Modern approaches to the diagnosis of malignant trophoblastic tumors

Malignant trophoblastic tumors (TO) include invasive and metastatic cystic drift, choriocarcinoma, TO of the placental bed, and epithelioid TO. They are rare, mainly in women of reproductive age, and most importantly, they are always associated with pregnancy. To date, the Blokhin National Medical Research Center of Oncology has accumulated a large and unique experience of modern diagnostics and treatment of patients with various forms of malignant TO. An obligatory stage of the examination is ultrasound diagnostics of the pelvic organs. In addition, performing an ultrasound examination during the treatment period, along with monitoring the level of chorionic gonadotropin, makes it possible to assess the effectiveness of treatment, diagnose tumor resistance and ascertain the onset of remission.

Nucleoside transporter-guided cytarabine-conjugated liposomes for intracellular methotrexate delivery and cooperative choriocarcinoma therapy

Gestational trophoblastic tumors seriously endanger child productive needs and the health of women in childbearing age. Nanodrug-based therapy mediated by transporters provides a novel strategy for the treatment of trophoblastic tumors. Focusing on the overexpression of human equilibrative nucleoside transporter 1 (ENT1) on the membrane of choriocarcinoma cells (JEG-3), cytarabine (Cy, a substrate of ENT1)-grafted liposomes (Cy-Lipo) were introduced for the targeted delivery of methotrexate (Cy-Lipo@MTX) for choriocarcinoma therapy in this study. ENT1 has a high affinity for Cy-Lipo and can mediate the endocytosis of the designed nanovehicles into JEG-3 cells. The ENT1 protein maintains its transportation function through circulation and regeneration during endocytosis. Therefore, Cy-Lipo-based formulations showed high tumor accumulation and retention in biodistribution studies. More importantly, the designed DSPE-PEG2k-Cy conjugation exhibited a synergistic therapeutic effect on choriocarcinoma. Finally, Cy-Lipo@MTX exerted an extremely powerful anti-choriocarcinoma effect with fewer side effects. This study suggests that the overexpressed ENT1 on choriocarcinoma cells holds great potential as a high-efficiency target for the rational design of active targeting nanotherapeutics. Graphic abstract

LPCAT1-TERT fusions are uniquely recurrent in epithelioid trophoblastic tumors and positively regulate cell growth

Gestational trophoblastic disease (GTD) is a heterogeneous group of lesions arising from placental tissue. Epithelioid trophoblastic tumor (ETT), derived from chorionic-type trophoblast, is the rarest form of GTD with only approximately 130 cases described in the literature. Due to its morphologic mimicry of epithelioid smooth muscle tumors and carcinoma, ETT can be misdiagnosed. To date, molecular characterization of ETTs is lacking. Furthermore, ETT is difficult to treat when disease spreads beyond the uterus. Here using RNA-Seq analysis in a cohort of ETTs and other gestational trophoblastic lesions we describe the discovery of LPCAT1-TERT fusion transcripts that occur in ETTs and coincide with underlying genomic deletions. Through cell-growth assays we demonstrate that LPCAT1-TERT fusion proteins can positively modulate cell proliferation and therefore may represent future treatment targets. Furthermore, we demonstrate that TERT upregulation appears to be a characteristic of ETTs, even in the absence of LPCAT1-TERT fusions, and that it appears linked to copy number gains of chromosome 5. No evidence of TERT upregulation was identified in other trophoblastic lesions tested, including placental site trophoblastic tumors and placental site nodules, which are thought to be the benign chorionic-type trophoblast counterpart to ETT. These findings indicate that LPCAT1-TERT fusions and copy-number driven TERT activation may represent novel markers for ETT, with the potential to improve the diagnosis, treatment, and outcome for women with this rare form of GTD.

A Million Reasons for Hyperthyroidism. Reporting a Case of Thyrotoxicosis in a Setting of Metastatic Choriocarcinoma

Background: Human chorionic gonadotropin (hCG) induced transient hyperthyroidism is often seen during pregnancy. Other rare causes of beta hCG induced hyperthyroidism include trophoblastic tumors (hydatidiform mole and choriocarcinoma) and in men, germ cell tumors. The mechanism for hCG induced thyrotoxicosis lies in the structural similarity between TSH and hCG molecules leading to the direct stimulation of the TSH receptors. In regard to treatment, while gestational thyrotoxicosis is usually mild, self-limited and does not need medications, the hyperthyroidism of trophoblastic tumors may require antithyroid medications in addition to treating the underlying tumor. Thionamide use is reserved for moderate to severe cases of hyperthyroidism and for presurgical optimization. In our case report, we present a 22-year-old African American female with choriocarcinoma induced thyrotoxicosis requiring thionamide therapy. Clinical Case: A 22-year-old African American female presented to our emergency room after a witnessed generalized tonic-clonic seizure. Her brain CT scan showed a 4 CM mass concerning for AVM malformation with a subsequent brain MRI confirming parenchymal hematoma with surrounding vasogenic edema. Past medical history was significant for molar pregnancy managed with dilation and curettage followed by laparotomy to remove the pelvic mass. Given her history of molar pregnancy, pelvic ultrasound was performed which showed complex heterologous structure of uterine origin concerning for malignancy. Additional imaging studies of the lung, brain, abdomen and pelvis were performed, which showed possible metastasis to the lung, adnexa, and to the brain. Her clinical exam showed heart rate of 130 beats/min with a normal rhythm, fine tremors, aphasia, and a decrease grip strength in her right upper extremity. Her thyroid gland was slightly enlarged with no tenderness. Laboratory tests showed hCG of >1,000,000 mIU/mL, TSH of < 0.01mcU/mL, free T4 of 5.1ng/dL. Her TPO and TSI were negative. With a diagnosis of hyperthyroidism due to trophoblastic disease, she was treated with methimazole and propranolol resulting in rapid clinical and biochemical improvement. Later, left frontal craniotomy and hematoma evacuation was performed with histology confirming the diagnosis of metastatic choriocarcinoma. She was later transferred to a specialized center where she received chemotherapy. Her hCG subsequently dropped down to 699 mIU/mL. Conclusion: We report a rare case of metastatic choriocarcinoma causing symptomatic hyperthyroidism. The diagnosis is made by excluding other common causes of hyperthyroidism and it should be considered in females of childbearing age. Methimazole is an effective agent to control the hyperthyroidism while waiting for treatment of the underlying cancer.

Placental site trophoblastic tumor during pregnancy complicated by uterine rupture

The placental site trophoblastic tumor is a rare highly malignant form of trophoblastic disease, which occurs in as few as 0.4-2.0 % of all trophoblastic tumors. Available publications describes not more than 200 clinical cases of this pathology often affecting patients of reproductive age, thereby underscoring special importance of its diagnostics and treatment. Here we describe the rare clinical case of spontaneous uterine rupture in pregnant woman at 26 weeks of gestation carrying placental site trophoblastic tumor, previously undescribed in research literature. The complexity of diagnosing such pathology that resulted in antenatal fetal death and hysterectomy is demonstrated.

Epithelioid trophoblastic tumor coexisting with choriocarcinoma around an abdominal wall cesarean scar: a case report and review of the literature

Background Mixed gestational trophoblastic neoplasms are extremely rare and comprise a group of fetal trophoblastic tumors including choriocarcinomas, epithelioid trophoblastic tumors, and placental site trophoblastic tumors. We present a case of a patient with extrauterine mixed gestational trophoblastic neoplasm adjacent to the abdominal wall cesarean scar. On the basis of a literature review, this type of case has never been reported before due to the unique lesion location and low incidence. Case presentation Our patient was a 39-year-old Chinese woman who had a history of two cesarean sections and one miscarriage. She had a recurrent anterior abdominal wall mass around her cesarean scar, and the mass was initially suspected of being choriocarcinoma of unknown origin. The patient had concomitant negative or mildly increased serum β-human chorionic gonadotropin at follow-up and no abnormal vaginal bleeding or abdominal pain. However, she underwent local excision twice and had two courses of chemotherapy with an etoposide and cisplatin regimen. She finally opted for exploratory laparotomy with abdominal wall lesion removal, subtotal hysterectomy, bilateral salpingectomy, and left ovarian cyst resection, which showed the abdominal wall lesion, whose components were revealed by microscopy and immunohistochemical staining to be approximately 90% epithelioid trophoblastic tumors and 10% choriocarcinomas from a solely extrauterine mixed gestational trophoblastic neoplasm around an abdominal wall cesarean scar. Conclusions It is worth noting whether epithelioid trophoblastic tumor exists in the setting of persistent positive low-level β-human chorionic gonadotropin. More studies are required to provide mechanistic insights into these mixed gestational trophoblastic neoplasms.