Epitheloid trophoblastic tumor (ETT) is the rarest type of trophoblastic tumor, originating from the chorionic-type intermediate trophoblast. ETT is clinically rare, and its biological behavior and pathogenesis remain unclear.
Pathogenesis
Molecular genetic studies of ETT suggest that the tumor tissues contain new alleles and Y-chromosome gene loci that may derive from the paternal genome, which are not detected in the surrounding normal tissues. This suggests that ETT originates from pregnancy rather than from the patient’s own tissues.
Pathology
Macroscopically, ETT presents as solid or mixed solid-cystic masses, typically with well-defined nodular boundaries. Localized invasion of surrounding tissues may be observed, often accompanied by hemorrhage and necrosis. Microscopically, the tumor consists of neoplastic chorionic-type intermediate trophoblastic cells, growing in a nodular pattern with widespread or “geographic” necrosis. Tumor cells are mononuclear, with eosinophilic or clear cytoplasm, and exhibit variable mitotic activity. Eosinophilic hyaline-like material is often seen between tumor cells or in the center of tumor nests, which is considered characteristic of ETT.
Clinical Features
ETT primarily occurs in women of reproductive age, commonly involving the uterine cervix or lower uterine segment. Some patients may only present with extrauterine metastatic lesions, most frequently in regions such as the vagina, fallopian tubes, broad ligaments, lungs, and liver.
ETT may follow various pregnancies, with term pregnancies being the most common precursor. Abnormal vaginal bleeding is the most common clinical presentation, while asymptomatic cases are rare.
Auxiliary Investigations
Imaging Studies
Ultrasound typically reveals a solitary, highly heterogenous echogenic nodule within the myometrium of the uterus and/or cervical canal, sometimes protruding into the uterine cavity. Unlike PSTT, ETT masses have well-defined boundaries and do not exhibit infiltrative growth. Doppler imaging shows low blood flow signal values. On MRI, ETT appears as a solid mass with strong T2-weighted signals. Depending on lesion size, hemorrhage, necrosis, or calcification may be present. The tumor diameter ranges from 0.5 to 14.8 cm, with various shapes such as solid nodules within the myometrium, lobulated masses protruding into the uterine cavity, or irregular lesions at cesarean scar sites. Pelvic CT can detect masses, but ETT lacks specific features on CT imaging. PET/CT has limited significance in diagnosing and staging ETT but may be valuable for high-risk patients.
Quantitative Measurement of Human Chorionic Gonadotropin (hCG)
Serum hCG levels are elevated in nearly all patients with ETT; however, levels are generally below 2,500 IU/L. Higher serum hCG levels are typically associated with larger tumor volumes and greater mitotic activity of the tumor.
Diagnosis
Due to the extremely low incidence and the lack of specific clinical manifestations, preoperative diagnosis of ETT is challenging. It is often an incidental postoperative pathological finding and requires differentiation from other gestational trophoblastic neoplasms (GTNs), such as choriocarcinoma and PSTT. Definitive diagnosis relies on histopathological examination.
Clinical Staging and High-Risk Factors
The FIGO anatomical staging system is applicable; however, the prognostic scoring system is not. High-risk factors for ETT include the following:
- Disease onset more than two years after the last pregnancy.
- Depth of invasion.
- Proportion of necrotic tissue in the tumor.
- Mitotic activity >5/10 high power fields (HPF).
Treatment
Currently, there is no standardized treatment protocol for ETT. Surgical intervention is generally considered the main treatment for localized disease. Upon diagnosis, timely hysterectomy is recommended. Lymph node dissection is performed if metastases cannot be ruled out. Young patients may retain bilateral ovaries. Due to the invasive nature of ETT and its insensitivity to chemotherapy, fertility-preserving surgery is not routinely recommended. For solitary extrauterine lesions, surgical removal is also an option.
The role of chemotherapy in ETT treatment remains uncertain. Studies have shown that ETT is not sensitive to conventional GTN chemotherapy regimens. Existing chemotherapy protocols for ETT are similar to those for PSTT. For recurrent or metastatic ETT, a combination of chemotherapy and immune checkpoint inhibitors may serve as an effective salvage therapy.
Prognosis
Overall, most researchers believe that in the absence of metastases, ETT is less aggressive than choriocarcinoma and has a prognosis similar to that of PSTT, with favorable outcomes. However, once uterine metastases occur, prognosis becomes poor.
Follow-Up
Follow-up after treatment is essential and is similar to that for other gestational trophoblastic tumors. Follow-up includes monitoring serum hCG levels, evaluating menstrual regularity, and assessing for symptoms such as abnormal vaginal bleeding, cough, hemoptysis, or other signs of metastases. A gynecological examination is performed, with imaging studies such as ultrasonography or CT as needed.