BACKGROUND: Patients with choriocarcinoma (CC) accompanying chemoresistance conventionally present a poor prognosis. Whether ras protein activator like-1 (RASAL1) functions as a tumor promoter or suppressor depends on tumor types. However, the role of RASAL1 in process of chemoresistance of CC and underlying molecular mechanism remain elusive.
METHODS: The expression pattern of RASAL1 in CC cells and tissues was measured using Western blotting, immunohistochemistry and qRT-PCR. Cell viability and proliferative ability were assessed by MTT assay, Tunnel assay and flow cytometric analysis. Additionally, the stemness was evaluated by the colony formation and tumor sphere formation. Methotrexate (MTX) was applied to exam the chemosensitivity of CC cells.
RESULTS: The expression of RASAL1 was reduced both at the protein and mRNA levels in CC tissues and cells compared to hydatidiform mole (HM) and invasive mole (IM). Loss of RASAL1 was attributed to its promoter hypermethylation and could be restored by 5-Aza. Knock-down of RASAL1 promoted the viability, proliferative potential, stemness and EMT phenotype of JEG-3 cells. However, induced overexpression of RASAL1 by 5-Aza significantly prohibited cell proliferation and stemness potential of the JAR cell. Additionally, the xenograft model indicated that knockdown of RASAL1 led to a remarkable increase of tumor volume and weight in comparison with its counterpart. Moreover, the stimulatory activity brought by decrease of RASAL1 could be deprived by β-catenin inhibitor XAV 939, yet the suppressive activity resulted from its promoter demethylation could be rescued by β-catenin activator BML-284, indicating that function of RASAL1 depends on β-catenin. Besides, the co-immunoprecipitation assay confirmed the physical binding between RASAL1 and β-catenin. Further investigations showed hypermethylated RASAL1 was regulated by TET2 but not DNMTs.
CONCLUSIONS: Taken together, the present data elucidated that reduced RASAL1 through its promoter hypermethylation regulated by TET2 promoted the tumorigenicity and chemoresistance of CC via modulating β-catenin both in vitro and in vivo.

Gestational trophoblastic neoplasia (GTN) with spinal metastasis is rare with few documented cases worldwide. Few studies have explored chemotherapy combined with radiotherapy in the treatment of such cases. However, because of its rarity, there is still no standardized treatment regimen. A 34-year-old Gravida 1 Para 0 (0010) was diagnosed with GTN with metastasis to the lumbosacral spine, resulting in conus medullaris syndrome with lumbar radiculopathy. She presented with a 14-month history of amenorrhea, left lower extremity pain, and urinary and bowel retention. On examination, there was a 10.0 × 7.0 cm lumbosacral mass and atrophy of the left lower extremity. Transvaginal ultrasound showed a cul de sac mass, and diluted β-human chorionic gonadotropin (β-hCG) titer was markedly elevated at more than 1000 000 mIU/mL. Magnetic resonance imaging (MRI) of the lumbosacral spine showed an ill-defined sacral mass measuring 13.3 × 11.5 × 6.3 cm with spinal canal, bone, muscle, and nerve root involvement. She was treated with 10 cycles of EMACO and palliative radiotherapy with 10 sessions of 30 Gy of external beam radiation therapy directed toward the lumbosacral mass. Repeat MRI showed a decrease in size of the mass to 6.6 × 8.2 × 4.1 cm with concurrent decrease in β-hCG to 1.30 mIU/ml, and resolution of leg pain and urinary and bowel symptoms. She was declared to be in remission 3 months after the last cycle of EMACO.

Choriocarcinoma is a rare and highly malignant tumor that primarily occurs in women of reproductive age. Choriocarcinoma can be classified as gestational or nongestational, based on its pathogenetic origin. Although primary nongestational choriocarcinoma has been described in the ovaries, it is very rare in the uterus, especially in postmenopausal women. It is crucial to differentiate between gestational and non-gestational choriocarcinoma, as it affects the choice of treatment and prognosis. Endometrial clear cell carcinoma is an aggressive subtype of endometrial cancer, accounting for less than 10% of all uterine carcinomas. Trophoblastic differentiation in uterine cancer is unusual and very rare, with only three examples of the subtype of clear cell endometrial cancer with gestational choriocarcinoma reported in the literature, including only one with nongestational choriocarcinoma. Here, we present an example of clear cell carcinoma with nongestational uterine choriocarcinoma differentiation in a postmenopausal woman.

Primary choriocarcinoma originating in the lung is a rare entity. These are highly malignant intrapulmonary tumors with a notoriously poor prognosis. The pathogenesis is unclear. A 34-year-old lady, with a history of abortion six months back, presented with left-sided chest pain for one month, dyspnea on exertion, weight loss, and loss of appetite. Computed tomography (CT) of the thorax was suggestive of a mass lesion 4 x 5 cm at the left upper lobe, which was invading the chest wall, and pleural effusion, histopathologically defined as adenocarcinoma. A positron emission tomography-computed tomography (PET-CT) scan showed a fluorodeoxyglucose (FDG) avid lesion in the left upper lobe of size 4 x 5 with invasion to the chest wall with no evidence of distant metastases. Urine pregnancy test (UPT) was negative for this patient. Thus, the patient was initially diagnosed with stage cT3N0M0 adenocarcinoma of left lung cancer. The sample was sent for the lung next-generation sequencing (NGS) panel. Meanwhile, the patient was empirically started on gefitinib. Tumor markers revealed raised beta-human chorionic gonadotropin (β-hCG) to 1,79,000 IU/ml. A review biopsy was done, which was suggestive of choriocarcinoma. Genetic testing of lung biopsy suggestive of XX chromosome, confirming the diagnosis of primary pulmonary choriocarcinoma (PPC). The patient was planned for chemotherapy with etoposide and cisplatin. The patient underwent embolization of the left internal mammary artery (IMA) and branches of the left subclavian vein. There was a gradual fall in β-hCG after the second dose of chemotherapy on day 7. For the diagnosis of PPC, immunohistochemistry (IHC) staining, β-hCG measurement, and examination to exclude primary gonadal malignancies are essential. A combination of surgery and chemotherapy is a favorable treatment. As it\'s a highly vascular tumor, selective arterial embolization can be life-saving in case of bleeding.

Hydatidiform moles, including both complete and partial moles, constitute a subset of gestational trophoblastic diseases characterized by abnormal fertilization resulting in villous hydrops and trophoblastic hyperplasia with or without embryonic development. This involves chromosomal abnormalities, where one or two sperms fertilize an empty oocyte (complete hydatidiform mole (CHM); mostly 46,XX) or two sperms fertilize one oocyte (partial hydatidiform mole (PHM); mostly 69,XXY). Notably, recurrent occurrences are associated with abnormal genomic imprinting of maternal effect genes such as NLRP7 (chromosome 19q13.4) and KHDC3L (chromosome 6q1). Ongoing efforts to enhance identification methods have led to the identification of growth-specific markers, including p57 (cyclin-dependent kinase inhibitor 1C; CDKN1C), which shows intact nuclear expression in the villous cytotrophoblast and villous stromal cells in PHMs and loss of expression in CHMs. Treatment of hydatidiform moles includes dilation and curettage for uterine evacuation of the molar pregnancy followed by surveillance of human chorionic gonadotropin (HCG) levels to confirm disease resolution and rule out the development of any gestational trophoblastic neoplasia. In this review, we provide a synopsis of the existing literature on hydatidiform moles, their diagnosis, histopathologic features, and management.

To retrospectively analyze the fertility outcomes and prognosis of gestational trophoblastic disease (GTD) patients, providing a basis for targeted fertility guidance and counseling. 82 GTD patients of childbearing age who received treatment at the Obstetrics and Gynecology Department of Lanzhou University First Hospital from January 2016 to January 2023 were stratified into re-pregnancy (n = 20) and non-re-pregnancy (n = 33) cohorts based on their pregnancy outcomes. The impacts of various factors on pregnancy outcomes were subsequently evaluated, encompassing the rates of subsequent pregnancies, live births, miscarriages, ectopic pregnancies, and ongoing pregnancies. Finally, logistics regression model was employed to analyze the risk factors affecting re-pregnancy in GTD patients. The study delineated those patients with different GTD pathologies had varying re-pregnancy rates (mole, erosive mole and choriocarcinoma accounted for 66.04%, 30.19% and 3.77%, respectively). Treatment predominantly involved uterine curettage, with fewer cases receiving chemotherapy alone or in conjunction with curettage accounted for 67.92%, 5.66%, and 26.42%, respectively. The average chemotherapy frequency was 4.59 ± 2.43 sessions, and a majority sought reproductive counseling. Re-pregnancy occurred in 37.74% of patients. The live birth rate was 65.00%, with miscarriage and ectopic pregnancy rates at 25.00% and 5.00% respectively. Logistic regression analysis pinpointed the absence of pre-pregnancy counseling as a significant independent risk factor for re-pregnancy in GTD patients (p < 0.05). While chemotherapy may influence ovarian function, with the majority of patients desiring children post-recovery, pregnancy rates remain high. Fertility counseling significantly enhances re-pregnancy success rates in GTD survivors, emphasizing its recommendation for those aiming to conceive post-recovery.

This is the first reported case of the use of immunotherapy in chemo-resistant Gestational Trophoblastic Neoplasia (GTN) in the country. A 41-year-old, Gravida 4 Para 3 (3013) with a diagnosis of GTN, Stage III: WHO risk score of 13 (Choriocarcinoma) was initially managed with 10 cycles of multiple agent Etoposide, Methotrexate, Actinomycin D-Cyclophosphomide and Vincristine (EMACO) and 19 cycles of Etoposide, Cisplatin-Etoposide Methotrexate and Actinomycin D (EP-EMA). With continuous rise in beta human chorionic gonadotropin (ßhCG) levels, the patient was referred to a Trophoblastic Disease Center where there was note of tumor progression to the brain. She was started on third-line salvage chemotherapy of Paclitaxel and Carboplatin (PC) with concomitant whole brain irradiation completing three cycles after which chemoresistance was again diagnosed with increasing hCG titers and increase in the number and size of the pulmonary masses which were deemed unresectable. Immunotherapy was started with Pembrolizumab showing a good response with marked fall in ßhCG levels. The onset of immune-related adverse events (irAEs) caused a marked delay in subsequent cycles of immunotherapy. With management of the irAEs, two more cycles of Pembrolizumab with fifty percent dose reduction were given with corresponding drop in ßhCG levels. However, the patient subsequently developed gram-negative septicemia with possible hematologic malignancy and finally succumbed to massive pulmonary embolism. The case highlights the importance of prompt diagnosis and referral to a Trophoblastic Disease Center and the use of immunotherapy in chemo-resistant GTN.

BACKGROUND: Choriocarcinoma is a highly malignant pregnancy-related trophoblastic neoplasm, characterized by early metastasis to the lungs. Therefore, patients may manifest nongynecological symptoms owing to distant metastases. The incidence of choriocarcinoma after a term pregnancy is really rare (1/160,000 pregnancies).
METHODS: We report a case of a 20-year-old Iranian woman, gravida 2 para 1 live 1 abortion 1, who was referred to our gynecology department with sudden onset dyspnea and pain in the left hemithorax the day after her labor. The index pregnancy was without any complications. After the initial workup, the elevation of β-human chorionic gonadotropin (HCG) levels (> 1,000,000) along with the identification of clinical (vaginal lesions) and radiological evidence of distant metastases (bilateral pulmonary nodes) directed us toward pulmonary metastatic choriocarcinoma diagnosis. After the oncology consult, the etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine chemotherapy regimen was started for the patient. She responded well to the treatment and is currently continuing her chemotherapy process.
CONCLUSIONS: The prognosis of choriocarcinoma is very good if the treatment is started on time. We suggest that clinicians should consider gestational trophoblastic neoplasia in their differential diagnosis of the post-natal period complications, especially after a term and nonmolar pregnancy.

Pulmonary arteries may rarely be involved by primary and secondary tumors. Clinical and imaging features mimic those of PE making it challenging to diagnose. Choriocarcinoma is a malignant germ cell tumor, typically in the female genital tract. Rarely, they can present as PA thrombus. Female patients with a history of a molar pregnancy, ectopic pregnancy, abortion or in this case a miscarriage, are at a higher risk of gestational trophoblastic disease which can manifest in this way, albeit this is rare. In this report we describe the case of a 52-year-old female who presented with a 1 month history of worsening dyspnea and pleuritic lower thoracic pain. A diagnosis of pulmonary embolism (PE) was confirmed on CT pulmonary angiogram, with a large volume thrombus in the left pulmonary artery (PA). She failed to improve on standard anticoagulation therapy and was found to have a raised beta-human chorionic gonadotropin of >100,000. This leads to an extensive malignancy work-up. The only pertinent finding was that of increased fluorodeoxyglucose (FDG) accumulation in the PA thrombus. Endovascular biopsy of the thrombus was performed, and the patient was diagnosed with choriocarcinoma of the PA. This case highlights the importance of further investigation in patients failing to respond to anticoagulation therapy for PE. It also illustrates the role of interventional radiology in obtaining histological diagnosis in patient\'s presenting with PA tumor thrombus.

OBJECTIVE: Few studies have quantified differences in histology and implications for survival between male children and adults with germ cell tumors (GCT). We evaluated these differences and associations with cancer-specific survival (CSS) using Surveillance, Epidemiology, and End Results (SEER) cancer registries.
METHODS: SEER (1988-2016) was used to identify male patients 0 to 40 years of age diagnosed with seminoma and nonseminomatous GCT (NSGCT). Demographic and tumor characteristics were tabulated with histology distributions compared by age group (0-4, 12-18, 19-40 years old). CSS was evaluated in multivariable Cox proportional hazards regression models.
RESULTS: Among 27,204 patients identified, 1,538 (5.7%) were pediatric (0-18 years). Seminoma (54.3%) predominated in adult patients (ages 19-40). Among 0 to 4 years-old, yolk sac tumor (71.2%) and teratoma (21.5%) were most common. Mixed GCT (52.7%) was most prevalent among 12 to 18 years-old with seminoma, embryonal, and teratoma occurring in 12 to 15% each. Relative to pediatric patients, adult patients had similar CSS for seminoma but worse CSS for NSGCT on Kaplan-Meier curves with 9 years mean follow-up. Choriocarcinoma and yolk sac tumors carried the worst prognosis relative to seminoma for both children (HR 5.7 and HR 11.1, respectively, both P < 0.01) and adults (HR 4.6 and HR 4.6, respectively, both P < 0.01) adjusted for stage.
CONCLUSIONS: Histology of GCTs vary by age with yolk sac tumors and teratoma predominating for male patients 0 to 4 years, mixed GCT for 12 to 18 years, and seminoma for 19 to 40 years. Pediatric patients with NSGCT had higher CSS than their adult counterparts. Mixed GCT represented an increasing proportion of GCT over the study period. Age, stage, and histology impact CSS in both pediatric and adult populations.