RARE DISEASE
Rare uterine cancer
Rare uterine cancer
Rare uterine cancer
Synonyms: Rare cancer of uterus, Rare malignant tumor of uterus, Rare uterine malignant tumor
Synonyms: Rare cancer of uterus, Rare malignant tumor of uterus, Rare uterine malignant tumor
Synonyms: Rare cancer of uterus, Rare malignant tumor of uterus, Rare uterine malignant tumor
Drug discovery
1
drug
With orphan designation
Overview
Rare uterine cancers encompass aggressive histologies like uterine serous carcinoma, clear-cell carcinoma, carcinosarcoma, and sarcomas (leiomyosarcoma, endometrial stromal sarcoma), representing <5% of uterine malignancies [1][15][20]. These tumors often present at advanced stages, resist standard therapies, and account for >70% of uterine cancer mortality [8][11].
Burden
5-year survival: 35-55% for sarcomas vs 81% overall for endometrial cancer [1][11][15]
Responsible for ~3.1/100,000 deaths annually; non-Hispanic Black women experience 9.5/100,000 mortality (vs 4.7 in White women) [2][7][19]
DALY rates increased 40% globally (1990-2019), driven by aging populations and obesity [4][11][13]
Therapies
Primary: Total hysterectomy with BSO ± lymph node assessment [1][10][16]
Adjuvant: Platinum-based chemotherapy (carboplatin/paclitaxel) ± radiation; targeted therapies (lenvatinib/pembrolizumab) for advanced dMMR/MSI-H tumors [12][16]
Emerging: RNR inhibitors (gemcitabine) for PP2A-mutant serous carcinoma; HER2-directed therapies in clinical trials [3][12]
Categories: rare gynecological and obstetric diseases, rare neoplastic diseases
Research Papers
929 drug discovery papers about Rare uterine cancer, with 1 first-in-class and 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
929 drug discovery papers about Rare uterine cancer, with 1 first-in-class and 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-26 | A Review of Proteomic Studies in Uterine Leiomyosarcoma: Biomarkers, Pathways, and Clinical Potential.
Uterine leiomyosarcoma (uLMS) is a rare but highly aggressive mesenchymal malignancy of smooth-muscle origin that represents a significant therapeutic challenge due to its poor prognosis and limited treatment options. Despite advances in molecular characterization, diagnosis remains difficult, and systemic therapies have shown limited success, contributing to a high recurrence rate and poor survival. Recent proteomic investigations have provided new insights into uLMS biology by exploring the global protein expression patterns that define malignant transformation and progression. Using high-resolution mass spectrometry (MS)-based techniques, quantitative proteomics, and integrated multi-omics approaches, researchers have begun to identify dysregulated proteins, signaling pathways, and post-translational modifications (PTMs) linked to tumor metabolism, extracellular matrix (ECM) remodeling, cell-cycle regulation, and chemoresistance. These studies have also uncovered candidate biomarkers that may improve the discrimination of uLMS from benign leiomyoma and have proposed novel therapeutic targets associated with metabolic reprogramming, kinase activation and tumor microenvironment (TME) modulation. This review summarizes recent advancements in uLMS proteomics, discusses their methodological underpinnings, highlights key molecular mechanisms and biomarkers, and explores their translational potential. Finally, we outline current limitations and future directions toward clinical implementation of proteomic findings in precision oncology for uLMS patients.
2026-09-21 | Integrated Genomic Profiling of PTEN and TP53 in Cervical Neuroendocrine Carcinoma: Synergistic Roles With HER2/KRAS/PIK3CA and Implications for Precision Oncology.
Neuroendocrine carcinoma (NEC) of the uterine cervix is a rare, highly aggressive malignancy with a poor prognosis. Expanding upon our previous work, which identified frequent mutations in HER2, KRAS, and PIK3CA in this disease, we sought to refine the genomic landscape by characterizing alterations in TP53 and PTEN, and their relationships with these oncogenic drivers. Genomic DNA from 12 cervical NECs with ≥ 50% tumor cellularity underwent targeted next-generation sequencing (NGS) using the Qiagen GeneRead DNAseq Targeted Panels V2. Variants were filtered against COSMIC and ClinVar, and the pathogenicity of missense changes was assessed with PolyPhen-2, with scores > 0.85 considered probably damaging. PTEN alterations were identified in 25.0% (3/12) of tumors, encompassing four truncating mutations (p.W111*, p.Q171*, p.Q245*, p.R335*) and three missense variants (p.R130Q, p.E394G, p.D395V). A TP53 DNA-binding domain hotspot mutation, p.R273H, was detected in 8.33% (1/12). These tumor-suppressor lesions frequently co-occurred with oncogenic driver mutations, including HER2/PTEN (8.33%), PIK3CA/PTEN (8.33%), and a KRAS/PTEN/TP53 "triple-hit" (8.33%), underscoring multipathway genomic complexity. Our findings suggest a genomic landscape consistent with a multihit hypothesis in cervical NEC, in which disruption of the reciprocal tumor-suppressive PTEN-p53 axis (25.0% and 8.33%, respectively) co-occurs with oncogenic HER2, KRAS, or PIK3CA alterations. Structural mapping indicates that TP53 p.R273H gain-of-function mutations and PTEN loss-of-function variants are associated with sustained PI3K/AKT/mTOR pathway activation. Integrating TP53 and PTEN status with oncogenic driver profiling may facilitate the identification of biologically defined subsets and inform precision therapeutic strategies for cervical NEC.
2026-08-28 | "Fibrosarcoma-like" Tumors of the Gynecologic Tract Show Distinct Molecular Subgroups: Tyrosine Kinase Fusions and Recurrent ERBB2/3 Mutations.
In recent years, rare fibrosarcoma-like tumors have been identified in the gynecologic tract, characterized by variable CD34 and S-100 positivity and recurrent tyrosine kinase gene fusions in many cases. We identified 17 of these tumors by searching for gynecologic sarcomas expressing S-100 and/or CD34 and supplementing these with cases contributed by collaborating institutions. Tumors involved the uterine cervix (n = 11), uterine corpus (n = 4), and vagina (n = 2). Patients ranged from 28 to 64 (median, 50 years) years. Fifteen tumors showed overlapping morphologic features, including haphazard or fascicular growth of relatively monotonous spindled to ovoid cells with minimal to moderate cytoplasm. Tyrosine kinase gene fusions were identified in 9 tumors, including NTRK fusions in 6 and COL1A1::PDGFB in 3 tumors. Oncogenic variants in ERBB2/ERBB3 were identified in 6 additional tumors. These 2 subgroups showed distinct immunohistochemical profiles, with all tyrosine kinase fusion-positive tumors being CD34 positive, variably S-100 positive, and SOX10 negative. In contrast, the ERBB-altered tumors were CD34 negative and diffusely positive for S-100 and SOX10. The remaining 2 tumors showed morphologic and immunohistochemical overlap with the tyrosine kinase fusion-positive sarcomas; 1 was negative for fusion or sequence variants, and sequencing failed in the other. In conclusion, most fibrosarcoma-like tumors of the gynecologic tract are defined by either tyrosine kinase fusions or ERBB2/3 mutations. Immunohistochemistry can be used to predict these subgroups to guide confirmatory genetic testing and targeted therapies.
2026-07-14 | Case Report: A case series on actionable genomic alterations guiding effective targeted therapy in rare sarcomas.
Advanced sarcomas have limited systemic therapy options, but genomic profiling can uncover actionable mutations. This case series illustrates the promise and limitations of next-generation sequencing (NGS) and targeted therapies in clinical practice across three sarcoma histologies. Case 1: A 36-year-old woman received local therapies for an angiosarcoma in her breast. Six months later, she developed osseous metastatic disease, and NGS revealed a GOPC-ROS1 fusion. She had a partial response to crizotinib. This ROS1 inhibitor and one course of radiation for oligometastatic progression controlled her disease for 12 months. Subsequent lines of therapy included pembrolizumab for high PD-L1 status, with suspected hyperprogression. Repotrectinib was trialed to overcome her ROS1 G2032R resistance mutation, but it had limited efficacy. She ultimately succumbed to her disease. Case 2: A 30-year-old woman with Neurofibromatosis Type 1 developed a high-grade, ALK-rearranged peripheral malignant nerve sheath tumor at her left antecubital fossa. Following resection, pulmonary metastases were identified. RNA transcriptome analysis revealed an EML4-ALK rearrangement. She had a prolonged partial response to alectinib. The ALK inhibitor and two courses of radiation for oligoprogression have continued to control her disease at 48 months. Case 3: A 51-year-old woman with uterine leiomyosarcoma developed pulmonary metastases shortly after completing adjuvant radiation. NGS revealed a BRCA2 deep deletion. After progressing on multiple lines of systemic therapies, her widely metastatic disease has been controlled for 62 months with niraparib and local therapies for oligoprogression. Three patients with advanced sarcomas achieved partial responses to NGS-guided targeted therapies, with disease control lasting from 1 to over 5 years. Two cases involved novel, targetable mutations not previously identified in these sarcoma subtypes. However, the limitations of targeted therapies are highlighted by one patient's lack of response to a novel ROS1 G2032R-directed treatment, and another patient's repeated oligometastatic progression despite using an ALK inhibitor without resistance mutations. Simply suppressing a driver-mutation clone with targeted therapy may be insufficient for long-term disease control in sarcoma. Local therapies can be critical adjuvants in achieving improved outcomes for aggressive sarcomas. We recommend careful consideration of NGS testing for all sarcomas as we continue to explore their vast mutational landscape, response to targeted therapies, and mechanisms of resistance.
2026-07-10 | A High-Fidelity and Ancestrally Inclusive Patient-Derived Organoid Platform Resolves Cancer Cell Plasticity in Uterine Carcinosarcoma.
Uterine carcinosarcoma (UCS) is a rare but extremely lethal endometrial cancer that metastasizes early and resists current treatment modalities. It is biphasic, built from malignant epithelial and mesenchymal cells. Genomic studies indicate that these tumors are clonal, and that the mesenchymal cells arise from the epithelial cells through cancer cell plasticity. This biology has been hard to study, because faithful patient-derived models are scarce. The gap is widened by inequity. Women of African ancestry carry the greatest burden of UCS, yet are underrepresented in existing models. To address this, we established patient-derived organoids (PDOs) from an ancestrally inclusive UCS cohort, alongside matched normal endometrial PDOs. The organoids reproduced the biphasic histology of the original tumors. Across four sequencing platforms, they retained the tumor mutation and copy-number landscape, remained stable across passages, and expanded for up to 28 months. At single-cell resolution, UCS PDOs captured both malignant compartments and traced continuous transcriptional trajectories along the epithelial-to-mesenchymal axis, capturing patient-specific cancer cell plasticity. The models also nominated candidate vulnerabilities in proof-of-concept therapeutic testing. UCS PDOs were enriched for CREB-family transcriptional programs, and CREB inhibition reduced their viability. Combined FGFR and YAP inhibition outperformed either agent alone. Together, this work delivers a histologically, genomically, and transcriptionally faithful, ancestrally inclusive, and lineage-resolved UCS organoid platform for studying cancer cell plasticity and its vulnerabilities in an aggressive and inequitably burdened cancer.
antibodies
2026-09-19 | Durable disease control following multidisciplinary treatment including pembrolizumab in POLE-mutated dedifferentiated endometrial carcinoma with brain metastases: A case report.
Dedifferentiated endometrial carcinoma (DEC) is a rare and aggressive subtype of endometrial cancer comprising undifferentiated carcinoma and a low-grade endometrioid component. Although POLE-mutated tumors usually show favorable outcomes owing to their ultramutated and immunogenic nature, the clinical relevance of POLE mutations in DEC remains unclear. In particular, the therapeutic effects of immune checkpoint inhibitors in POLE-mutated DEC with brain metastases have not been well characterized. Here, we report the case of a 58-year-old woman with POLE-mutated DEC who presented with headache, dizziness, and generalized weakness due to multiple brain and pulmonary metastases. The clinical course, pathological and genomic findings, multidisciplinary treatment, and treatment outcomes were evaluated. Endometrial biopsy confirmed dedifferentiated carcinoma. Genomic profiling identified a pathogenic POLE exonuclease domain mutation (V411L) and a high tumor mutational burden (49.7 mutations/Mb). The patient underwent urgent cerebellar resection, followed by radiotherapy, during which a new intracranial lesion developed. Systemic therapy with carboplatin, paclitaxel, and pembrolizumab resulted in marked regression of uterine and pulmonary lesions. Her symptoms resolved completely, and the Eastern Cooperative Oncology Group performance status improved from 2 to 0. During maintenance pembrolizumab therapy, further tumor regression was observed, and durable disease control was maintained thereafter. At 14 months, the patient remained progression-free without significant adverse events. This case demonstrated a dramatic and sustained response following multidisciplinary treatment, including surgery, radiotherapy, chemotherapy, and immune checkpoint inhibitor therapy, in POLE-mutated DEC with brain metastases. This highlights the importance of molecular profiling in identifying patients who may benefit from immunotherapy, even in aggressive and widely metastatic disease.
2026-09-19 | Clear Cell Carcinoma With Enteroblast-Like Differentiation Involving Multiple Gynecologic Sites: An Integrated Clinicopathologic, Whole-Exome, and Transcriptomic Analysis.
Clear cell carcinoma with enteroblastic differentiation arising in the female genital tract is exceptionally rare, and its pathogenesis, diagnostic features, and therapeutic implications remain poorly understood. We report a rare case in a 67-year-old woman with tumor involvement of the cervix, uterine cavity, fallopian tubes, and ovaries, and highlight the value of multi-site sequencing for resolving tumor origin and biological heterogeneity. Histologically, the tumor exhibited a fetal intestinal-like morphology with glycogen-rich clear cytoplasm. Immunohistochemistry revealed positive staining for HNF1β, with variable immunoreactivity for Glypican-3 and SALL4. Multi-site whole-exome sequencing revealed marked inter-lesional genomic heterogeneity, divergent clonal evolution, and a molecular phylogenetic pattern supporting the fallopian tube as the most likely primary site. RNA sequencing further demonstrated a more immunogenic microenvironment in the fallopian tube lesion, characterized by increased infiltration of CD4+ T cells and B cells and a higher immunophenoscore, suggesting potential sensitivity to immunotherapy. Comparison with previously reported cases also helped define immunophenotypic features of diagnostic relevance. Collectively, this case underscores the value of integrating clinicopathologic evaluation with multi-site whole-exome and transcriptomic sequencing to refine diagnosis, infer tumor origin, and identify potential therapeutic opportunities in this rare gynecologic tumor subtype.
2026-08-25 | Frequency of mismatch repair deficiency for primary endometrial neuroendocrine carcinoma and its therapeutic outcome in Japan.
To investigate the frequency of mismatch repair (MMR) deficiency in primary endometrial neuroendocrine carcinoma (PENEC) and analyze its therapeutic outcomes in Japan. A multicenter retrospective study of 17 cases of PENEC diagnosed between 2011 and 2023 was conducted. MMR status was evaluated by immunohistochemistry, and clinical outcomes were assessed. Among the 17 cases, 10 (58.8%) were diagnosed at advanced stages (stage III and Ⅳ). The median overall survival was 16 months, indicating extremely poor prognosis. MMR deficiency was observed in 41% of cases, a rate higher than that reported for other endometrial cancer subtypes. PENEC demonstrates aggressive behavior and poor prognosis compared to other histological subtypes of endometrial cancer. The higher rate of MMR deficiency suggests that immune checkpoint inhibitors may serve as key components of initial treatment strategies, potentially contributing to improved outcomes for this rare and aggressive malignancy.
2026-06-12 | Clinicopathologic Study of 39 Mismatch Repair-deficient Sarcomas Demonstrates Recurrent Histologic Patterns and Supports Universal Screening of Pleomorphic Rhabdomyosarcoma, Uterine Leiomyosarcoma, and Undifferentiated and Unclassified Sarcomas.
Mismatch repair-deficient (dMMR) sarcomas are rare and incompletely characterized. Here, we studied 39 sarcomas with high microsatellite instability (MSI-H) and/or biallelic MMR gene inactivation (21 MSH2, 9 MLH1, 4 PMS2, 4 MSH6, 1 EPCAM). All tumors evaluated with immunohistochemistry (IHC; n = 36) showed loss of MMR protein expression. Eight sarcomas were index neoplasms among the 15 patients with documented Lynch syndrome. Eighteen of 1531 sarcomas (1.2%) in our sequencing database were dMMR, with enrichment in pleomorphic rhabdomyosarcoma (PRMS; 1/5), uterine leiomyosarcoma (LMS; 7/124; 5.6%), and unclassified/undifferentiated pleomorphic sarcoma (UPS; 6/259; 2.3%). MMR IHC screening of independent cases confirmed MMR deficiency in PRMS (2/20), uterine LMS (2/20), and unclassified/UPS (1/20). Two histologic patterns were identified among unclassified/UPS. Ten tumors, designated "distinctive lobulated inflammatory sarcoma" (DLIS), showed lobular architecture, florid inflammation, and histiocytoid, variably pleomorphic neoplastic cells. All 6 patients with DLIS and follow-up (median: 6.0 y; range: 3 mo to 8.6 y) were alive with no evidence of disease (ANED), and 2 DLIS responded completely to immune checkpoint inhibition. A morphologically different group of 6 unclassified high-grade sarcomas showed sheets of epithelioid-to-rhabdoid cells with eosinophilic cytoplasm; among 5 patients with follow-up (median: 1.1 y; range: 4 mo to 6.9 y), only 1 was ANED. Surprisingly, all 3 PRMS patients with follow-up (median: 5.7 y; range: 4.2 to 8.3 y) were ANED, including 2 with complete responses of metastases to systemic therapy. We conclude that PRMS, uterine LMS, and unclassified/UPS showed sufficiently prevalent MMR deficiency to justify prospective MMR IHC screening for Lynch syndrome and to identify patients who might benefit from immune checkpoint inhibition. Histologic subtyping of unclassified sarcomas predicted prognosis and therapeutic response. We propose universal MMR IHC screening of (1) PRMS, (2) uterine LMS, (3) unclassified/UPS, and (4) any sarcoma in a patient with a personal or family history of Lynch syndrome.
2026-05-11 | Prolonged disease-free survival with immunotherapy combined with chemotherapy in a patient with advanced stage large cell neuroendocrine carcinoma of the uterus.
Large Cell Neuroendocrine Carcinoma (LCNEC) is a rare and aggressive high-grade neuroendocrine malignancy that only infrequently arises in the uterus. Owing to its rarity, there are no standardized treatment guidelines, and management is generally extrapolated from neuroendocrine carcinomas of the lung or cervix. Data on the role of immune checkpoint inhibition in uterine LCNEC are lacking. We report, to our knowledge, the first case of mismatch repair (MMR)-deficient endometrial LCNEC treated with multimodal therapy including adjuvant chemotherapy, radiation, and maintenance immunotherapy, resulting in prolonged disease-free survival. A 62-year-old woman presented with postmenopausal bleeding. Endometrial biopsy showed poorly differentiated endometrial adenocarcinoma. Computed tomography revealed a uterine mass, prominent left adnexa, and retroperitoneal, para-aortic, and right external iliac lymphadenopathy. She underwent exploratory laparotomy, total abdominal hysterectomy, bilateral salpingo-oophorectomy with radical debulking, right pelvic lymph node dissection, and para-aortic lymphadenectomy, achieving no gross residual disease. Histopathology demonstrated a mixed carcinoma with a predominant LCNEC component (∼95%) and focal endometrioid adenocarcinoma (∼5%), with full-thickness myometrial and cervical invasion, parametrial involvement, extensive lymphovascular invasion, and metastases to multiple pelvic and para-aortic nodes, consistent with FIGO 2023 stage IIIC2. The tumor was MMR-deficient with loss of MLH1 and PMS2, p53 wild type, HER2-negative, FOLR1-negative, and PD-L1 combined positive score of 10. Post-operatively, she received six cycles of carboplatin, paclitaxel, and dostarlimab every three weeks, followed by maintenance dostarlimab. Given the extent of local disease, she also received vaginal brachytherapy and external beam radiation to the pelvis and para-aortic regions. At 29 months post-operation, she remains on maintenance immunotherapy with excellent functional status and no radiographic evidence of disease. This case illustrates that aggressive multimodal therapy including immune checkpoint inhibition may achieve durable disease control in advanced-stage MMR-deficient uterine LCNEC. While the relative contributions of surgery, chemotherapy, radiation, and immunotherapy cannot be separated, the favorable outcome supports further investigation of immunotherapy in rare high-grade endometrial neuroendocrine carcinomas and underscores the importance of including these histologies in clinical trials.
oligonucleotides
2025-09-22 | Downregulation of Chromosome 19 miRNA Cluster and the Tumor-Suppressive Role of miR-517a-3p in Choriocarcinoma.
Choriocarcinoma is a rare gynecologic malignancy. MicroRNAs, which are noncoding RNAs approximately 22 nucleotides in length, are known to regulate gene expression and play important roles in various cancers; however, their functions in choriocarcinoma remain largely unknown. This study aimed to identify disease-specific microRNAs involved in choriocarcinoma development. Eleven cases of choriocarcinoma and five cases of complete hydatidiform mole treated at our institution were analyzed. Total RNA was extracted from trophoblast cells in formalin-fixed, paraffin-embedded specimens using laser capture microdissection, and microRNA sequencing was performed. The analysis revealed that 87 microRNAs were significantly upregulated, whereas 28 were downregulated in choriocarcinoma compared to complete hydatidiform mole. Notably, 13 of the 28 downregulated microRNAs belonged to the chromosome 19 microRNA cluster. In vitro experiments demonstrated that overexpression of miR-517a-3p, a representative member of this cluster, significantly suppressed cell proliferation, migration, and invasion in JEG-3 and BeWo cell lines. Further transcriptome sequencing and computational analysis identified SRSF1 as a target gene of miR-517a-3p, which was validated by dual-luciferase reporter assays. Knockdown of SRSF1 also led to significant reductions in proliferation, migration, and invasion, supporting its functional relevance. Immunohistochemical analysis confirmed that SRSF1 protein was highly expressed in choriocarcinoma tissues compared to complete hydatidiform mole. These findings indicate that downregulation of the chromosome 19 microRNA cluster is a characteristic feature of choriocarcinoma and that miR-517a-3p functions as a tumor suppressor by directly regulating SRSF1 expression.
2023-05-17 | Monitoring Treatment Response, Early Recurrence, and Survival in Uterine Serous Carcinoma and Carcinosarcoma Patients Using Personalized Circulating Tumor DNA Biomarkers
Uterine serous carcinoma (USC) and carcinosarcomas (CSs) are rare, highly aggressive variants of endometrial cancer. No reliable tumor biomarkers are currently available to guide response to treatment or detection of early recurrence in USC/CS patients. Circulating tumor DNA (ctDNA) identified using ultrasensitive technology such as droplet digital polymerase chain reaction (ddPCR) may represent a novel platform for the identification of occult disease. We explored the use of personalized ctDNA markers for monitoring USC and CS patients. Tumor and plasma samples from USC/CS patients were collected at the time of surgery and/or during the treatment course for assessment of tumor-specific somatic structural variants (SSVs) by a clinical-grade next-generation sequencing (NGS) platform (i.e., Foundation Medicine) and a droplet digital PCR instrument (Raindance, ddPCR). The level of ctDNA was quantified by droplet digital PCR in plasma samples and correlated to clinical findings, including CA-125 serum and/or computed tomography (CT) scanning results. The genomic-profiling-based assay identified mutated "driver" target genes for ctDNA analysis in all USC/CS patients. In multiple patients, longitudinal ctDNA testing was able to detect the presence of cancer cells before the recurrent tumor was clinically detectable by either CA-125 or CT scanning. Persistent undetectable levels of ctDNA following initial treatment were associated with prolonged progression-free and overall survival. In a USC patient, CA-125 and TP53 mutations but not PIK3CA mutations become undetectable in the plasma at the time of recurrence, suggesting that more than one customized probe should be used for monitoring ctDNA. Longitudinal ctDNA testing using tumor-informed assays may identify the presence of residual tumors, predict responses to treatment, and identify early recurrences in USC/CS patients. Recognition of disease persistence and/or recurrence through ctDNA surveillance may allow earlier treatment of recurrent disease and has the potential to change clinical practice in the management of USC and CS patients. CtDNA validation studies in USC/CS patients prospectively enrolled in treatment trials are warranted.
2020-10-26 | 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.
2020-04-27 | miR-522 facilitates the prosperities of endometrial carcinoma cells by directly binding to monoamine oxidase B.
It is well known that microRNAs (miRNAs) are crucial regulatory factors in tumorigenesis, as tumor suppressors or cancer-promoting factors. However, the study of endometrial carcinoma relevance in miR-522 is rare, indicating an undefined molecular mechanism for its role. Therefore, we performed this study to examine the role of miR-522 on the biological behaviors of endometrial carcinoma. In this work, we found that miR-522 was highly expressed in endometrial carcinoma and negatively regulated monoamine oxidase B (MAOB) expression. They also have the opposite effect on prognosis of endometrial carcinoma patients. More importantly, miR-522 could decreased MAOB expression by binding to MAOB with a putative site, thereby promoting cell proliferation, migration, and invasion through in vitro functional analyses, including MTT assay, wound-healing and transwell invasion experiments. Upregulation of MAOB rescued the impacts of miR-522 mimic on cell behaviors. In conclusion, our observations demonstrated that miR-522 accelerated the progression of endometrial carcinoma by inhibiting MAOB, which might lead to a novel therapeutic therapy for endometrial carcinoma.
2018-07-20 | LncRNA MEG3 inhibit endometrial carcinoma tumorigenesis and progression through PI3K pathway.
Long noncoding RNAs (lncRNAs) are RNA molecules more than 200 nucleotides in length that do not encode proteins. Recent studies have reported increasing numbers of functional lncRNAs. Maternally expressed gene 3 (MEG3) is a maternally imprinted gene encoding an lncRNA that plays a tumor suppressor role in various tumors. However, there has been rare report on mechanism of tumorigenesis and progression of endometrial carcinoma. In the present study, we found significantly lower MEG3 expression in endometrial carcinoma tissues than in normal endometrial tissues. MEG3 overexpression inhibited endometrial cancer cell proliferation, invasion, and metastasis; promoted apoptosis; and inhibited the activation of the phosphoinositide 3-kinase (PI3K)/m-TOR signaling pathway. RNA immunoprecipitation assay (RIP) showed that MEG3 can combine directly with PI3K. Tumor xenograft implantation in nude mice showed that MEG3 could significantly suppress tumor growth. These findings provide potential new therapeutic targets for treating endometrial cancer.
cell therapies
2026-09-23 | Fertility-sparing surgery for a patient with a pre-operative suspected diagnosis of a Uterine Smooth Muscle Tumor of Uncertain Malignant Potential (STUMP): A case report.
Uterine smooth muscle tumors of uncertain malignant potential (STUMPs) are rare tumors that share features with benign leiomyomas and malignant leiomyosarcomas. The standard treatment is a total hysterectomy for those without intentions of future pregnancy. However, myomectomy has been reported as a potential fertility-sparing option based on retrospective data. We report a case of a healthy 34-year-old gravida 0 patient with a history of fibroids and chronic pelvic pain who presented for a fertility evaluation. She was referred to minimally invasive gynecologic surgery for management of a uterine fibroid and underwent a hysteroscopic partial myomectomy. Initial pathology of the biopsy was concerning for STUMP. A follow-up MRI and PET CT showed no evidence of abnormal features or uptake in the lesion or metastasis. The patient strongly desired future fertility. After shared decision making with the patient and consultation with gynecologic oncology, a fertility-sparing surgical approach was taken. She subsequently underwent an abdominal myomectomy without morcellation. Final pathology of the lesion was benign and consistent with symplastic leiomyoma, or leiomyoma with bizarre nuclei (LBN). In patients desiring future fertility and concern for STUMP, myomectomy without morcellation and continued surveillance can be considered as an alternate treatment option.
2026-06-23 | Fertility-sparing strategy in a rare case of uterine adenosarcoma and consecutive spontaneous pregnancy and livebirth.
We present the rare case of a 29-year-old patient with uterine adenosarcoma who received fertility-sparing treatment, subsequently conceived spontaneously, and gave birth to a healthy infant. In August 2022, the nulliparous patient presented with acyclic uterine bleeding. Diagnostic hysteroscopy and targeted resection of a polyp located at the cervicouterine junction revealed uterine adenosarcoma without sarcomatous overgrowth (FIGO stage T1a). Imaging confirmed no residual tumor or metastasis. A fertility-sparing management strategy was chosen, avoiding hysterectomy but involving close oncological surveillance with quarterly MRI scans. During follow-up, a concurrent diagnosis of symptomatic endometriosis introduced therapeutic challenges. The patient spontaneously conceived in 2023 and delivered a healthy infant by cesarean section at term in 2024. Subsequent hysteroscopy and imaging in 2025 showed no evidence of recurrence, therefore fertility-preserving management was continued. A short narrative of the patient's perspective on her initial diagnosis, possible fertility loss, and the emotional turmoil of pregnancy after uterine adenosarcoma is presented. Treating young patients diagnosed with uterine adenosarcoma poses a challenge to the treating physician due to the lack of guidelines and evidence regarding fertility-preserving treatment of this rare tumor. This report adds to the limited literature on successful pregnancy after uterine adenosarcoma and discusses indications and limitations of fertility-sparing treatment. Fertility preservation may be possible in selected early-stage uterine adenosarcoma cases without high-risk features such as sarcomatous overgrowth or myometrial invasion, with thorough counseling and strict follow-up. Further research is needed to develop standardized protocols and improve management in this context.
2026-06-18 | Balancing Fertility and Oncologic Uncertainty: Robotic Myomectomy With Bilateral Uterine Artery Ligation for Smooth Muscle Tumor of Uncertain Malignant Potential (STUMP).
Smooth muscle tumor of uncertain malignant potential (STUMP) is a rare uterine neoplasm characterized by ambiguous histopathological features and unpredictable clinical behavior. Management is particularly challenging in young, nulliparous women, where the standard approach of hysterectomy conflicts with fertility preservation. We report a case of a young nulliparous woman who underwent fertility-preserving robotic myomectomy with bilateral uterine artery ligation for a presumed atypical leiomyoma, later diagnosed as STUMP on histopathology. This case highlights the diagnostic limitations of preoperative assessment, the intraoperative decision-making involved in fertility-sparing surgery, and the role of robotic-assisted techniques in optimizing surgical precision and uterine preservation. In the absence of standardized management guidelines, treatment of STUMP requires individualized decision-making, balancing oncologic risk with reproductive goals. Careful patient selection, multidisciplinary evaluation, and long-term surveillance are essential. This case supports the feasibility and safety of a conservative robotic approach in selected patients.
2026-02-06 | Fertility-sparing vs hysterectomy for uterine STUMP: A pragmatic clinical study.
Uterine smooth muscle tumors of uncertain malignant potential (STUMP) are rare neoplasms with unpredictable clinical behavior. Optimal management, particularly in reproductive-aged women, remains controversial, with limited data comparing the safety of fertility-sparing versus hysterectomy. This multicentre retrospective cohort study included women aged 18-85 with histologically confirmed STUMP treated at 17 Italian gynecologic oncology centers from 2010 to 2023. Patients underwent either fertility-sparing surgery (myomectomy or hysteroscopic resection) or definitive surgery (hysterectomy ± salpingo-oophorectomy). Kaplan-Meier and Cox models were used to compare recurrence-free survival (RFS) and overall survival (OS). Median (range) follow-up was 51 (1-291) months. Among 401 women, 106 (26.4 %) received fertility-sparing treatment (mean [± SD] age: 35.3 ± 6.8 years) and 295 (73.6 %) underwent definitive surgery (mean [± SD] age: 47.7 ± 9.2). At total follow-up, recurrence occurred in 12.5 % of patients, predominantly within the pelvis. Median RFS was longer after definitive surgery than after fertility-sparing procedures (50.0 vs 42.5 months; HR 2.39 [95 % CI 1.36-4.19]), although this difference disappeared when benign (leiomyoma) recurrences were excluded (HR 1.74 [95 % CI 0.90-3.34]). At last available follow-up, 97.5 % of patients were alive, with no significant OS difference between treatment groups (HR 0.22 [95 % CI 0.27-1.79]). Outcomes were comparable across menopausal status and concurrent adnexal removal. Definitive surgery reduces recurrence risk, but long-term survival is similarly excellent after fertility-sparing surgery in appropriately selected women with STUMP. Conservative management represents a reasonable option for patients desiring fertility, provided they receive counseling regarding recurrence risk, diagnostic uncertainty, and the need for long-term surveillance.
2025-09-15 | Establishment of KGAS, a cell line derived from gastric-type adenocarcinoma of the uterine cervix.
Gastric-type adenocarcinoma (GAS) of the uterine cervix is a rare and aggressive subtype of cervical adenocarcinoma characterized by intrinsic resistance to chemotherapy and poor clinical outcomes due to the lack of effective treatment options. To address this critical unmet need, we established a novel GAS-derived cell line, KGAS, from ascitic fluid collected from a patient with recurrent GAS. Short tandem repeat (STR) analysis confirmed the genetic identity between the primary tumor and the cell line. Upon transplantation into immunocompromised mice, KGAS cells formed tumors that expressed Claudin-18 and MUC6, clinically recognized markers of GAS. Furthermore, KGAS cells exhibited marked resistance to paclitaxel and carboplatin, showing significantly reduced growth inhibition compared to HeLa cells. We also established a paclitaxel- and carboplatin-resistant subline, rKGAS, and performed microRNA (miRNA) sequencing to explore the molecular basis of acquired chemoresistance. Seventeen differentially expressed miRNAs were identified between KGAS and rKGAS cells. Upregulated miRNAs in rKGAS were predicted to target oncogenes such as BCL2, MET, SIRT1, and VEGFA, whereas downregulated miRNAs were associated with tumor suppressor genes, including IGF1R, TNFAIP3, and MTOR. The KGAS and rKGAS cell lines represent valuable preclinical models for elucidating the molecular mechanisms of chemoresistance and malignant progression in cervical GAS, and may contribute to the development of novel therapeutic strategies for this challenging cancer subtype.
other
2025-12-23 | Immune thrombocytopenia triggered by dostarlimab in a patient with endometrial carcinoma: first reported case.
Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for various malignancies, but they are associated with a range of immunerelated adverse events, including rare hematological complications. Immune thrombocytopenia (ITP) has been reported with other antiPD1 agents such as nivolumab and pembrolizumab, but to date, no cases have been described with dostarlimab. We report the first case of ITP in a patient receiving dostarlimab for relapsed endometrial carcinoma. A 55yearold woman developed severe thrombocytopenia (3 × 109/L) accompanied by rectal bleeding, resulting in a lifethreatening condition. Secondary causes were excluded, and bone marrow findings supported a diagnosis of ITP. Initial treatment with highdose corticosteroids and intravenous immunoglobulin achieved only a partial response, while sustained platelet recovery was obtained with the addition of romiplostim. The patient remained on dostarlimab following hematological recovery without further episodes of ITP. This case highlights a potentially lifethreatening adverse effect of a widely used immunotherapy and underscores the importance of early recognition and timely escalation of treatment in ICIinduced ITP.
2025-09-22 | Immunotherapy for high-grade endometrial stromal sarcoma: a narrative review bridging molecular insights to clinical translation.
High-grade endometrial stromal sarcoma (HGESS) is a rare solid malignancy characterized by a poor prognosis and highly aggressive behavior. Currently, surgical resection remains the primary treatment for HGESS. Radiotherapy and chemotherapy can address local symptoms and enhance the quality of life of patients; however, they do not improve patient survival rates. Recent studies have found that the molecular characteristics of HGESS (such as gene fusions like YWHAE-NUTM2, ZC3H7B-BCOR, etc.) drive the high invasiveness of the tumor. Although immunotherapy has achieved significant breakthroughs in solid tumors, the immunosuppressive microenvironment of HGESS remains a key focus for future immunotherapy research. This narrative review comprehensively analyzes the interactions between alterations in the tumor microenvironment and immune escape mechanisms in HGESS. It also proposes a diverse range of immunotherapy options, including Oncolytic virus therapy, adoptive cell transfer therapy, immune checkpoint inhibitors, cancer vaccines, and combination strategies. We hold the view that a profound comprehension of the molecular immunological characteristics of HGESS, the identification of effective biomarkers, and the implementation of well-designed clinical studies are the indispensable routes to successfully translate immunotherapy into an effective treatment for this intractable HGESS.
2025-04-24 | Retrospective analysis of treatment and prognosis for clear cell carcinoma of the uterine cervix: 15-year experience at a single institution.
Clear cell carcinoma of the uterine cervix (CCCUC) is a rare disease, accounting for 4% to 9% of cervical adenocarcinomas. Because it is so rare, its pathogenesis is largely unknown, and the standard treatment is unclear due to a lack of prospective studies. Our aim is to investigate the clinical features, treatment, and prognosis of CCCUC. We retrospectively evaluated the clinical characteristics, treatment choices, and outcomes of 12 patients with CCCUC treated at our institution between January 2009 and July 2024. The median patient age was 62.5 years (range, 14-90 years). The most common stage was IB (IA, n = 3; IB, n = 4; IIB, n = 1; IIIC, n = 2; IVB, n = 2). Ten patients underwent surgery as initial treatment: 6 underwent radical hysterectomy plus pelvic lymphadenectomy (PLD) or sentinel lymph node biopsy (SLNB), with or without para-aortic lymphadenectomy (PALD); 3 underwent modified radical hysterectomy plus PLD with or without PALD; and 1 underwent radical trachelectomy with SLNB as fertility-preserving surgery. All patients underwent bilateral salpingo-oophorectomy except for the patient who opted for radical trachelectomy. Five patients received adjuvant treatment: 3 received platinum-based systemic chemotherapy (2 of whom had combination therapy with bevacizumab), and 2 received concurrent chemoradiotherapy. The median follow-up was 43.5 months (range, 1-123 months). The 5-year progression-free survival rate was 64.5%. Systemic platinum-based chemotherapy with bevacizumab may be more effective than concurrent chemoradiotherapy as adjuvant therapy for CCCUC.
2025-03-23 | Immunogenicity and safety of an Escherichia coli-produced bivalent human papillomavirus vaccine (Cecolin) in girls aged 9-14 years in Ghana and Bangladesh: a randomised, controlled, open-label, non-inferiority, phase 3 trial.
Human papillomavirus (HPV) vaccines have been available for nearly 20 years. However, the overall coverage of girls aged 15 years and younger is low, especially in low-resource settings, where the burden of cervical cancer is highest. Increasing access and facilitating implementation of HPV vaccination will contribute to cervical cancer elimination efforts. To generate data in different dosing regimens and in low-resource settings, we aimed to evaluate the safety and immunogenicity of various schedules of an Escherichia coli-expressed bivalent HPV vaccine (2vHPV) compared with a widely used quadrivalent vaccine. This randomised, controlled, open-label, non-inferiority, phase 3 trial enrolled healthy girls aged 9-14 years from single sites in Ghana and Bangladesh. Participants were randomly assigned via interactive web response system technology equally into five study groups, stratified by site: two doses of 2vHPV, the first at baseline and the second 6, 12, or 24 months later; a quadrivalent HPV vaccine (4vHPV) at baseline followed 24 months later by 2vHPV; or two doses of 4vHPV given 6 months apart (referent). We tested for antigen-specific (HPV-16 and HPV-18) binding antibodies by ELISA at baseline and before and 1 month after the second dose. The primary objective was to show immunological non-inferiority of the 2vHPV vaccine schedules to the referent 1 month after the second dose in the per-protocol population, with a non-inferiority margin of 0·5 for the lower bound of the 98·3% CI for the geometric mean concentration (GMC) ratio. Adverse events and serious adverse events were evaluated as secondary endpoints in the total vaccinated population. The study is registered at ClinicalTrials.gov (NCT04508309) and is completed. Between March 15 and Nov 18, 2021, 1025 girls were enrolled and received 2vHPV at baseline and 6 months (n=205), 12 months (n=206), or 24 months (n=204); 4vHPV at baseline and 6 months (n=205); or 4vHPV at baseline and 2vHPV at 24 months (n=205). 96-99% of participants across groups were included in the per-protocol analysis. 1 month after the second dose, 2vHPV non-inferiority was shown, with GMC ratios between 1·1 and 2·4 (lower bound of the 98·3% CI of the GMC ratio between 0·9 and 1·9) for HPV-16, and between 1·3 and 1·7 (1·0 and 1·4) for HPV-18. As an exploratory objective, we assessed 2vHPV immunogenicity after one dose, finding that it was similar to that of 4vHPV up to 24 months, with GMC ratios at 24 months of 1·1 (95% CI 0·9-1·4) for HPV-16 and 1·4 (1·1-1·7) for HPV-18. The frequency of adverse events was similar across study groups, with no related unsolicited events reported. Serious adverse events were rare and none were determined to be related to vaccination. Non-inferior immune responses for extended two-dose regimens of 2vHPV support dosing flexibility. For up to 24 months, one dose of 2vHPV elicited immunogenicity that was similar to one dose of 4vHPV, for which single-dose efficacy has been shown, supporting a single-dose use of 2vHPV. The Bill & Melinda Gates Foundation and the German Federal Ministry of Education and Research and immunological testing was funded in part by the National Cancer Institute, National Institutes of Health. For the Bengali translation of the abstract see Supplementary Materials section.
2025-01-27 | Surgical management of endometrial cancer in patient with musculocontractural Ehlers-Danlos Syndrome harboring pathogenic variants in CHST14 (mcEDS-CHST14): A case report.
Musculocontractural Ehlers-Danlos syndrome (mcEDS) is a rare autosomal recessive connective tissue disorder caused by systemic depletion of dermatan sulfate. Symptoms characteristic of mcEDS include multiple contractures, fragile skin with subcutaneous bleeding, and hypermobile joints, which suggest difficulty in perioperative management. However, safe surgical techniques and perioperative management of this disorder remain unknown because of its rarity. We report a patient with mcEDS who developed endometrial cancer and underwent surgery, with emphasis on perioperative management. A female patient, who had been genetically diagnosed with mcEDS-CHST14 at the age of 25, presented with symptoms characteristic of mcEDS, including: congenital contractures of fingers and clubfeet, recurrent joint dislocation, progressive foot and spinal deformities, and large subcutaneous hematomas. At age 33, she had been diagnosed with atypical endometrial hyperplasia, and scheduled to undergo total abdominal hysterectomy. To address the risk of massive hemorrhage during the surgery due to mcEDS-related tissue fragility, plasma-derived factor VIII concentrate was prophylactically administered before surgery. During the surgery, neither fragility, hyperextensibility, nor hemorrhagic tendency of the uterus or adnexa observed was observed. The surgery was uneventful, with blood loss of 180 mL and operative time of 2 h and 54 min. However, on the sixth postoperative day, a 2.5-cm dissection was noted at the site of skin incision. Subcutaneous fluid accumulation developed under the skin incision and it persisted for 1.5 months. The postoperative pathological diagnosis was endometrioid carcinoma grade 1, stage IA. The present case suggested that the prophylactic use of factor VIII was effective for the prevention of hemorrhage during surgery. However, delayed wound healing of the skin and subcutaneous tissues was considered a subject for future improvement.
small molecules
2026-09-26 | A Review of Proteomic Studies in Uterine Leiomyosarcoma: Biomarkers, Pathways, and Clinical Potential.
Uterine leiomyosarcoma (uLMS) is a rare but highly aggressive mesenchymal malignancy of smooth-muscle origin that represents a significant therapeutic challenge due to its poor prognosis and limited treatment options. Despite advances in molecular characterization, diagnosis remains difficult, and systemic therapies have shown limited success, contributing to a high recurrence rate and poor survival. Recent proteomic investigations have provided new insights into uLMS biology by exploring the global protein expression patterns that define malignant transformation and progression. Using high-resolution mass spectrometry (MS)-based techniques, quantitative proteomics, and integrated multi-omics approaches, researchers have begun to identify dysregulated proteins, signaling pathways, and post-translational modifications (PTMs) linked to tumor metabolism, extracellular matrix (ECM) remodeling, cell-cycle regulation, and chemoresistance. These studies have also uncovered candidate biomarkers that may improve the discrimination of uLMS from benign leiomyoma and have proposed novel therapeutic targets associated with metabolic reprogramming, kinase activation and tumor microenvironment (TME) modulation. This review summarizes recent advancements in uLMS proteomics, discusses their methodological underpinnings, highlights key molecular mechanisms and biomarkers, and explores their translational potential. Finally, we outline current limitations and future directions toward clinical implementation of proteomic findings in precision oncology for uLMS patients.
2026-09-21 | Integrated Genomic Profiling of PTEN and TP53 in Cervical Neuroendocrine Carcinoma: Synergistic Roles With HER2/KRAS/PIK3CA and Implications for Precision Oncology.
Neuroendocrine carcinoma (NEC) of the uterine cervix is a rare, highly aggressive malignancy with a poor prognosis. Expanding upon our previous work, which identified frequent mutations in HER2, KRAS, and PIK3CA in this disease, we sought to refine the genomic landscape by characterizing alterations in TP53 and PTEN, and their relationships with these oncogenic drivers. Genomic DNA from 12 cervical NECs with ≥ 50% tumor cellularity underwent targeted next-generation sequencing (NGS) using the Qiagen GeneRead DNAseq Targeted Panels V2. Variants were filtered against COSMIC and ClinVar, and the pathogenicity of missense changes was assessed with PolyPhen-2, with scores > 0.85 considered probably damaging. PTEN alterations were identified in 25.0% (3/12) of tumors, encompassing four truncating mutations (p.W111*, p.Q171*, p.Q245*, p.R335*) and three missense variants (p.R130Q, p.E394G, p.D395V). A TP53 DNA-binding domain hotspot mutation, p.R273H, was detected in 8.33% (1/12). These tumor-suppressor lesions frequently co-occurred with oncogenic driver mutations, including HER2/PTEN (8.33%), PIK3CA/PTEN (8.33%), and a KRAS/PTEN/TP53 "triple-hit" (8.33%), underscoring multipathway genomic complexity. Our findings suggest a genomic landscape consistent with a multihit hypothesis in cervical NEC, in which disruption of the reciprocal tumor-suppressive PTEN-p53 axis (25.0% and 8.33%, respectively) co-occurs with oncogenic HER2, KRAS, or PIK3CA alterations. Structural mapping indicates that TP53 p.R273H gain-of-function mutations and PTEN loss-of-function variants are associated with sustained PI3K/AKT/mTOR pathway activation. Integrating TP53 and PTEN status with oncogenic driver profiling may facilitate the identification of biologically defined subsets and inform precision therapeutic strategies for cervical NEC.
2026-08-28 | "Fibrosarcoma-like" Tumors of the Gynecologic Tract Show Distinct Molecular Subgroups: Tyrosine Kinase Fusions and Recurrent ERBB2/3 Mutations.
In recent years, rare fibrosarcoma-like tumors have been identified in the gynecologic tract, characterized by variable CD34 and S-100 positivity and recurrent tyrosine kinase gene fusions in many cases. We identified 17 of these tumors by searching for gynecologic sarcomas expressing S-100 and/or CD34 and supplementing these with cases contributed by collaborating institutions. Tumors involved the uterine cervix (n = 11), uterine corpus (n = 4), and vagina (n = 2). Patients ranged from 28 to 64 (median, 50 years) years. Fifteen tumors showed overlapping morphologic features, including haphazard or fascicular growth of relatively monotonous spindled to ovoid cells with minimal to moderate cytoplasm. Tyrosine kinase gene fusions were identified in 9 tumors, including NTRK fusions in 6 and COL1A1::PDGFB in 3 tumors. Oncogenic variants in ERBB2/ERBB3 were identified in 6 additional tumors. These 2 subgroups showed distinct immunohistochemical profiles, with all tyrosine kinase fusion-positive tumors being CD34 positive, variably S-100 positive, and SOX10 negative. In contrast, the ERBB-altered tumors were CD34 negative and diffusely positive for S-100 and SOX10. The remaining 2 tumors showed morphologic and immunohistochemical overlap with the tyrosine kinase fusion-positive sarcomas; 1 was negative for fusion or sequence variants, and sequencing failed in the other. In conclusion, most fibrosarcoma-like tumors of the gynecologic tract are defined by either tyrosine kinase fusions or ERBB2/3 mutations. Immunohistochemistry can be used to predict these subgroups to guide confirmatory genetic testing and targeted therapies.
2026-07-14 | Case Report: A case series on actionable genomic alterations guiding effective targeted therapy in rare sarcomas.
Advanced sarcomas have limited systemic therapy options, but genomic profiling can uncover actionable mutations. This case series illustrates the promise and limitations of next-generation sequencing (NGS) and targeted therapies in clinical practice across three sarcoma histologies. Case 1: A 36-year-old woman received local therapies for an angiosarcoma in her breast. Six months later, she developed osseous metastatic disease, and NGS revealed a GOPC-ROS1 fusion. She had a partial response to crizotinib. This ROS1 inhibitor and one course of radiation for oligometastatic progression controlled her disease for 12 months. Subsequent lines of therapy included pembrolizumab for high PD-L1 status, with suspected hyperprogression. Repotrectinib was trialed to overcome her ROS1 G2032R resistance mutation, but it had limited efficacy. She ultimately succumbed to her disease. Case 2: A 30-year-old woman with Neurofibromatosis Type 1 developed a high-grade, ALK-rearranged peripheral malignant nerve sheath tumor at her left antecubital fossa. Following resection, pulmonary metastases were identified. RNA transcriptome analysis revealed an EML4-ALK rearrangement. She had a prolonged partial response to alectinib. The ALK inhibitor and two courses of radiation for oligoprogression have continued to control her disease at 48 months. Case 3: A 51-year-old woman with uterine leiomyosarcoma developed pulmonary metastases shortly after completing adjuvant radiation. NGS revealed a BRCA2 deep deletion. After progressing on multiple lines of systemic therapies, her widely metastatic disease has been controlled for 62 months with niraparib and local therapies for oligoprogression. Three patients with advanced sarcomas achieved partial responses to NGS-guided targeted therapies, with disease control lasting from 1 to over 5 years. Two cases involved novel, targetable mutations not previously identified in these sarcoma subtypes. However, the limitations of targeted therapies are highlighted by one patient's lack of response to a novel ROS1 G2032R-directed treatment, and another patient's repeated oligometastatic progression despite using an ALK inhibitor without resistance mutations. Simply suppressing a driver-mutation clone with targeted therapy may be insufficient for long-term disease control in sarcoma. Local therapies can be critical adjuvants in achieving improved outcomes for aggressive sarcomas. We recommend careful consideration of NGS testing for all sarcomas as we continue to explore their vast mutational landscape, response to targeted therapies, and mechanisms of resistance.
2026-07-10 | A High-Fidelity and Ancestrally Inclusive Patient-Derived Organoid Platform Resolves Cancer Cell Plasticity in Uterine Carcinosarcoma.
Uterine carcinosarcoma (UCS) is a rare but extremely lethal endometrial cancer that metastasizes early and resists current treatment modalities. It is biphasic, built from malignant epithelial and mesenchymal cells. Genomic studies indicate that these tumors are clonal, and that the mesenchymal cells arise from the epithelial cells through cancer cell plasticity. This biology has been hard to study, because faithful patient-derived models are scarce. The gap is widened by inequity. Women of African ancestry carry the greatest burden of UCS, yet are underrepresented in existing models. To address this, we established patient-derived organoids (PDOs) from an ancestrally inclusive UCS cohort, alongside matched normal endometrial PDOs. The organoids reproduced the biphasic histology of the original tumors. Across four sequencing platforms, they retained the tumor mutation and copy-number landscape, remained stable across passages, and expanded for up to 28 months. At single-cell resolution, UCS PDOs captured both malignant compartments and traced continuous transcriptional trajectories along the epithelial-to-mesenchymal axis, capturing patient-specific cancer cell plasticity. The models also nominated candidate vulnerabilities in proof-of-concept therapeutic testing. UCS PDOs were enriched for CREB-family transcriptional programs, and CREB inhibition reduced their viability. Combined FGFR and YAP inhibition outperformed either agent alone. Together, this work delivers a histologically, genomically, and transcriptionally faithful, ancestrally inclusive, and lineage-resolved UCS organoid platform for studying cancer cell plasticity and its vulnerabilities in an aggressive and inequitably burdened cancer.
antibodies
2026-09-19 | Durable disease control following multidisciplinary treatment including pembrolizumab in POLE-mutated dedifferentiated endometrial carcinoma with brain metastases: A case report.
Dedifferentiated endometrial carcinoma (DEC) is a rare and aggressive subtype of endometrial cancer comprising undifferentiated carcinoma and a low-grade endometrioid component. Although POLE-mutated tumors usually show favorable outcomes owing to their ultramutated and immunogenic nature, the clinical relevance of POLE mutations in DEC remains unclear. In particular, the therapeutic effects of immune checkpoint inhibitors in POLE-mutated DEC with brain metastases have not been well characterized. Here, we report the case of a 58-year-old woman with POLE-mutated DEC who presented with headache, dizziness, and generalized weakness due to multiple brain and pulmonary metastases. The clinical course, pathological and genomic findings, multidisciplinary treatment, and treatment outcomes were evaluated. Endometrial biopsy confirmed dedifferentiated carcinoma. Genomic profiling identified a pathogenic POLE exonuclease domain mutation (V411L) and a high tumor mutational burden (49.7 mutations/Mb). The patient underwent urgent cerebellar resection, followed by radiotherapy, during which a new intracranial lesion developed. Systemic therapy with carboplatin, paclitaxel, and pembrolizumab resulted in marked regression of uterine and pulmonary lesions. Her symptoms resolved completely, and the Eastern Cooperative Oncology Group performance status improved from 2 to 0. During maintenance pembrolizumab therapy, further tumor regression was observed, and durable disease control was maintained thereafter. At 14 months, the patient remained progression-free without significant adverse events. This case demonstrated a dramatic and sustained response following multidisciplinary treatment, including surgery, radiotherapy, chemotherapy, and immune checkpoint inhibitor therapy, in POLE-mutated DEC with brain metastases. This highlights the importance of molecular profiling in identifying patients who may benefit from immunotherapy, even in aggressive and widely metastatic disease.
2026-09-19 | Clear Cell Carcinoma With Enteroblast-Like Differentiation Involving Multiple Gynecologic Sites: An Integrated Clinicopathologic, Whole-Exome, and Transcriptomic Analysis.
Clear cell carcinoma with enteroblastic differentiation arising in the female genital tract is exceptionally rare, and its pathogenesis, diagnostic features, and therapeutic implications remain poorly understood. We report a rare case in a 67-year-old woman with tumor involvement of the cervix, uterine cavity, fallopian tubes, and ovaries, and highlight the value of multi-site sequencing for resolving tumor origin and biological heterogeneity. Histologically, the tumor exhibited a fetal intestinal-like morphology with glycogen-rich clear cytoplasm. Immunohistochemistry revealed positive staining for HNF1β, with variable immunoreactivity for Glypican-3 and SALL4. Multi-site whole-exome sequencing revealed marked inter-lesional genomic heterogeneity, divergent clonal evolution, and a molecular phylogenetic pattern supporting the fallopian tube as the most likely primary site. RNA sequencing further demonstrated a more immunogenic microenvironment in the fallopian tube lesion, characterized by increased infiltration of CD4+ T cells and B cells and a higher immunophenoscore, suggesting potential sensitivity to immunotherapy. Comparison with previously reported cases also helped define immunophenotypic features of diagnostic relevance. Collectively, this case underscores the value of integrating clinicopathologic evaluation with multi-site whole-exome and transcriptomic sequencing to refine diagnosis, infer tumor origin, and identify potential therapeutic opportunities in this rare gynecologic tumor subtype.
2026-08-25 | Frequency of mismatch repair deficiency for primary endometrial neuroendocrine carcinoma and its therapeutic outcome in Japan.
To investigate the frequency of mismatch repair (MMR) deficiency in primary endometrial neuroendocrine carcinoma (PENEC) and analyze its therapeutic outcomes in Japan. A multicenter retrospective study of 17 cases of PENEC diagnosed between 2011 and 2023 was conducted. MMR status was evaluated by immunohistochemistry, and clinical outcomes were assessed. Among the 17 cases, 10 (58.8%) were diagnosed at advanced stages (stage III and Ⅳ). The median overall survival was 16 months, indicating extremely poor prognosis. MMR deficiency was observed in 41% of cases, a rate higher than that reported for other endometrial cancer subtypes. PENEC demonstrates aggressive behavior and poor prognosis compared to other histological subtypes of endometrial cancer. The higher rate of MMR deficiency suggests that immune checkpoint inhibitors may serve as key components of initial treatment strategies, potentially contributing to improved outcomes for this rare and aggressive malignancy.
2026-06-12 | Clinicopathologic Study of 39 Mismatch Repair-deficient Sarcomas Demonstrates Recurrent Histologic Patterns and Supports Universal Screening of Pleomorphic Rhabdomyosarcoma, Uterine Leiomyosarcoma, and Undifferentiated and Unclassified Sarcomas.
Mismatch repair-deficient (dMMR) sarcomas are rare and incompletely characterized. Here, we studied 39 sarcomas with high microsatellite instability (MSI-H) and/or biallelic MMR gene inactivation (21 MSH2, 9 MLH1, 4 PMS2, 4 MSH6, 1 EPCAM). All tumors evaluated with immunohistochemistry (IHC; n = 36) showed loss of MMR protein expression. Eight sarcomas were index neoplasms among the 15 patients with documented Lynch syndrome. Eighteen of 1531 sarcomas (1.2%) in our sequencing database were dMMR, with enrichment in pleomorphic rhabdomyosarcoma (PRMS; 1/5), uterine leiomyosarcoma (LMS; 7/124; 5.6%), and unclassified/undifferentiated pleomorphic sarcoma (UPS; 6/259; 2.3%). MMR IHC screening of independent cases confirmed MMR deficiency in PRMS (2/20), uterine LMS (2/20), and unclassified/UPS (1/20). Two histologic patterns were identified among unclassified/UPS. Ten tumors, designated "distinctive lobulated inflammatory sarcoma" (DLIS), showed lobular architecture, florid inflammation, and histiocytoid, variably pleomorphic neoplastic cells. All 6 patients with DLIS and follow-up (median: 6.0 y; range: 3 mo to 8.6 y) were alive with no evidence of disease (ANED), and 2 DLIS responded completely to immune checkpoint inhibition. A morphologically different group of 6 unclassified high-grade sarcomas showed sheets of epithelioid-to-rhabdoid cells with eosinophilic cytoplasm; among 5 patients with follow-up (median: 1.1 y; range: 4 mo to 6.9 y), only 1 was ANED. Surprisingly, all 3 PRMS patients with follow-up (median: 5.7 y; range: 4.2 to 8.3 y) were ANED, including 2 with complete responses of metastases to systemic therapy. We conclude that PRMS, uterine LMS, and unclassified/UPS showed sufficiently prevalent MMR deficiency to justify prospective MMR IHC screening for Lynch syndrome and to identify patients who might benefit from immune checkpoint inhibition. Histologic subtyping of unclassified sarcomas predicted prognosis and therapeutic response. We propose universal MMR IHC screening of (1) PRMS, (2) uterine LMS, (3) unclassified/UPS, and (4) any sarcoma in a patient with a personal or family history of Lynch syndrome.
2026-05-11 | Prolonged disease-free survival with immunotherapy combined with chemotherapy in a patient with advanced stage large cell neuroendocrine carcinoma of the uterus.
Large Cell Neuroendocrine Carcinoma (LCNEC) is a rare and aggressive high-grade neuroendocrine malignancy that only infrequently arises in the uterus. Owing to its rarity, there are no standardized treatment guidelines, and management is generally extrapolated from neuroendocrine carcinomas of the lung or cervix. Data on the role of immune checkpoint inhibition in uterine LCNEC are lacking. We report, to our knowledge, the first case of mismatch repair (MMR)-deficient endometrial LCNEC treated with multimodal therapy including adjuvant chemotherapy, radiation, and maintenance immunotherapy, resulting in prolonged disease-free survival. A 62-year-old woman presented with postmenopausal bleeding. Endometrial biopsy showed poorly differentiated endometrial adenocarcinoma. Computed tomography revealed a uterine mass, prominent left adnexa, and retroperitoneal, para-aortic, and right external iliac lymphadenopathy. She underwent exploratory laparotomy, total abdominal hysterectomy, bilateral salpingo-oophorectomy with radical debulking, right pelvic lymph node dissection, and para-aortic lymphadenectomy, achieving no gross residual disease. Histopathology demonstrated a mixed carcinoma with a predominant LCNEC component (∼95%) and focal endometrioid adenocarcinoma (∼5%), with full-thickness myometrial and cervical invasion, parametrial involvement, extensive lymphovascular invasion, and metastases to multiple pelvic and para-aortic nodes, consistent with FIGO 2023 stage IIIC2. The tumor was MMR-deficient with loss of MLH1 and PMS2, p53 wild type, HER2-negative, FOLR1-negative, and PD-L1 combined positive score of 10. Post-operatively, she received six cycles of carboplatin, paclitaxel, and dostarlimab every three weeks, followed by maintenance dostarlimab. Given the extent of local disease, she also received vaginal brachytherapy and external beam radiation to the pelvis and para-aortic regions. At 29 months post-operation, she remains on maintenance immunotherapy with excellent functional status and no radiographic evidence of disease. This case illustrates that aggressive multimodal therapy including immune checkpoint inhibition may achieve durable disease control in advanced-stage MMR-deficient uterine LCNEC. While the relative contributions of surgery, chemotherapy, radiation, and immunotherapy cannot be separated, the favorable outcome supports further investigation of immunotherapy in rare high-grade endometrial neuroendocrine carcinomas and underscores the importance of including these histologies in clinical trials.
oligonucleotides
2025-09-22 | Downregulation of Chromosome 19 miRNA Cluster and the Tumor-Suppressive Role of miR-517a-3p in Choriocarcinoma.
Choriocarcinoma is a rare gynecologic malignancy. MicroRNAs, which are noncoding RNAs approximately 22 nucleotides in length, are known to regulate gene expression and play important roles in various cancers; however, their functions in choriocarcinoma remain largely unknown. This study aimed to identify disease-specific microRNAs involved in choriocarcinoma development. Eleven cases of choriocarcinoma and five cases of complete hydatidiform mole treated at our institution were analyzed. Total RNA was extracted from trophoblast cells in formalin-fixed, paraffin-embedded specimens using laser capture microdissection, and microRNA sequencing was performed. The analysis revealed that 87 microRNAs were significantly upregulated, whereas 28 were downregulated in choriocarcinoma compared to complete hydatidiform mole. Notably, 13 of the 28 downregulated microRNAs belonged to the chromosome 19 microRNA cluster. In vitro experiments demonstrated that overexpression of miR-517a-3p, a representative member of this cluster, significantly suppressed cell proliferation, migration, and invasion in JEG-3 and BeWo cell lines. Further transcriptome sequencing and computational analysis identified SRSF1 as a target gene of miR-517a-3p, which was validated by dual-luciferase reporter assays. Knockdown of SRSF1 also led to significant reductions in proliferation, migration, and invasion, supporting its functional relevance. Immunohistochemical analysis confirmed that SRSF1 protein was highly expressed in choriocarcinoma tissues compared to complete hydatidiform mole. These findings indicate that downregulation of the chromosome 19 microRNA cluster is a characteristic feature of choriocarcinoma and that miR-517a-3p functions as a tumor suppressor by directly regulating SRSF1 expression.
2023-05-17 | Monitoring Treatment Response, Early Recurrence, and Survival in Uterine Serous Carcinoma and Carcinosarcoma Patients Using Personalized Circulating Tumor DNA Biomarkers
Uterine serous carcinoma (USC) and carcinosarcomas (CSs) are rare, highly aggressive variants of endometrial cancer. No reliable tumor biomarkers are currently available to guide response to treatment or detection of early recurrence in USC/CS patients. Circulating tumor DNA (ctDNA) identified using ultrasensitive technology such as droplet digital polymerase chain reaction (ddPCR) may represent a novel platform for the identification of occult disease. We explored the use of personalized ctDNA markers for monitoring USC and CS patients. Tumor and plasma samples from USC/CS patients were collected at the time of surgery and/or during the treatment course for assessment of tumor-specific somatic structural variants (SSVs) by a clinical-grade next-generation sequencing (NGS) platform (i.e., Foundation Medicine) and a droplet digital PCR instrument (Raindance, ddPCR). The level of ctDNA was quantified by droplet digital PCR in plasma samples and correlated to clinical findings, including CA-125 serum and/or computed tomography (CT) scanning results. The genomic-profiling-based assay identified mutated "driver" target genes for ctDNA analysis in all USC/CS patients. In multiple patients, longitudinal ctDNA testing was able to detect the presence of cancer cells before the recurrent tumor was clinically detectable by either CA-125 or CT scanning. Persistent undetectable levels of ctDNA following initial treatment were associated with prolonged progression-free and overall survival. In a USC patient, CA-125 and TP53 mutations but not PIK3CA mutations become undetectable in the plasma at the time of recurrence, suggesting that more than one customized probe should be used for monitoring ctDNA. Longitudinal ctDNA testing using tumor-informed assays may identify the presence of residual tumors, predict responses to treatment, and identify early recurrences in USC/CS patients. Recognition of disease persistence and/or recurrence through ctDNA surveillance may allow earlier treatment of recurrent disease and has the potential to change clinical practice in the management of USC and CS patients. CtDNA validation studies in USC/CS patients prospectively enrolled in treatment trials are warranted.
2020-10-26 | 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.
2020-04-27 | miR-522 facilitates the prosperities of endometrial carcinoma cells by directly binding to monoamine oxidase B.
It is well known that microRNAs (miRNAs) are crucial regulatory factors in tumorigenesis, as tumor suppressors or cancer-promoting factors. However, the study of endometrial carcinoma relevance in miR-522 is rare, indicating an undefined molecular mechanism for its role. Therefore, we performed this study to examine the role of miR-522 on the biological behaviors of endometrial carcinoma. In this work, we found that miR-522 was highly expressed in endometrial carcinoma and negatively regulated monoamine oxidase B (MAOB) expression. They also have the opposite effect on prognosis of endometrial carcinoma patients. More importantly, miR-522 could decreased MAOB expression by binding to MAOB with a putative site, thereby promoting cell proliferation, migration, and invasion through in vitro functional analyses, including MTT assay, wound-healing and transwell invasion experiments. Upregulation of MAOB rescued the impacts of miR-522 mimic on cell behaviors. In conclusion, our observations demonstrated that miR-522 accelerated the progression of endometrial carcinoma by inhibiting MAOB, which might lead to a novel therapeutic therapy for endometrial carcinoma.
2018-07-20 | LncRNA MEG3 inhibit endometrial carcinoma tumorigenesis and progression through PI3K pathway.
Long noncoding RNAs (lncRNAs) are RNA molecules more than 200 nucleotides in length that do not encode proteins. Recent studies have reported increasing numbers of functional lncRNAs. Maternally expressed gene 3 (MEG3) is a maternally imprinted gene encoding an lncRNA that plays a tumor suppressor role in various tumors. However, there has been rare report on mechanism of tumorigenesis and progression of endometrial carcinoma. In the present study, we found significantly lower MEG3 expression in endometrial carcinoma tissues than in normal endometrial tissues. MEG3 overexpression inhibited endometrial cancer cell proliferation, invasion, and metastasis; promoted apoptosis; and inhibited the activation of the phosphoinositide 3-kinase (PI3K)/m-TOR signaling pathway. RNA immunoprecipitation assay (RIP) showed that MEG3 can combine directly with PI3K. Tumor xenograft implantation in nude mice showed that MEG3 could significantly suppress tumor growth. These findings provide potential new therapeutic targets for treating endometrial cancer.
cell therapies
2026-09-23 | Fertility-sparing surgery for a patient with a pre-operative suspected diagnosis of a Uterine Smooth Muscle Tumor of Uncertain Malignant Potential (STUMP): A case report.
Uterine smooth muscle tumors of uncertain malignant potential (STUMPs) are rare tumors that share features with benign leiomyomas and malignant leiomyosarcomas. The standard treatment is a total hysterectomy for those without intentions of future pregnancy. However, myomectomy has been reported as a potential fertility-sparing option based on retrospective data. We report a case of a healthy 34-year-old gravida 0 patient with a history of fibroids and chronic pelvic pain who presented for a fertility evaluation. She was referred to minimally invasive gynecologic surgery for management of a uterine fibroid and underwent a hysteroscopic partial myomectomy. Initial pathology of the biopsy was concerning for STUMP. A follow-up MRI and PET CT showed no evidence of abnormal features or uptake in the lesion or metastasis. The patient strongly desired future fertility. After shared decision making with the patient and consultation with gynecologic oncology, a fertility-sparing surgical approach was taken. She subsequently underwent an abdominal myomectomy without morcellation. Final pathology of the lesion was benign and consistent with symplastic leiomyoma, or leiomyoma with bizarre nuclei (LBN). In patients desiring future fertility and concern for STUMP, myomectomy without morcellation and continued surveillance can be considered as an alternate treatment option.
2026-06-23 | Fertility-sparing strategy in a rare case of uterine adenosarcoma and consecutive spontaneous pregnancy and livebirth.
We present the rare case of a 29-year-old patient with uterine adenosarcoma who received fertility-sparing treatment, subsequently conceived spontaneously, and gave birth to a healthy infant. In August 2022, the nulliparous patient presented with acyclic uterine bleeding. Diagnostic hysteroscopy and targeted resection of a polyp located at the cervicouterine junction revealed uterine adenosarcoma without sarcomatous overgrowth (FIGO stage T1a). Imaging confirmed no residual tumor or metastasis. A fertility-sparing management strategy was chosen, avoiding hysterectomy but involving close oncological surveillance with quarterly MRI scans. During follow-up, a concurrent diagnosis of symptomatic endometriosis introduced therapeutic challenges. The patient spontaneously conceived in 2023 and delivered a healthy infant by cesarean section at term in 2024. Subsequent hysteroscopy and imaging in 2025 showed no evidence of recurrence, therefore fertility-preserving management was continued. A short narrative of the patient's perspective on her initial diagnosis, possible fertility loss, and the emotional turmoil of pregnancy after uterine adenosarcoma is presented. Treating young patients diagnosed with uterine adenosarcoma poses a challenge to the treating physician due to the lack of guidelines and evidence regarding fertility-preserving treatment of this rare tumor. This report adds to the limited literature on successful pregnancy after uterine adenosarcoma and discusses indications and limitations of fertility-sparing treatment. Fertility preservation may be possible in selected early-stage uterine adenosarcoma cases without high-risk features such as sarcomatous overgrowth or myometrial invasion, with thorough counseling and strict follow-up. Further research is needed to develop standardized protocols and improve management in this context.
2026-06-18 | Balancing Fertility and Oncologic Uncertainty: Robotic Myomectomy With Bilateral Uterine Artery Ligation for Smooth Muscle Tumor of Uncertain Malignant Potential (STUMP).
Smooth muscle tumor of uncertain malignant potential (STUMP) is a rare uterine neoplasm characterized by ambiguous histopathological features and unpredictable clinical behavior. Management is particularly challenging in young, nulliparous women, where the standard approach of hysterectomy conflicts with fertility preservation. We report a case of a young nulliparous woman who underwent fertility-preserving robotic myomectomy with bilateral uterine artery ligation for a presumed atypical leiomyoma, later diagnosed as STUMP on histopathology. This case highlights the diagnostic limitations of preoperative assessment, the intraoperative decision-making involved in fertility-sparing surgery, and the role of robotic-assisted techniques in optimizing surgical precision and uterine preservation. In the absence of standardized management guidelines, treatment of STUMP requires individualized decision-making, balancing oncologic risk with reproductive goals. Careful patient selection, multidisciplinary evaluation, and long-term surveillance are essential. This case supports the feasibility and safety of a conservative robotic approach in selected patients.
2026-02-06 | Fertility-sparing vs hysterectomy for uterine STUMP: A pragmatic clinical study.
Uterine smooth muscle tumors of uncertain malignant potential (STUMP) are rare neoplasms with unpredictable clinical behavior. Optimal management, particularly in reproductive-aged women, remains controversial, with limited data comparing the safety of fertility-sparing versus hysterectomy. This multicentre retrospective cohort study included women aged 18-85 with histologically confirmed STUMP treated at 17 Italian gynecologic oncology centers from 2010 to 2023. Patients underwent either fertility-sparing surgery (myomectomy or hysteroscopic resection) or definitive surgery (hysterectomy ± salpingo-oophorectomy). Kaplan-Meier and Cox models were used to compare recurrence-free survival (RFS) and overall survival (OS). Median (range) follow-up was 51 (1-291) months. Among 401 women, 106 (26.4 %) received fertility-sparing treatment (mean [± SD] age: 35.3 ± 6.8 years) and 295 (73.6 %) underwent definitive surgery (mean [± SD] age: 47.7 ± 9.2). At total follow-up, recurrence occurred in 12.5 % of patients, predominantly within the pelvis. Median RFS was longer after definitive surgery than after fertility-sparing procedures (50.0 vs 42.5 months; HR 2.39 [95 % CI 1.36-4.19]), although this difference disappeared when benign (leiomyoma) recurrences were excluded (HR 1.74 [95 % CI 0.90-3.34]). At last available follow-up, 97.5 % of patients were alive, with no significant OS difference between treatment groups (HR 0.22 [95 % CI 0.27-1.79]). Outcomes were comparable across menopausal status and concurrent adnexal removal. Definitive surgery reduces recurrence risk, but long-term survival is similarly excellent after fertility-sparing surgery in appropriately selected women with STUMP. Conservative management represents a reasonable option for patients desiring fertility, provided they receive counseling regarding recurrence risk, diagnostic uncertainty, and the need for long-term surveillance.
2025-09-15 | Establishment of KGAS, a cell line derived from gastric-type adenocarcinoma of the uterine cervix.
Gastric-type adenocarcinoma (GAS) of the uterine cervix is a rare and aggressive subtype of cervical adenocarcinoma characterized by intrinsic resistance to chemotherapy and poor clinical outcomes due to the lack of effective treatment options. To address this critical unmet need, we established a novel GAS-derived cell line, KGAS, from ascitic fluid collected from a patient with recurrent GAS. Short tandem repeat (STR) analysis confirmed the genetic identity between the primary tumor and the cell line. Upon transplantation into immunocompromised mice, KGAS cells formed tumors that expressed Claudin-18 and MUC6, clinically recognized markers of GAS. Furthermore, KGAS cells exhibited marked resistance to paclitaxel and carboplatin, showing significantly reduced growth inhibition compared to HeLa cells. We also established a paclitaxel- and carboplatin-resistant subline, rKGAS, and performed microRNA (miRNA) sequencing to explore the molecular basis of acquired chemoresistance. Seventeen differentially expressed miRNAs were identified between KGAS and rKGAS cells. Upregulated miRNAs in rKGAS were predicted to target oncogenes such as BCL2, MET, SIRT1, and VEGFA, whereas downregulated miRNAs were associated with tumor suppressor genes, including IGF1R, TNFAIP3, and MTOR. The KGAS and rKGAS cell lines represent valuable preclinical models for elucidating the molecular mechanisms of chemoresistance and malignant progression in cervical GAS, and may contribute to the development of novel therapeutic strategies for this challenging cancer subtype.
other
2025-12-23 | Immune thrombocytopenia triggered by dostarlimab in a patient with endometrial carcinoma: first reported case.
Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for various malignancies, but they are associated with a range of immunerelated adverse events, including rare hematological complications. Immune thrombocytopenia (ITP) has been reported with other antiPD1 agents such as nivolumab and pembrolizumab, but to date, no cases have been described with dostarlimab. We report the first case of ITP in a patient receiving dostarlimab for relapsed endometrial carcinoma. A 55yearold woman developed severe thrombocytopenia (3 × 109/L) accompanied by rectal bleeding, resulting in a lifethreatening condition. Secondary causes were excluded, and bone marrow findings supported a diagnosis of ITP. Initial treatment with highdose corticosteroids and intravenous immunoglobulin achieved only a partial response, while sustained platelet recovery was obtained with the addition of romiplostim. The patient remained on dostarlimab following hematological recovery without further episodes of ITP. This case highlights a potentially lifethreatening adverse effect of a widely used immunotherapy and underscores the importance of early recognition and timely escalation of treatment in ICIinduced ITP.
2025-09-22 | Immunotherapy for high-grade endometrial stromal sarcoma: a narrative review bridging molecular insights to clinical translation.
High-grade endometrial stromal sarcoma (HGESS) is a rare solid malignancy characterized by a poor prognosis and highly aggressive behavior. Currently, surgical resection remains the primary treatment for HGESS. Radiotherapy and chemotherapy can address local symptoms and enhance the quality of life of patients; however, they do not improve patient survival rates. Recent studies have found that the molecular characteristics of HGESS (such as gene fusions like YWHAE-NUTM2, ZC3H7B-BCOR, etc.) drive the high invasiveness of the tumor. Although immunotherapy has achieved significant breakthroughs in solid tumors, the immunosuppressive microenvironment of HGESS remains a key focus for future immunotherapy research. This narrative review comprehensively analyzes the interactions between alterations in the tumor microenvironment and immune escape mechanisms in HGESS. It also proposes a diverse range of immunotherapy options, including Oncolytic virus therapy, adoptive cell transfer therapy, immune checkpoint inhibitors, cancer vaccines, and combination strategies. We hold the view that a profound comprehension of the molecular immunological characteristics of HGESS, the identification of effective biomarkers, and the implementation of well-designed clinical studies are the indispensable routes to successfully translate immunotherapy into an effective treatment for this intractable HGESS.
2025-04-24 | Retrospective analysis of treatment and prognosis for clear cell carcinoma of the uterine cervix: 15-year experience at a single institution.
Clear cell carcinoma of the uterine cervix (CCCUC) is a rare disease, accounting for 4% to 9% of cervical adenocarcinomas. Because it is so rare, its pathogenesis is largely unknown, and the standard treatment is unclear due to a lack of prospective studies. Our aim is to investigate the clinical features, treatment, and prognosis of CCCUC. We retrospectively evaluated the clinical characteristics, treatment choices, and outcomes of 12 patients with CCCUC treated at our institution between January 2009 and July 2024. The median patient age was 62.5 years (range, 14-90 years). The most common stage was IB (IA, n = 3; IB, n = 4; IIB, n = 1; IIIC, n = 2; IVB, n = 2). Ten patients underwent surgery as initial treatment: 6 underwent radical hysterectomy plus pelvic lymphadenectomy (PLD) or sentinel lymph node biopsy (SLNB), with or without para-aortic lymphadenectomy (PALD); 3 underwent modified radical hysterectomy plus PLD with or without PALD; and 1 underwent radical trachelectomy with SLNB as fertility-preserving surgery. All patients underwent bilateral salpingo-oophorectomy except for the patient who opted for radical trachelectomy. Five patients received adjuvant treatment: 3 received platinum-based systemic chemotherapy (2 of whom had combination therapy with bevacizumab), and 2 received concurrent chemoradiotherapy. The median follow-up was 43.5 months (range, 1-123 months). The 5-year progression-free survival rate was 64.5%. Systemic platinum-based chemotherapy with bevacizumab may be more effective than concurrent chemoradiotherapy as adjuvant therapy for CCCUC.
2025-03-23 | Immunogenicity and safety of an Escherichia coli-produced bivalent human papillomavirus vaccine (Cecolin) in girls aged 9-14 years in Ghana and Bangladesh: a randomised, controlled, open-label, non-inferiority, phase 3 trial.
Human papillomavirus (HPV) vaccines have been available for nearly 20 years. However, the overall coverage of girls aged 15 years and younger is low, especially in low-resource settings, where the burden of cervical cancer is highest. Increasing access and facilitating implementation of HPV vaccination will contribute to cervical cancer elimination efforts. To generate data in different dosing regimens and in low-resource settings, we aimed to evaluate the safety and immunogenicity of various schedules of an Escherichia coli-expressed bivalent HPV vaccine (2vHPV) compared with a widely used quadrivalent vaccine. This randomised, controlled, open-label, non-inferiority, phase 3 trial enrolled healthy girls aged 9-14 years from single sites in Ghana and Bangladesh. Participants were randomly assigned via interactive web response system technology equally into five study groups, stratified by site: two doses of 2vHPV, the first at baseline and the second 6, 12, or 24 months later; a quadrivalent HPV vaccine (4vHPV) at baseline followed 24 months later by 2vHPV; or two doses of 4vHPV given 6 months apart (referent). We tested for antigen-specific (HPV-16 and HPV-18) binding antibodies by ELISA at baseline and before and 1 month after the second dose. The primary objective was to show immunological non-inferiority of the 2vHPV vaccine schedules to the referent 1 month after the second dose in the per-protocol population, with a non-inferiority margin of 0·5 for the lower bound of the 98·3% CI for the geometric mean concentration (GMC) ratio. Adverse events and serious adverse events were evaluated as secondary endpoints in the total vaccinated population. The study is registered at ClinicalTrials.gov (NCT04508309) and is completed. Between March 15 and Nov 18, 2021, 1025 girls were enrolled and received 2vHPV at baseline and 6 months (n=205), 12 months (n=206), or 24 months (n=204); 4vHPV at baseline and 6 months (n=205); or 4vHPV at baseline and 2vHPV at 24 months (n=205). 96-99% of participants across groups were included in the per-protocol analysis. 1 month after the second dose, 2vHPV non-inferiority was shown, with GMC ratios between 1·1 and 2·4 (lower bound of the 98·3% CI of the GMC ratio between 0·9 and 1·9) for HPV-16, and between 1·3 and 1·7 (1·0 and 1·4) for HPV-18. As an exploratory objective, we assessed 2vHPV immunogenicity after one dose, finding that it was similar to that of 4vHPV up to 24 months, with GMC ratios at 24 months of 1·1 (95% CI 0·9-1·4) for HPV-16 and 1·4 (1·1-1·7) for HPV-18. The frequency of adverse events was similar across study groups, with no related unsolicited events reported. Serious adverse events were rare and none were determined to be related to vaccination. Non-inferior immune responses for extended two-dose regimens of 2vHPV support dosing flexibility. For up to 24 months, one dose of 2vHPV elicited immunogenicity that was similar to one dose of 4vHPV, for which single-dose efficacy has been shown, supporting a single-dose use of 2vHPV. The Bill & Melinda Gates Foundation and the German Federal Ministry of Education and Research and immunological testing was funded in part by the National Cancer Institute, National Institutes of Health. For the Bengali translation of the abstract see Supplementary Materials section.
2025-01-27 | Surgical management of endometrial cancer in patient with musculocontractural Ehlers-Danlos Syndrome harboring pathogenic variants in CHST14 (mcEDS-CHST14): A case report.
Musculocontractural Ehlers-Danlos syndrome (mcEDS) is a rare autosomal recessive connective tissue disorder caused by systemic depletion of dermatan sulfate. Symptoms characteristic of mcEDS include multiple contractures, fragile skin with subcutaneous bleeding, and hypermobile joints, which suggest difficulty in perioperative management. However, safe surgical techniques and perioperative management of this disorder remain unknown because of its rarity. We report a patient with mcEDS who developed endometrial cancer and underwent surgery, with emphasis on perioperative management. A female patient, who had been genetically diagnosed with mcEDS-CHST14 at the age of 25, presented with symptoms characteristic of mcEDS, including: congenital contractures of fingers and clubfeet, recurrent joint dislocation, progressive foot and spinal deformities, and large subcutaneous hematomas. At age 33, she had been diagnosed with atypical endometrial hyperplasia, and scheduled to undergo total abdominal hysterectomy. To address the risk of massive hemorrhage during the surgery due to mcEDS-related tissue fragility, plasma-derived factor VIII concentrate was prophylactically administered before surgery. During the surgery, neither fragility, hyperextensibility, nor hemorrhagic tendency of the uterus or adnexa observed was observed. The surgery was uneventful, with blood loss of 180 mL and operative time of 2 h and 54 min. However, on the sixth postoperative day, a 2.5-cm dissection was noted at the site of skin incision. Subcutaneous fluid accumulation developed under the skin incision and it persisted for 1.5 months. The postoperative pathological diagnosis was endometrioid carcinoma grade 1, stage IA. The present case suggested that the prophylactic use of factor VIII was effective for the prevention of hemorrhage during surgery. However, delayed wound healing of the skin and subcutaneous tissues was considered a subject for future improvement.
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Drug Discovery Landscape
1 orphan drug designation for Rare uterine cancer.
1 orphan drug designation for Rare uterine cancer.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
cridanimod | small molecules | FDA | Xenetic Biosciences, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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