherapy, prognosis depends on the type of GTN and whether the tumor has spread to other areas of the body.

Cause and Risk factors

The exact cause of gestational trophoblastic neoplasia (GTN) is unknown. GTN often arises after molar pregnancies but can also occur after any gestation including miscarriages and term pregnancies. Although risk factors may impact on the development of the tumor, most do not directly cause of disease. According to some studies, the risk of complete molar pregnancy is highest in women over age 35 and younger than 20. The risk is even higher for women over age 45.

Signs and Symptoms

The symptoms of GTN will vary from person to person. People with the same disease may not have all the symptoms listed.

Diagnosis

Initial screening tests for GTN include:

Tumor staging

FIGO (International Federation of Gynecology and Obstetrics) 2000 Anatomical staging is commonly used to evaluate stage of GTN. Stage I - Disease confined to the uterus Stage II - GTN extends outside of the uterus, but is limited to the genital structures (adnexa, vagina, broad ligament) Stage III - GTN extends to the lungs, with or without known genital tract involvement Stage IV - All other metastatic sites

Pathophysiology

All types of gestational trophoblastic neoplasia originate from the placenta. A placenta develops in the uterus during pregnancy and becomes first site of nutrient and gas exchange between mother and fetus. It has two components such as fetal component and mother component. A fetal component is composed of cytotrophoblast and syncytiotrophoblast. The exact pathogenesis of choriocarcinoma has not been fully understood, but studies have shown cytotrophoblast cells function as stem cells and transform into malignant form. The neoplastic cytotrophoblast further differentiates into either intermediate trophoblasts or syncytiotrophoblast.

Treatment

Several treatment methods are available for GTN that include surgery, chemotherapy or combination of these. Surgery treatment is most common initial method for some types of the disease but it depends on the stage of the tumor. Common surgical options include dilation and curettage, and hysterectomy.

Prognosis

FIGO modified Prognostic Scoring System. The system evaluates the patients to those with GTN as low-risk and high-risk based on several risk factors such as age, pregnancy or interval of pregnancies, size or metastases of tumor and prior chemotherapy. Each risk factors are rated at levels 0-4 scores. The numbers are then added up, and the overall score determines a woman's risk level. Therefore, some studies have shown that the condition is harder to cure if the cancer has spread to the liver or brain or β-hCG level is higher than 40,000 mIU/mL when treatment begins, cancer returns after having chemotherapy or symptoms/ pregnancy occurred for more than 4 months before treatment.

Epidemiology

According to studies, GTN is found more frequently in Asia compared to North America or Europe. As of 2020, the reported incidence of choriocarcinoma ranges from 1 in 40 000 pregnancies in North America and Europe, to 9.2 and 3.3 per 40 000 pregnancies in Southeast Asia and Japan, respectively. Epidemiological studies have reported that hydatidiform mole appears to be caused by abnormal gametogenesis and fertilization more frequent at the extremes of reproductive age of younger than 15 and older than 45 years of age and pregnancies at these ages are a risk factor for hydatidiform mole. The risk increases after age 35 and there is a 5–10 times increased risk after 45 years.

Research

Recently, in order to provide more comprehension tools of GTN pathogenesis, epigenetic modifications and molecular biology techniques could be applied for proper diagnosis, management, and treatment of such neoplasia. The progression of anti-angiogenesis therapy and molecular targeted cancer therapies would be capable of improving the therapeutic perspective among patients with drug resistance. Although chemotherapy and hysterectomy are currently used in a clinical setting, the use of diverse treatments including anti-body and gene therapy also being attempted to cure GTN. In addition, gene delivery tools using genetically engineered neural stem cells are presently being examined for the treatment of GTN and previous studies have indicated a significant inhibitory effect on tumor growth.