FOXO3a deregulation in uterine smooth muscle tumors.

OBJECTIVE: The present study aimed to investigate FOXO3a deregulation in Uterine Smooth Muscle Tumors (USMT) and its potential association with cancer development and prognosis. METHODS: The authors analyzed gene and protein expression profiles of FOXO3a in 56 uterine Leiomyosarcomas (LMS), 119 leiomyomas (comprising conventional and unusual leiomyomas), and 20 Myometrium (MM) samples. The authors used techniques such as Immunohistochemistry (IHC), FISH/CISH, and qRT-PCR for the present analyses. Additionally, the authors conducted an in-silico analysis to understand the interaction network involving FOXO3a and its correlated genes. RESULTS: This investigation revealed distinct expression patterns of the FOXO3a gene and protein, including both normal and phosphorylated forms. Expression levels were notably elevated in LMS, and Unusual Leiomyomas (ULM) compared to conventional Leiomyomas (LM) and Myometrium (MM) samples. This upregulation was significantly associated with metastasis and Overall Survival (OS) in LMS patients. Intriguingly, FOXO3a deregulation did not seem to be influenced by EGF/HER-2 signaling, as there were minimal levels of EGF and VEGF expression detected, and HER-2 and EGFR were negative in the analyzed samples. In the examination of miRNAs, the authors observed upregulation of miR-96-5p and miR-155-5p, which are known negative regulators of FOXO3a, in LMS samples. Conversely, the tumor suppressor miR-let7c-5p was downregulated. CONCLUSIONS: In summary, the outcomes of the present study suggest that the imbalance in FOXO3a within Uterine Smooth Muscle Tumors might arise from both protein phosphorylation and miRNA activity. FOXO3a could emerge as a promising therapeutic target for individuals with Unusual Leiomyomas and Leiomyosarcomas (ULM and LMS), offering novel directions for treatment strategies.

Novel MIR143HG::PLAG1 gene fusion identified in a rectal myxoid leiomyosarcoma.

Myxoid leiomyosarcoma (MLS) is a rare but well-documented tumor that often portends a poor prognosis compared to the conventional leiomyosarcoma. This rare sarcoma has been reported in the uterus, external female genitalia, soft tissue, and other locations. However, a definite rectal MLS has not been reported. Recently five cases of MLS were reported to harbor PLAG1 fusions (TRPS1::PLAG1, RAD51B::PLAG1, and TRIM13::PLAG1). In this report, we present a case of rectal MLS with a novel MIR143HG::PLAG1 fusion detected by RNA next-generation sequencing.

A case report of uterine leiomyosarcoma: unusual clinical presentation with unilateral hydronephrosis and importance of an appropriate diagnosis.

Uterine leiomyosarcoma is a rare malignant gynecologic tumor that arises from the myometrial or endometrial stromal precursor cells. This tumor has the highest prevalence in the pre- and post-is more frequent between 40 and 60 years old. It has a very unfavorable prognosis: only early-stage tumors have an acceptable prognosis; unfortunately, it is often diagnosed accidentally, typically on an advanced stage, when hematological metastases have already spread. Surgery is the main treatment strategy, while systemic treatment and radiotherapy are not recommended due to the lack of results. Since metastatization is mainly hematological, lymphadenectomy is not recommended. Recent progresses have been achieved in advanced and recurrent disease, often inoperable, thanks to new chemotherapies, target therapies and immunotherapies. We reported the case of a 51-year-old woman evaluated for lumbar pain in the right region compatible with renal colic. The ultrasound evaluation revealed right hydronephrosis and the presence of a paraovarian or intraligamentary mass compatible with fibroma. The abdominal CT confirmed the presence of a mass with heterogeneous vascularization. Therefore, the patient underwent laparoscopic surgery to remove the lesion which resulted to be a leiomyosarcoma G2. During the following week the patient underwent a laparoscopic hysterectomy. The first step for differential diagnosis consists in the evaluation of clinicopathological features, followed by the analysis of preoperative imaging. Pelvic MRI represents the gold standard, while CT is used to detect metastases. The main issue is that imaging shows limited ability in differential diagnosis between benign and malign smooth muscle tumor. The definitive diagnosis is confirmed by histological analysis; this implies the necessity of improved attentions on the surgical procedure, which is often performed by steps with prolongation of the treatment pathway. To distinguish which fibroids presents a major risk to be misdiagnosed, some risk scores were developed (rPRESS in 2014 and pLMS in 2019), though actually they are not applied in clinical practice. Uterine leiomyosarcoma (uLMS) is rare but causes several deaths in perimenopausal women due to lack of effective treatments, although target therapies represent a future hope. Furthermore, clinical practice needs support through the development and improvement of diagnostic risk scores and their integration into guidelines.

Sarcoma of the uterine cervix: experience of a single center.

OBJECTIVES: To investigate the clinicopathological characteristics and prognosis of patients with primary sarcoma of the uterine cervix. METHODS: We identified all patients with primary cervical sarcomas treated at our institution from 2002 to 2020 and analyzed the clinicopathological characteristics and prognosis. RESULTS: 34 patients were identified, 7 (20.6%) patients had leiomyosarcoma, 6 (17.6%) had carcinosarcoma, 5 (14.7%) had Ewing sarcoma, 4 (11.8%) had rhabdomyosarcoma, 4 (11.8%) had undifferentiated sarcoma, 2 (5.9%) had adenosarcoma, 2 (5.9%) had endometrial stromal sarcoma, 1 (2.9%) had dermatofibrosarcoma protuberans, 1 (2.9%) had alveolar soft tissue sarcoma and 2 (5.9%) had sarcoma not otherwise specified. The median age of the whole patients was 43.5 years (range, 13-63). The median age of patients with Ewing sarcoma or rhabdomyosarcoma was 22 years (range, 13-39) and 17 years (range, 13-36 years), respectively. The distribution by stage was: stage I in 21 (61.8%) patients, stage II in 4 (11.8%), stage III in 6 (17.6%) and stage IV in 3 (8.8%). Overall, 30 patients (88.2%) received surgical treatment. The median follow-up was 33.3 months (range 3.6-187.3 months). 11 patients died within 2 years after diagnosis, most of them were patients with carcinosarcoma or undifferentiated sarcoma (45.5%, 5/11). In the entire cohort, 2- and 5-year OS were 67.2% and 56.9%, respectively. 5-year OS was 25.0% for undifferentiated sarcoma, 50.0% for rhabdomyosarcoma, 50.0% for carcinosarcoma, 53.3% for Ewing sarcoma, 57.1% for leiomyosarcoma. CONCLUSION: Cervical sarcomas are rare neoplasms with multiple histological subtypes and follow an aggressive course. Prognosis may be associated with tumor histology and stage.

Primary left ventricular leiomyosarcoma: a case report.

Cardiac leiomyosarcomas are a rare subset of the already infrequent, primary malignant cardiac neoplasia spectrum. The most common site for a primary leiomyosarcoma of the ventricle is on the right with fewer than five globally reported cases in the left ventricle. Most present with non-specific symptoms but attention is usually sought after the appearance of compressive symptoms or arrhythmias. We present a case of a left ventricular leiomyosarcoma in a 50-year old female patient that had a delayed diagnosis and its subsequent surgical resection and oncological management with docetaxel and gemcitabine. This case highlights the need for a high index of suspicion for cardiac masses especially if there are competing chronic diseases with similar symptomatology. Given the rare presentation of left ventricular leiomyosarcomas, case reports may provide valuable information that is otherwise unavailable.

Posterior mediastinal leiomyosarcoma: Case report and literature review.

BACKGROUND: Posterior mediastinal leiomyosarcoma is an extremely rare malignant mesenchymal tumor with no special clinical symptoms, which is easily confused with some common tumors in the posterior mediastinum, affecting the accuracy of the first diagnosis by clinicians and delaying the treatment of patients. CASE SUMMARY: We report a 59-year-old woman with a space-occupying lesion in the posterior mediastinum. The patient was mistakenly diagnosed with lumbar muscle or vertebral body lesions due to chest and back pain and underwent conservative treatment, but her symptoms did not improve significantly and she gradually developed pain in both lower limbs. Chest computed tomography (CT) scan indicated the left lower lung paraspinal space and underwent standard single-aperture video-assisted thoracoscopic surgery (VATS), which was pathologically confirmed as posterior mediastinal leiomyosarcoma. CONCLUSION: Complete surgical resection of posterior mediastinal leiomyosarcoma can achieve good clinical results.

Findings of an Extraluminal Leiomyosarcoma of the Urinary Bladder in a Dog.

A 9 yr old male miniature poodle presented with acute diarrhea, vomiting, and a distended abdomen. A large and firm mass was palpated in the caudal abdomen. Radiography showed a large soft-tissue mass in the mid ventral abdomen. The mass was mildly contrast-enhancing and in contact with the right cranial aspect of the bladder on computed tomography. The mass was heterogeneous with minimal blood flow on Doppler examination. Surgery confirmed its origin of the urinary bladder, and it was diagnosed leiomyosarcoma on pathology. This is the first report of extraluminal leiomyosarcoma of the bladder wall with imaging characteristics using various modalities.

Molecular Heterogeneity in Leiomyosarcoma and Implications for Personalised Medicine.

OPINION STATEMENT: Leiomyosarcoma (LMS) is one of the more common subtypes of soft tissue sarcomas (STS), accounting for about 20% of cases. Differences in anatomical location, risk of recurrence and histomorphological variants contribute to the substantial clinical heterogeneity in survival outcomes and therapy responses observed in patients. There is therefore a need to move away from the current one-size-fits-all treatment approach towards a personalised strategy tailored for individual patients. Over the past decade, tissue profiling studies have revealed key genomic features and an additional layer of molecular heterogeneity among patients, with potential utility for optimal risk stratification and biomarker-matched therapies. Furthermore, recent studies investigating intratumour heterogeneity and tumour evolution patterns in LMS suggest some key features that may need to be taken into consideration when designing treatment strategies and clinical trials. Moving forward, national and international collaborative efforts to aggregate expertise, data, resources and tools are needed to achieve a step change in improving patient survival outcomes in this disease of unmet need.

Tumor nasal de músculo liso de comportamiento maligno incierto: informe de un caso / Nasal smooth muscle tumor of uncertain malignant potential: A case report

Los tumores de músculo liso que no pueden ser clasificados según su histología como leiomiomas o leiomiosarcomas se denominan tumores de músculo liso de comportamiento maligno incierto. La localización nasal de estos tumores es muy infrecuente y la extensión adecuada de la cirugía para tratar estas neoplasias no está bien definida. Se describe el caso clínico de una adolescente de 16 años, que consultó por padecer un tumor de aspecto vascular en la cavidad nasal derecha y que fue tratada con éxito mediante cirugía intranasal. El diagnóstico histológico fue tumor de músculo liso de comportamiento maligno incierto. Por la rareza de estas neoplasias, su infrecuente localización nasal y la falta de evidencia que soporte cuál debe ser la extensión de la cirugía, es relevante la descripción y discusión del caso clínico.

Smooth muscle tumors that cannot be histologically classified as leiomyomas or leiomyosarcomas are defined as smooth muscle tumors of uncertain malignant potential. The location of these tumors in the nose is very rare, and the appropriate surgical extent to manage these neoplasms has not been adequately defined. Here we describe the case of a 16-year-old female adolescent who consulted due to a vascular-like tumor in the right nasal cavity who was successfully treated with intranasal surgery. The histological diagnosis was smooth muscle tumor of uncertain malignant potential. Given that these neoplasms are rare, the uncommon location in the nose, and the lack of evidence indicating the extent of surgery, it is relevant to describe and discuss this clinical case.

Developing Novel Genomic Risk Stratification Models in Soft Tissue and Uterine Leiomyosarcoma.

PURPOSE: Leiomyosarcomas (LMS) are clinically and molecularly heterogeneous tumors. Despite recent large-scale genomic studies, current LMS risk stratification is not informed by molecular alterations. We propose a clinically applicable genomic risk stratification model. EXPERIMENTAL DESIGN: We performed comprehensive genomic profiling in a cohort of 195 soft tissue LMS (STLMS), 151 primary at presentation, and a control group of 238 uterine LMS (ULMS), 177 primary at presentation, with at least 1-year follow-up. RESULTS: In STLMS, French Federation of Cancer Centers (FNCLCC) grade but not tumor size predicted progression-free survival (PFS) or disease-specific survival (DSS). In contrast, in ULMS, tumor size, mitotic rate, and necrosis were associated with inferior PFS and DSS. In STLMS, a 3-tier genomic risk stratification performed well for DSS: high risk: co-occurrence of RB1 mutation and chr12q deletion (del12q)/ATRX mutation; intermediate risk: presence of RB1 mutation, ATRX mutation, or del12q; low risk: lack of any of these three alterations. The ability of RB1 and ATRX alterations to stratify STLMS was validated in an external AACR GENIE cohort. In ULMS, a 3-tier genomic risk stratification was significant for both PFS and DSS: high risk: concurrent TP53 mutation and chr20q amplification/ATRX mutations; intermediate risk: presence of TP53 mutation, ATRX mutation, or amp20q; low risk: lack of any of these three alterations. Longitudinal sequencing showed that most molecular alterations were early clonal events that persisted during disease progression. CONCLUSIONS: Compared with traditional clinicopathologic models, genomic risk stratification demonstrates superior prediction of clinical outcome in STLMS and is comparable in ULMS.

Uterine Leiomyosarcoma Associated With Perivascular Epithelioid Cell Tumor: A Phenomenon of Differentiation/Dedifferentiation and Evidence Suggesting Cell-of-Origin.

Perivascular epithelioid cell tumor (PEComa) is a mesenchymal tumor thought to originate from perivascular epithelioid cells (PECs). The normal counterpart to PEC, however, has not been identified in any human organ, and the debate as to whether PEComa is related to smooth muscle tumors has persisted for many years. The current series characterizes 4 cases of uterine leiomyosarcoma (LMS) coexisting with PEComas. All cases exhibited an abrupt transition from the LMS to PEComa components. The LMS component displayed typical spindled morphology and fascicular growth pattern and was diffusely positive for desmin and smooth muscle myosin heavy chain, completely negative for HMB-45 and Melan A, and either negative or had focal/weak expression of cathepsin K and GPNMB. In contrast, the PEComa tumor cells in case 1 contained glycogen or lipid-distended cytoplasm with a foamy appearance (low grade), and in cases 2, 3, and 4, they displayed a similar morphology characterized by epithelioid cells with eosinophilic and granular cytoplasm and high-grade nuclear atypia. Different from the LMS component, the epithelioid PEComa cells in all cases were focally positive for HMB-45, and diffusely immunoreactive for cathepsin K and GPNMB. Melan A was focally positive in cases 1 and 3. Loss of fumarate hydratase expression (case 1) and RB1 expression (cases 2, 3, 4) was identified in both LMS and PEComa components, indicating that they are clonally related. In addition, both components showed an identical TP53 p.R196* somatic mutation and complete loss of p53 and ATRX expression in case 2 and complete loss of p53 expression in case 3. We hypothesize that LMSs containing smooth muscle progenitor cells may give rise to divergent, lineage-specific PEComatous lesions through differentiation or dedifferentiation. While we do not dispute the recognition of PEComas as a distinct entity, we advocate the hypothesis that modified smooth muscle cells represent the origin of a subset of PEComas, and our case series provides evidence to suggest this theory.

Roles of Matrix Metalloproteinases 2 and 9 in Uterine Leiomyosarcoma.

BACKGROUND/AIM: Uterine leiomyosarcoma (uLMS) is a rare, highly malignant, and invasive cancer, with early metastasis. Mismatch repair (MMR) proteins and matrix metalloproteinases (MMPs) are associated with the occurrence, proliferation, and invasion of most malignant cancers; however, their abnormal expression in uLMS remains poorly clarified. PATIENTS AND METHODS: Immunohistochemistry was performed to assess MMR protein and MMP2/9 expression as well as Ki67 marker proliferation in benign and malignant uterine smooth muscle tumors. Data from 28 cases of uterine leiomyoma and 31 cases of uLMS were analyzed. RESULTS: Tumor tissues from patients with uLMS had higher expression levels of MMP2 (p<0.001), MMP9 (p<0.05), and Ki67 (p<0.001) than those from patients with uterine leiomyoma; MMR protein expression showed the opposite trend (p<0.05). uLMS proliferation and metastasis correlated positively with MMP2 (p=0.012 and 0.015, respectively) but negatively with MMP9 (p=0.021 and 0.04, respectively). MMR protein expression did not correlate with uLMS proliferation or metastasis (p>0.05). CONCLUSION: Expression levels of MMP2 and MMP9 were upregulated in malignant uLMS tumors when compared with those in benign uterine leiomyoma tumors. Increased MMP2 expression might promote uLMS invasion and migration. MMP9 overexpression might be related to uLMS occurrence; however, it protects against uLMS invasion and metastasis. MMP2 and MMP9 may be potential predictors of uLMS cell proliferation, metastasis, and prognosis. These findings could be helpful in developing new strategies for diagnosing and treating uLMS.

Leiomyosarcoma of sphenoid sinus- A rare tumor at an unusual site.

Leimyosarcoma (lms) is a malignant soft tissue tumor of smooth muscles. The tumor arises intramuscularly and in subcutaneous locations. It is unusual to encounter lms in head and neck region, even more infrequent to discover lms in nasal and paranasal sinuses. A case of 28 years old male with leiomyosarcoma originating from sphenoid sinus with intracranial extension is being presented with aim to highlight its rarity and to highlight the differential diagnosis and the need for prudent diagnosis in the work-up of the patient.

[Radiation-induced parotid leiomyosarcoma]. / Léiomyosarcome parotidien en territoire irradié.

INTRODUCTION: First case of radiation-induced parotid leiomyosarcoma. ANATOMO-CLINICAL OBSERVATION: A 50-year-old woman with a history of cervical irradiation for Hodgkin's lymphoma presented with a right parotid tumefaction. Examination noted a deep adherent pretragal mass with peripheral facial palsy. A total parotidectomy with intra-operative examination and cervical curage was performed. Histopathological analysis concluded to a grade 3 parotid leiomyosarcoma according to the National Federation of Cancer Centers. Adjuvant radiotherapy was performed. After 24 months of follow-up, the patient presented bone and liver metastases without local recurrence. DISCUSSION: This is the first case of radiation-induced leiomyosarcoma and the 12th case of parotid leiomyosarcoma described in the literature. The management associates surgery with adjuvant radiotherapy. Follow-up is by clinical examination, parotid MRI, and annual thoracoabdominal CT scan to search for metastases. Recurrences occur during the first year in 40 to 64% of cases, and distant metastases in 40 to 60% of cases. The 5-year survival rate is between 10 and 30%.

[A rare malignant tumor of the renal vein]. / Une tumeur maligne rare de la veine rénale.

The renal vein is an exceptional location for leiomyosarcoma, an aggressive malignant tumor of smooth-muscle origin with a poor prognosis. We report the case of a 55-year-old female patient who consulted for left flank pain that had been present for 6 months. A CT scan revealed a 9.4cm left retroperitoneal mass in contact with the psoas muscle, left kidney, stomach, spleen, left colon and extending up to the pancreas, raising the suspicion of a tumour originating in the retroperitoneal tissues. A biopsy revealed a smooth-muscle cell tumour with a degree of malignancy difficult to define. The patient underwent a monobloc left compartmentectomy, which led to the diagnosis of leiomyosarcoma of the left renal vein. A review of the literature on these rare tumours in this location is presented.

Conjunctival leiomyosarcoma: A clinico-pathological study with in deep molecular characterization.

BACKGROUND: Primary and metastatic leiomyosarcomas (LMS) involving the orbital region are well known to occur however, the conjunctiva represents an extremely rare site of occurrence. METHODS: A 97-year-old male was referred to the Ocular Oncology Unit due to a rapidly growing painful mass (16×12×20 mm) in the nasal conjunctiva of his left eye. Wide excision followed by radiotherapy was performed. RESULTS: Based on the microscopic features (hypercellular neoplasm composed of spindle cells with cigar shaped and blunt ended nuclei with brightly eosinophilic fibrillary cytoplasm) and immunohistochemical findings (positive staining for Vimentin, Desmin, Caldesmon, and SMA and negative staining for AE1/AE3, EMA, CD117, S100, MelanA, SOX10, HMB45, TLE1, CD99, EMA and AE1 / AE3) the final diagnosis of grade 2 leyomiosarcoma was rendered. Moreover, 'in deep' DNA sequencing (>500 genes analysis) revealed a neoplasm with high TMB: 64 muts/Mb and numerous VUS and several pathogenic/oncogenic molecular alterations, including CNV loss or gain in > 10 genes. At the last follow-up visit, residual disease was observed in the superior fornix, at the nasal limbus and the cornea. At the time of writing, after a follow-up of 2 month the patients is still alive without evidence of metastatic disease. CONCLUSION: An uncommon molecular finding observed in our case was the presence of TSC1 gene mutation usually associated with soft tissue and gynecological PEComas. Our finding may harbor important therapeutic implications since the inactivation of the tumor suppressor genes TSC1 and TSC2 lead to upregulation of mTOR signaling, providing the rationale for target therapy with mTOR inhibitors. Additional studies on larger series are needed to validate our findings.

Immune evasion in lung metastasis of leiomyosarcoma: upregulation of EPCAM inhibits CD8+ T cell infiltration.

BACKGROUND: Leiomyosarcomas are among the most common histological types of soft tissue sarcoma (STS), with no effective treatment available for advanced patients. Lung metastasis, the most common site of distant metastasis, is the primary prognostic factor. We analysed the immune environment targeting lung metastasis of STS to explore new targets for immunotherapy. METHODS: We analysed the immune environment of primary and lung metastases in 38 patients with STS using immunohistochemistry. Next, we performed gene expression analyses on primary and lung metastatic tissues from six patients with leiomyosarcoma. Using human leiomyosarcoma cell lines, the effects of the identified genes on immune cells were assessed in vitro. RESULTS: Immunohistochemistry showed a significant decrease in CD8+ cells in the lung metastases of leiomyosarcoma. Among the genes upregulated in lung metastases, epithelial cellular adhesion molecule (EPCAM) showed the strongest negative correlation with the number of CD8+ cells. Transwell assay results showed that the migration of CD8+ T cells was significantly increased in the conditioned media obtained after inhibition or knock down of EPCAM. CONCLUSIONS: EPCAM was upregulated in lung metastases of leiomyosarcoma, suggesting inhibition of CD8+ T cell migration. Our findings suggest that EPCAM could serve as a potential novel therapeutic target for leiomyosarcoma.

Inflammatory Rhabdomyoblastic Tumor: From a Nebulous Smooth Muscle Neoplasm to a Novel Skeletal Muscle Tumor Subtype.

Inflammatory rhabdomyoblastic tumor is a recently introduced name for neoplasms currently included in the World Health Organization classification of soft tissue tumors under the rubric inflammatory leiomyosarcoma. Inflammatory rhabdomyoblastic tumor is an excellent example of how surgical pathologists working in conjunction with tumor biologists can greatly improve tumor classification to the benefit of patients. Over the last 28 years, understanding of this entity has undergone a fascinating evolution. This review serves as a summary of the latest findings in inflammatory rhabdomyoblastic tumor research and a diagnostic manual for the practicing surgical pathologist.

MMP14 expression and collagen remodelling support uterine leiomyosarcoma aggressiveness.

Fibrillar collagen deposition, stiffness and downstream signalling support the development of leiomyomas (LMs), common benign mesenchymal tumours of the uterus, and are associated with aggressiveness in multiple carcinomas. Compared with epithelial carcinomas, however, the impact of fibrillar collagens on malignant mesenchymal tumours, including uterine leiomyosarcoma (uLMS), remains elusive. In this study, we analyse the network morphology and density of fibrillar collagens combined with the gene expression within uLMS, LM and normal myometrium (MM). We find that, in contrast to LM, uLMS tumours present low collagen density and increased expression of collagen-remodelling genes, features associated with tumour aggressiveness. Using collagen-based 3D matrices, we show that matrix metalloproteinase-14 (MMP14), a central protein with collagen-remodelling functions that is particularly overexpressed in uLMS, supports uLMS cell proliferation. In addition, we find that, unlike MM and LM cells, uLMS proliferation and migration are less sensitive to changes in collagen substrate stiffness. We demonstrate that uLMS cell growth in low-stiffness substrates is sustained by an enhanced basal yes-associated protein 1 (YAP) activity. Altogether, our results indicate that uLMS cells acquire increased collagen remodelling capabilities and are adapted to grow and migrate in low collagen and soft microenvironments. These results further suggest that matrix remodelling and YAP are potential therapeutic targets for this deadly disease.