Molecular profiling of gestational trophoblastic neoplasia: Identifying therapeutic targets.

OBJECTIVE: The treatment for high risk or recurrent gestational trophoblastic neoplasia (GTN) is a highly toxic multi-agent chemotherapy. For patients with progressive or recurrent GTN, checkpoint inhibitors have demonstrated anti-tumor activity; however, identification of novel therapies for GTN remain an unmet need. Therefore, we sought to characterize the molecular landscape of GTN to identify potential therapeutic targets. METHODS: GTN samples were analyzed using a combination of molecular - next-generation sequencing (NGS) or whole exome sequencing (WES)- and protein- Immunohistochemistry (IHC) analyses. GTN samples encompassed complete moles, choriocarcinoma, epithelioid trophoblastic tumors (ETT), and placental site trophoblastic tumors (PSTT). RESULTS: We analyzed 30 cases of GTN including 15 choriocarcinoma, 7 ETT, 5 PSTT, 1 invasive mole and 2 mixed histologies. The median age was 41.5. GTN samples were found to be PD-L1 positive (92.3%), tumor mutational burden (TMB) low (92.8%), and microsatellite stable (MSS) (100%). Forty-six percent of choriocarcinoma specimens contained a genomic alteration including TP53 (33%) and homologous recombination repair (HRR) (13%) genes. Alterations in RTK-RAS pathway signaling was present in 40% of ETT cases. CONCLUSIONS: The high rate of PD-L1 positivity in this real-world database and reported in prior literature support continued clinical trial development evaluating immunotherapy for treatment of GTN. Other potential targeted treatments identified include Wee1, PARP and MEK inhibitors based on molecular alterations in TP53, HRR genes, and RTK-RAS pathways respectively.

Expression profiling of lncRNAs and mRNAs in placental site trophoblastic tumor (PSTT) by microarray.

As a rare type of gestational trophoblastic disease, placental site trophoblastic tumor (PSTT) is originated from intermediate trophoblast cells. Long noncoding RNAs (lncRNAs) regulate numerous biological process. However, the role of lncRNAs in PSTT remains poorly understood. In the present study, expression levels of lncRNAs and mRNAs in four human PSTT tissues and four normal placental villi were investigated. The results of microarray were validated by the reverse transcription and quantitative real-time polymerase reaction (RT-qPCR) and immunohistochemistry analyses. Furthermore, GO and KEGG pathway analyses were performed to identify the underlying biological processes and signaling pathways of aberrantly expressed lncRNAs and mRNAs. We also conducted the coding-non-coding gene co-expression (CNC) network to explore the interaction of altered lncRNAs and mRNAs. In total, we identified 1247 up-regulated lncRNAs and 1013 down-regulated lncRNAs as well as 828 up-regulated mRNAs and 1393 down-regulated mRNAs in PSTT tissues compared to normal villi (fold change ≥ 2.0, p < 0.05). GO analysis showed that mitochondrion was the most significantly down-regulated GO term, and immune response was the most significantly up-regulated term. A CNC network profile based on six confirmed lncRNAs (NONHSAT114519, NR_103711, NONHSAT003875, NONHSAT136587, NONHSAT134431, NONHSAT102500) as well as 354 mRNAs was composed of 497 edges. GO and KEGG analyses indicated that interacted mRNAs were enriched in the signal-recognition particle (SRP)-dependent cotranslational protein targeting to membrane and Ribosome pathway. It contributes to expand the understanding of the aberrant lncRNAs and mRNAs profiles of PSTT, which may be helpful for the exploration of new diagnosis and treatment of PSTT.

lnc003875/miR-363/EGR1 regulatory network in the carcinoma -associated fibroblasts controls the angiogenesis of human placental site trophoblastic tumor (PSTT).

The rare gestational trophoblastic neoplasia placental site trophoblastic tumor (PSTT) frequently demonstrates a high degree of vascularization, which may facilitate the tumor metastasis. However, the underlying mechanisms remain largely unknown. In the present study, we found that early growth response 1 (EGR1) was highly expressed in the carcinoma-associated fibroblasts (CAFs) of PSTT tissues. Further data showed that miR-363 down-regulated EGR1 expression whereas long non-coding RNA NONHSAT003875 (lnc003875) up-regulated EGR1 expression in PSTT derived CAFs. lnc003875 exerted no effect on miR-363 expression, but it recovered the decrease of EGR1 caused by miR-363 mimic. The conditioned media from PSTT CAFs treated with miR-363 mimic abrogated the tube formation capacity of human umbilical vein endothelial cells (HUVECs), which can be partially restored by lnc003875 over-expression. Moreover, over-expression of EGR1 promoted the secretion of Angiopoietin-1 (Ang-1) in PSTT derived CAFs and improved the tube formation of HUVECs, which could be effectively abrogated by Ang-1 siRNAs. In vivo vasculogenesis assay demonstrated that lnc003875/EGR1 in PSTT derived CAFs promoted the vasculogenesis of HUVECs in C57BL/6 mice. Collectively, these findings indicated that lnc003875/miR-363/EGR1/Ang-1 in CAFs may be crucial for the angiogenesis of PSTT.

A case of placental site trophoblastic tumor managed in a low resource setting.

Placental trophoblastic site tumor (PSTT) is a rare type of gestational trophoblastic neoplasia (GTN). PSTT has a higher mortality than other types of gestational trophoblastic disease (GTD), with a rate of 16.1%, due to its relatively unpredictable behavior and reduced response to chemotherapy. Its diagnostic and management are very challenging in Low resources settings particularity in Haiti where MRI, PET Scan and IHC are not available. Further, the follow-up is very difficult because of social, political, and economic issues limiting the capacity of our patients to be present at all scheduled visits. No case of PSTT has been publicly described yet the Haitian experience in the literature in the management of such case compared to the developed world. We present a case of PSTT successfully diagnosed and managed at Mirebalais University Hospital (MUH) in Haiti with the support of telepathology and intentional partners while highlighting the difference that we observed compare to the developed world.

Placental Site Trophoblastic Tumor in Mediastinal Recurrence of Mixed Germ Cell Tumor of the Testis: Report of a Case and Review of the Literature.

We present a rare case of a 42-year-old man diagnosed with a placental site trophoblastic tumor in combination with teratoma in a mediastinal recurrence of a testicular germ cell tumor post-orchiectomy and chemotherapy. To the best of our knowledge, this is the eighth case of placental site trophoblastic tumor in a male reported so far in the English literature. The purpose of this case report is to add data to the existing literature, review the literature, discuss the differential diagnoses with emphasis on morphologic and immunohistochemical differences between trophoblastic tumors, and highlight the management implications of a correct diagnosis.

Placental-site trophoblastic tumor with bone metastasis: A diagnostic and therapeutic challenge.

Placental-site trophoblastic tumor (PSTT) is a rare pathological entity included in the spectrum of gestational trophoblastic neoplasia (GTN). It is a neoplasia with metastatic potential that, once metastasized, has poor prognosis because the tumor tends to be less sensitive to chemotherapy. We present a rare case of gestational trophoblastic neoplasia, in which hysterectomy for persistent gestational trophoblastic disease after hydatidiform mole, revealed a primary PSTT in the uterus. Subsequently, a slight persistent elevation of the beta fraction of human chorionic gonadotropin hormone (B-hCG) during follow-up revealed the presence of bone metastases. This location is not usual from this tumor, being even more rare the case of PSTT with isolated bone metastases. Metastasic foci were only identified with PET-CT since the usual diagnostic resources were not able to do it. Finally, it is also remarkable in our case that the treatment required the confluence of chemotherapy together with immunotherapy to achieve a favorable response.

Epithelioid trophoblastic tumor presenting as a Caesarean scar defect: A case report.

BACKGROUND: Epithelioid trophoblastic tumor is a rare form of gestational trophoblastic neoplasia. We present the first known case of this rare malignancy presenting as a Caesarean scar defect. CASE: A patient with 3 prior Caesarean sections presented with vaginal bleeding 2 months following management of retained products of conception. Her hCG was negative. She underwent surgical repair of a Caesarean scar defect, and pathology was consistent with epithelioid trophoblastic tumor. CONCLUSION: This case highlights the possibility of malignancy presenting to the general gynecologist as a Caesarean scar defect. The diagnosis of gestational trophoblastic neoplasia should always be considered in the differential diagnosis of a patient with postpartum vaginal bleeding. Limited evidence on fertility conserving treatment of epithelioid trophoblastic tumors does not seem favorable.

Long-term survival in multiresistant metastatic choriocarcinoma after pembrolizumab treatment: A case report.

•Checkpoint inhibitor therapy affecting PD-L1 as treatment for advanced solid tumors.•Success in trial pembrolizumab therapy in multiresistant metastatic choriocarcinoma.•Long-term remission after pembrolizumab therapy in multiresistant choriocarcinoma.•Only six reported cases, one with comparable follow-up and outcome.

Core 2 ß1,6-N-acetylglucosaminyltransferases accelerate the escape of choriocarcinoma from natural killer cell immunity.

Hyperglycosylated human chorionic gonadotropin (H-hCG) is secreted from choriocarcinoma and contains a core2 O-glycan formed by core2 ß1,6-N-acetylglucosaminyl transferase (C2GnT). Choriocarcinoma is considered immunogenic as it is gestational and contains paternal chromosomal components. Here we examined the function of C2GnT in the evasion of choriocarcinoma cells from natural killer (NK) cell-mediating killing. We determined that C2GnT is highly expressed in malignant gestational trophoblastic neoplasms. C2GnT KO downregulates core2 O-glycan expression in choriocarcinoma cells, which are more efficiently killed by NK cells than control cells. C2GnT KO cell containing tumor necrosis factor-related apoptosis inducing ligand have lower viability than control cells. Additionally, poly-N-acetyllactosamine in core2 branched oligosaccharides on MHC class I-related chain A (MICA) and mucin1 (MUC1) is significantly reduced in C2GnT KO cells. Meanwhile, the cumulative survival rate of nude mice inoculated with C2GnT KO tumors was higher than that of the control group. These findings suggest that choriocarcinoma cells may escape NK cell-mediated killing via glycosylation of MICA and MUC1.

Impact of different phased-array coils on the quality of prostate magnetic resonance images.

PURPOSE: To evaluate the influence of body phased-array (BPA) receive coil setups on signal-to-noise ratio (SNR) and image quality (IQ) in prostate MRI. METHODS: This prospective study evaluated axial T2-weighted images (T2W-TSE) and DWI of the prostate in ten healthy volunteers with 18-channel (18CH), 30-channel and 60-channel (60CH) BPA receive coil setups. SNR and ADC values were assessed in the peripheral and transition zones (TZ). Two radiologists rated IQ features. Differences in qualitative and quantitative image features between BPA receive coil setups were compared. After correction for multiple comparisons, p-values <0.004 for quantitative and p-values <0.017 for qualitative image analysis were considered statistically significant. RESULTS: Significantly higher SNR was found in T2W-TSE images in the TZ using 60CH BPA compared to 18CH BPA coil setups (15.20 ± 4.22 vs. 7.68 ± 2.37; p = 0.001). There were no significant differences between all other quantitative (T2W-TSE, p = 0.007-0.308; DWI, p = 0.024-0.574) and qualitative image features (T2W-TSE, p = 0.083-1.0; DWI, p = 0.046-1.0). CONCLUSION: 60CH BPA receive coil setup showed marginal SNR improvement in T2W-TSE images. Good IQ could be achieved with 18CH BPA coil setups.

Gestational trophoblastic neoplasms (GTNs) do not display epithelial-to-mesenchymal transition (EMT) features.

Although epithelial-to-mesenchymal transition (EMT) has been described in the development of complete hydatidiform moles and the invasion of the maternal decidua by trophoblasts during normal human placentation, its implication in gestational trophoblastic neoplasm (GTN) without villi is totally unknown. We studied the immunoexpression of EMT transcription factors (TWIST1, ZEB1, ZEB2), E-cadherin, and vimentin in 18 trophoblastic tumors and pseudo-tumors. Weak nuclear TWIST1 immunostaining was seen in 5% to 10% of all trophoblastic cells, without ZEB1 and ZEB2 nuclear staining. Trophoblastic cells did not express vimentin, and the expression of E-cadherin was maintained in all cases, indicating the absence of EMT features in GTN.

Placental site trophoblastic tumor: A case report and literature review.

Here, we report a case of a placental site trophoblastic tumor (PSTT) in a 36-year-old Chinese woman 10 months after a normal pregnancy. Two months postpartum, the woman presented with abnormal vaginal discharge and her condition was overlooked by her local hospital. The woman did not receive further attention until a mass with a heterogeneous echo was found in an ultrasound examination eight months postpartum. The final diagnosis was confirmed by histological examinations in conjunction with immunohistochemical studies. Since the patient had potential risk factors, she was successfully treated with a hysterectomy and peri- and post-operative chemotherapy. The latest follow-up (16 months after diagnosis) was uneventful, and the patient exhibited no signs of recurrence or metastasis.

Atypical recurrence of a placental site trophoblastic tumor four years after hysterectomy for benign condition: Case report and review of literature.

•Rare case of PSTT limited to the vagina presenting eight years after last pregnancy and four years after hysterectomy•Differential diagnosis with other vaginal tumors can be challenging but it is critical because behavior and management are different.•Stage-adapted management is proposed and surgery is the mainstay treatment for localized disease.

Diagnosis and treatment of placental site trophoblastic tumor.

Here we report a case of a placental site trophoblastic tumor in a 36 year old Chinese woman, 31 months following a prior normal pregnancy. Her clinical presentation and ultrasound findings were uncharacteristic; and the final definitive diagnosis was established based on histological examination in conjunction with immunohistochemistry studies and a normal beta human chorionic gonadotropin level. The tumor exhibited high grade histological features with tumor necrosis, nuclear atypia and high mitosis. The patient was successfully treated with hysterectomy with pre- and post-operative chemotherapy.