[Diagnosis of uterine sarcomas and rare uterine mesenchymal tumours with malignant potential. Guidelines of the French Sarcoma Group and Rare Gynaecological Tumours]. / Diagnostic des sarcomes utérins et tumeurs mésenchymateuses utérines rares à potentiel de malignité. Référentiels du Groupe Sarcome Français et des Tumeurs Rares Gynécologiques.

The landscape of uterine sarcomas is becoming more complex with the description of new entities associated with recurrent driver molecular alterations. Uterine sarcomas, in analogy with soft tissue sarcomas, are distinguished into complex genomic and simple genomic sarcomas. Leiomyosarcomas and undifferentiated uterine sarcomas belong to complex genomic sarcomas group. Low-grade and high-grade endometrial stromal sarcomas, other rare tumors associated with fusion transcripts (such as NTRK, PDGFB, ALK, RET ROS1) and SMARCA4-deficient uterine sarcoma are considered simple genomic sarcomas. The most common uterine sarcoma are first leiomyosarcoma and secondly endometrial stromal sarcomas. Three different histological subtypes of leiomyosarcoma (fusiform, myxoid, epithelioid) are identified, myxoid and epithelioid leiomyosarcoma being more aggressive than fusiform leiomyosarcoma. The distinction between low-grade and high-grade endometrial stromal sarcoma is primarily morphological and immunohistochemical and the detection of fusion transcripts can help the diagnosis. Uterine PEComa is a rare tumor, which is distinguished into borderline and malignant, according to a risk assessment algorithm. Embryonal rhabdomyosarcoma of the uterine cervix is more common in children but can also occur in adult women. Embryonal rhabdomyosarcoma of the uterine cervix is almost always DICER1 mutated, unlike that of the vagina which is wild-type DICER1, and adenosarcoma which can be DICER1 mutated but with less frequency. Among the emerging entities, sarcomas associated with fusion transcripts involving the NTRK, ALK, PDGFB genes benefit from targeted therapy. The integration of molecular data with histology and clinical data allows better identification of uterine sarcomas in order to better treat them.

Subcutaneous Leiomyosarcoma: An Aggressive Malignancy Portending a Significant Risk of Metastasis and Death.

Subcutaneous leiomyosarcoma (LMS) is a rare, poorly understood variant. The current literature on the subject is sparse, consisting of isolated case reports and small clinicopathologic studies compromised by the inclusion of both its more common and indolent counterpart, cutaneous LMS (atypical intradermal smooth muscle neoplasm), as well as highly aggressive deep-seated tumors. Thus, precise clinicopathologic characterization is limited. Cases of subcutaneous LMS reviewed at the University of Michigan and Cleveland Clinic from 1994 to 2022 were included in this retrospective study. A total of 39 cases were identified. The mean age was 61 years, and the cohort was predominantly male (23/39; 59%). Tumors averaged 4.2 cm and most commonly arose on the extremities (32/39; 82%). The majority (38/39; 97%) were diagnosed at an early pathologic stage (pT1 or pT2). Histopathologically, most tumors were well-circumscribed and were assigned a Fédération Nationale des Centers de Lutte Contre le Cancer grade of either 1 or 2 (24/39; 62%). The majority (22/39; 56%) appeared to arise in association with a blood vessel. Of the 36 cases with accessible clinical data and follow-up (mean 34 mo, range 0 to 94 mo), 12 (33%) were noted to have metastasized, with the lung representing the most common anatomic location. One case recurred locally. Six of 36 patients (17%) died from the disease at an average of 47 months after diagnosis (range 16 to 94 mo). Metastasis or death from disease was significantly associated with the Fédération Nationale des Centers de Lutte Contre le Cancer grade ( P =0.0015), the presence of necrosis ( P =0.032), tumor size ( P =0.049), and AJCC tumor stage ( P =0.036). These data demonstrate that subcutaneous LMS are more aggressive than dermal-based tumors and have a prognosis akin to that of deep-seated LMS.

The rare entity of gastrointestinal leiomyosarcomas: An Italian multicenter retrospective study in high-volume referral centers.

BACKGROUND: After a huge efficacy of imatinib in treating patients with gastrointestinal stromal tumors (GISTs) was proven, a maximum effort was made to make a differential diagnosis between GISTs and gastrointestinal leiomyosarcomas (GI-LMS), showing the latter to be an extremely rare tumor entity. Limited data on GI-LMS biology, clinical behavior and drug-sensibility are available, and the clinical decision-making in this subgroup of patients is usually challenging. METHODS: We conducted a multicenter, retrospective observational study on patients with diagnosed GI-LMS from 2004 to 2020 within six high-volume referral centers in Italy. RESULTS: Thirty-three patients had diagnosis of KIT-negative GI-LMS confirmed by sarcoma-expert pathologist. The most common site of origin was the intestine. Twenty-two patients had localized disease and underwent surgery: with a median follow-up of 72 months, median disease-free survival was 42 months. Overall survival (OS)-rate at 5 years was 73% and median OS was 193 months. Five out of 10 patients with local relapse received a salvage surgery, and 2/5 remained with no evidence of disease. Thirteen patients received neoadjuvant (6) or adjuvant (7) chemotherapy, and 2/13 patients remained free from relapse. The median OS for patients with metastatic LMS was 16.4 months. CONCLUSION: GI-LMS is very rare and extremely aggressive subgroup of sarcomas with a high tendency to systemic spread. Localized GI-LMS at diagnosis may be cured if treated with adequate surgery with or without (neo) adjuvant chemotherapy, while de-novo metastatic disease appeared to have a poor prognosis. Clinical effort to understand GI-LMS biology and clinical behavior and to develop active treatment strategy, especially for metastatic-disease, is warranted.

Epithelioid leiomyosarcoma: An unusual presentation.

Uterine mesenchymal tumors are a heterogeneous group of neoplasms that can be diagnostically challenging. Thorough investigations and histopathological findings are highly significant to arrive at the correct diagnosis, thus ensuring appropriate and prompt treatment to the patient. Leiomyosarcoma (LMS) is an uncommon uterine malignancy, which arises from the smooth muscle of the uterine wall. They usually present in postmenopausal women with abnormal uterine bleeding. It follows an aggressive clinical course with an extremely poor prognosis. Surgical management followed by adjuvant chemotherapy is usually the treatment for such cases. Here, we report the case of a 57-year-old menopausal female who presented with a large abdominal swelling that was seen infiltrating the adjacent structures. On resection and histopathological evaluation, a diagnosis of epithelioid LMS was made, which was confirmed by immunohistochemistry.

Lymph node dissection in uterine leiomyosarcomas: A matched-pair study.

OBJECTIVE: To assess the impact of the lymph node dissection (LND) in the disease-free (DFS) and overall survival (OS) of the women treated surgically of uterine leiomyosarcoma (ULMS). MATERIAL AND METHODS: A multicentric retrospective study was conducted among European countries collecting patients diagnosed of uterine sarcoma (SARcoma of the UTerus - SARCUT study). A total of 390 ULMS were selected for the present study to compare patients who underwent LND and those who did not. A further matched-pair subanalysis identified 116 women, 58 pairs (58 with LND and 58 without it) comparable in age, tumor size, surgical procedures, extrauterine disease and adjuvant treatment. Demographic data, pathology results and follow-up were abstracted from medical records and analyzed. Disease-free (DFS) and overall survival (OS) were studied using Kaplan-Meier curves and Cox regression analysis. RESULTS: Among the 390 patients, the 5-year DFS was significantly higher in no-LDN group comparing to the LDN group (57.7% vs. 33.0%; HR 1.75, 95% CI 1.19-2.56; p = 0.007), but not the 5-year OS (64.6% vs. 64.3%; HR 1,10 95% CI 0,77-1,79; p = 0.704). In the matched-pair subanalysis, there were no statistical differences between the study groups. The 5- year DFS was 50.5% in the no-LND and 33.0% in the LND group (HR 1.38; 95% CI 0,83-2.31; p = 0,218) and the 5-year OS was 59.7% and 64.3% respectively (HR 0.81; 95% CI 0,45-1,49; p = 0,509). CONCLUSIONS: LND performed in women diagnosed of ULMS have no impact neither in the disease-free nor in the overall survival compared to patients without LDN in a complete homogeneous group.

[Uterine leiomyosarcoma - French guidelines from the GSF/NETSARC and TMRG groups]. / Léiomyosarcomes utérins ­ Référentiel de prise en charge du GSF-GETO/NETSARC+ et du groupe TMRG.

Uterine leiomyosarcomas represent the most common uterine sarcomas. The prognosis is poor with metastatic recurrence in more than half of the cases. The purpose of this review is to make French recommendations for the management of uterine leiomyosarcomas within the framework of the French Sarcoma Group - Bone Tumor Study Group (GSF-GETO)/NETSARC+ and Malignant Rare Gynecological Tumors (TMRG) networks in order to optimize their therapeutic management. The initial assessment includes a MRI with diffusion perfusion sequence. The diagnosis is histological with a review in an expert center (Reference Network in Sarcoma Pathology (RRePS)). Total hysterectomy with bilateral salpingectomy, en bloc without morcellation, is performed when complete resection is possible, whatever the stage. There is no indication of systematic lymph node dissection. Bilateral oophorectomy is indicated in peri-menopausal or menopausal women. Adjuvant external radiotherapy is not a standard. Adjuvant chemotherapy is not a standard. It can be an option and consists in doxorobucin based protocols. In the event of local recurrence, the therapeutic options are based on revision surgery and/or radiotherapy. Systemic treatment with chemotherapy is most often indicated. In case of metastatic disease, surgical treatment remains indicated when resecable. In cases of oligo-metastatic disease, focal treatment of metastases should be considered. In the case of stage IV, chemotherapy is indicated, and is based on first-line doxorubicin-based protocols. In the event of excessive deterioration in general condition, management by exclusive supportive care is recommended. External palliative radiotherapy can be proposed for symptomatic purposes.

The biology and treatment of leiomyosarcomas.

Leiomyosarcoma (LMS) is a soft tissue sarcoma of smooth muscle origin that can arise in multiple anatomical sites and is broadly classified as extra-uterine LMS or uterine LMS. There is substantial interpatient heterogeneity within this histological subtype, and despite multi-modal therapy, clinical management remains challenging with poor patient prognosis and few new therapies available. Here we discuss the current treatment landscape of LMS in both the localised and advanced disease setting. We further describe the latest advances in our evolving understanding of the genetics and biology of this group of heterogeneous diseases and summarise the key studies delineating the mechanisms of acquired and intrinsic chemotherapy resistance in this histological subtype. We conclude by providing a perspective on how novel targeted agents such as PARP inhibitors may usher in a new paradigm of biomarker-driven therapies that will ultimately impact the outcomes of patients with LMS.

On the road to improved outcomes by capturing leiomyosarcoma patients' views.

An international collaborative project set up as a 'priority setting partnership' used a questionnaire to capture the views of patients, carers and clinicians about the sarcoma research agenda. Responses from 25 patients with leiomyosarcoma (LMS) in eight countries provided useful insight from the patient's perspective. Unmet needs identified by patients were in the areas of: LMS-specific trial design; exploring new therapeutic avenues; avoiding morcellation; exploring the immune system in LMS; investigating circulating tumor DNA; implementing molecular characterization of LMS; conducting basic research and a translational pipeline; evaluating imaging modalities; improving early diagnosis; identifying patient-reported outcomes; improving communication, information and support; and addressing survivorship and end-of-life care. Each of the unmet needs is described in more detail.

Epstein-Barr virus-associated leiomyosarcoma of the larynx in an adult patient with human immunodeficiency virus infection: Case report and review of the literature.

We investigated the clinical features, treatment, and prognosis of laryngeal leiomyosarcoma (LLMS) and Epstein-Barr virus-associated (EBV-associated) LMS. We report a case of EBV-associated LLMS in an adult patient with HIV infection. We also conducted a review of the English-language literature on LLMS and EBV-associated leiomyosarcoma. To the best of our knowledge, 62 cases of LLMS and EBV-associated leiomyosarcoma have been reported to date. Of patients with LLS, 18.9% had distant metastases and 17.0% had local recurrence. The overall 5-year survival rate was 64.0%. Distant metastases affected the survival of patients with LLMS (p = 0.04). EBV-positive patients had a low survival rate (p = 0.01). Among patients with EBV-associated LMS, 8.2% had distant metastases and recurrence and the overall 5-year survival rate was 50.0%. EBV-associated LLMS is rare. The EBV infection might be a poor prognostic factor of LLMS.

Utilization and outcomes of adjuvant therapy for stage II and III uterine leiomyosarcoma.

OBJECTIVES: The optimal adjuvant therapy for uterine leiomyosarcoma (uLMS) remains uncertain. We analyzed the utilization of adjuvant chemotherapy and radiation therapy for stage II and III uLMS and explored the association between use of adjuvant therapy and survival. METHODS: Patients with stage II or III uLMS treated from 2004 to 2016 and recorded in the National Cancer Database were identified. Multivariable regression models were fit to estimate predictors of use of either adjuvant radiation therapy or chemotherapy. To analyze the impact of chemotherapy on all-cause mortality, an inverse probability of treatment weighted (IPTW) propensity score method was used to account for measured confounders, and the receipt of radiation therapy was adjusted in the outcome model. The process was repeated to analyze the impact of radiation therapy on all-cause mortality by using an IPTW propensity score method and adjusting for the receipt of adjuvant chemotherapy. RESULTS: A total of 890 patients were identified. Adjuvant chemotherapy use increased from 62.2% in 2010 to 70.4% in 2016, whereas radiation usage decreased from 26.7% in 2010 to 10.4% in 2016. Patients with stage III (vs. stage II) disease were less likely to receive radiation therapy. After propensity score weighting, chemotherapy was associated with a 30% decreased risk of all-cause mortality in stage III patients (HR 0.70, 95% CI 0.45-0.98) but had no effect on mortality for stage II patients (HR 0.93, 95% CI 0.70-1.20). Radiation therapy was associated with a 26% decreased risk of mortality for stage II tumors (HR 0.74; 95% CI, 0.53-0.99) and a 57% decrease in mortality for stage III disease (HR 0.43, 95% CI 0.18-0.99). CONCLUSIONS: Among women with stage II-III uLMS, use of chemotherapy is increasing while use of radiation therapy is decreasing. Radiation therapy is associated with improved survival in both stage II and III disease, while there was no association between use of adjuvant chemotherapy and survival in stage II patients.

Leiomyosarcoma: Current Clinical Management and Future Horizons.

Leiomyosarcomas are soft tissue tumors that are derived from smooth muscle mainly in the pelvis and retroperitoneum. Percutaneous biopsy is paramount to confirm diagnosis. Imaging is necessary to complete clinical staging. Multimodal treatment should be directed by expert sarcoma multidisciplinary teams that see a critical volume of these rare tumors. Surgery is the mainstay of curative intent treatment; however due to its high metastatic progression, there may be a benefit for neoadjuvant systemic treatment. Adjuvant systemic treatment has no proven disease-free survival, and its main role is in the palliative setting to potentially prolong overall survival.

Can Posttransarterial Chemoembolization Volumetric Oil Deposition on Computed Tomography Predict Treatment Response on Magnetic Resonance Imaging in Leiomyosarcoma Metastases to the Liver?

OBJECTIVE: To predict early tumor response to transarterial chemoembolization (TACE) based on volumetric oil deposition on posttreatment computed tomography (CT) in patients with leiomyosarcoma liver metastases. METHODS: This retrospective lesion-by-lesion based study included 32 lesions. The volumetric percent enhancing tumor on pre-TACE and 1-month post-TACE venous phase magnetic resonance imaging (MRI), and the percent oil deposition on CT 1 day after TACE were calculated. The predicted post-TACE enhanced percentage was computed by subtracting percent oil deposition from baseline percent enhanced. RESULTS: Mean percentage of viable tumor on pre-TACE MRI was 90.6% ± 9.3%. Mean oil deposition was calculated as 51.4% ± 26.2%. Mean percentage of measured residual tumor enhancement 1 month after TACE was 58.3% ± 27%, which correlates with predicted enhancement percentage of 43.9% ± 25.1% (r = 0.72, P < 0.001). A threshold of 35.5% for enhancement reduction was determined to predict tumor response with an accuracy of 78.1%. CONCLUSION: Volumetric oil deposition on CT can predict residual enhancement on post-TACE MRI.

Leiomyosarcoma in the extremities and trunk wall: systematic review and meta-analysis of the oncological outcomes.

BACKGROUND: Leiomyosarcomas are aggressive malignancies which can occur on the trunk and extremities whose pathogenesis is poorly understood. We aim to quantify the prognostic impact of various clinical and pathological markers on survival and recurrence of leiomyosarcomas. METHODS: We conducted a systematic review as per PRISMA protocol. Survival, local recurrence, and metastasis were the outcome measures. Data were extracted from the studies for the outcome variables; the resultant odds ratios (OR) and 95% confidence interval (CI) were used for the synthesis of a forest plot. RESULTS: Our search revealed thirteen studies comprising 1380 patients. Seven of these 13 publications were since 2012. Our analysis showed that tumor size larger than 5 cm adversely affected the outcome with an OR 3.39 (2.26-5.10, p < 0.01). Other factors which reduced the overall survival were positive margins of excision OR 2.12 (1.36-3.32, p < 0.01). A reduced risk of metastasis has strongly associated the use of radiotherapy with OR 10.84 (4.41-26.61, p < 0.01). Only a few studies analyzed the impact of factors on local recurrence. CONCLUSIONS: Size larger than 5 cm and positive margins of excision are associated with poor overall survival. In comparison, the use of adjuvant radiotherapy was associated with a lower metastatic rate. There is a need for methodically high-quality studies with more uniform study design and reporting to evaluate the impact of various risk factors on local recurrence and metastases. LEVEL OF EVIDENCE: Level 1 Prognostic.

Current molecular and therapeutic advances in liposarcoma, rhabdomyosarcoma, leiomyosarcoma, synovial sarcoma, and angiosarcoma.

Sarcomas probably develop after malignant transformation of embryonic mesenchymal cells and have broad spectrum histopathologically since they can develop from striated skeletal muscle and smooth muscle, fat and fibrous tissue, bone, cartilage and other mesenchymal tissues. The most common histological subtypes of soft tissue sarcoma in adults are: liposarcoma, leiomyosarcoma, poorly differentiated pleomorphic sarcoma, and gastrointestinal stromal tumor. Molecular and genetic studies of soft tissue sarcomas, which are considered as heterogeneous groups in terms of their molecular and clinical characteristics, are still an important area of ​​interest The heterogeneity of the molecular and genetic alterations of these malignancies, which are mostly treated with surgery and chemotherapy, also offers hope to the researchers in terms of treatment targets. In this article, molecular biologic features of the soft tissue sarcomas including liposarcoma, rhabdomyosarcoma, leiomyosarcoma, synovial sarcoma, and angiosarcoma are discussed in the light of recent developments in molecular biology, targeted therapies and immunotherapy.

Comprehensive immunohistochemical analysis based on the origin of leiomyosarcoma.

Diagnostic criteria, biological behavior, and treatment approaches of leiomyosarcomas (LMS) may differ according to the origin of the tumor. This is important in terms of patient's management, especially in tumors located in the peritoneum and retroperitoneal sites. In our study, we aimed to demonstrate the immunophenotypic characteristics of uterine and extra-uterine LMS using a large antibody panel, and to determine whether they potentially play a role in the differences among these tumor groups. Between 2006 and 2018, 29 uterine and 42 extra-uterine primary LMS were included in this study. Using tissue samples taken from the areas that best represented the tumor, an immunohistochemical study was performed on the blocks prepared by tissue micro-array method with estrogen and progesterone receptor (PR), WT-1, SMA, desmin, caldesmon, calponin, p16, p53, MDM2, CDK4, bcl-2, cyclin D1, fascin, EMMPRIN, FOXM1, c-erb-B2, c-Myc, PAX8, and CD117. Staining results of uterine and extra-uterine LMS were evaluated with these 20 antibodies. In uterine LMS compared with extra-uterine LMS, estrogen receptor (48% vs. 12%), PR (62% vs. 21%), desmin (79% vs. 50%), and EMMPRIN (69% vs. 45%) staining rate was detected higher. In extra-uterine LMS, caldesmon (88% vs. 69%), c-Myc (33% vs. 10%), and cyclin D1 (52% vs. 28%) were stained higher than uterine LMS (p < 0.05). No significant staining difference was detected with other antibodies. We concluded that estrogen receptor, PR, desmin, EMMPRIN, caldesmon, c-Myc, and cyclin D1 antibodies may help to determine primary origin of the tumor in LMS cases.

Leiomyosarcoma of urinary bladder with unusual recurrence in intestinal mucosa and peritoneum: a case report.

BACKGROUND: Leiomyosarcomas of urinary bladder constitute rare malignant sarcomas with very few cases reported in literature. CASE PRESENTATION: Here, we present a case of bladder leiomyosarcoma in a well-preserved female. She failed to respond to standard chemotherapy and had a rapidly downhill course with unusual metastases in anastomotic site and peritoneum soon after surgery. Despite multimodality management including resection of primary and metastatic site, systemic therapy and pelvic radiotherapy, our patient had dismal prognosis with an overall survival of 1.7 years. CONCLUSION: Leiomyosarcomas of bladder are aggressive tumors and have a very poor prognosis; thus, future research should focus on optimizing more effective treatment regimes.

Leiomyosarcoma: Does Location of Primary Help to Determine the Best Systemic Therapy Options?

OPINION STATEMENT: Management of leiomyosarcoma is based on the specifics of each individual case. Specifically, the location of the disease and whether the disease is metastatic or localized and if localized disease, whether the tumor is resectable or unresectable. In patients with recurrent or metastatic disease, factors such as disease-free interval and pattern of spread should be considered within the context of treatment planning. In general, patients with metastatic disease are typically treated with systemic chemotherapy with either an anthracycline-based regimen or gemcitabine-based regimen as first-line therapy. Additional systemic options include trabectedin, pazopanib, eribulin, and DTIC. Uterine LMS has been the most studied site-specific LMS with respect to systemic therapy. The increasing use of tumor genomics may ultimately define subsets which may benefit from tailored systemic therapies.

Uterine leiomyosarcoma: a rare clinical entity.

Leiomyosarcoma is a rare aggressive malignant mesenchymal tumour, accounting for 1% of all uterine malignancies. It spreads rapidly through the intraperitoneal and haematogenous pathways. It is often diagnosed postoperatively following myomectomy, hysterectomy or supracervical hysterectomy for presumed benign disease. It has a predilection for perimenopausal women with a median age of 50 years. Individuals may describe symptoms of vaginal or abdominal pressure. Physical examination may reveal a large palpable pelvic mass, which may haemorrhage. Surgery remains the mainstay of treatment. Hysterectomy and a bilateral salpingo-oophorectomy may be considered, depending on the individual's menopausal status. Ovarian preservation can be considered in young patients. Adjuvant systemic treatment and radiotherapy are of no benefit. Gemcitabine/docetaxel and doxorubicin have shown benefit in the treatment of advanced or recurrent disease. The authors present the case of a 44-year-old woman with lower abdominal pain, vaginal bleeding and a uterine fibroid. Laboratory investigations confirmed a leucocytosis, neutrophilia and a thrombocythaemia. Further investigation with an MRI pelvis showed a very large, heterogeneous, malignant appearing pelvic mass compressing the right ureter and it appeared uterine in nature. Her staging CT showed multiple lung metastases. The diagnosis of uterine leiomyosarcoma was subsequently established. Due to the aggressive behaviour of this sarcoma subtype, novel early detection strategies and targeted therapies are required.

Therapeutic Management of Rare Primary Ovarian Neoplasms: Carcinosarcoma, Leiomyosarcoma, Melanoma and Carcinoid.

Carcinosarcoma, leiomyosarcoma, melanoma and carcinoid as primary tumors in the ovary are extremely rare. In this paper, the authors reviewed the literature from 2010 to 2021, based on specific criteria, to analyze the treatment of these rare ovarian neoplasms. We also aimed to verify whether modern therapies have been found in recent years. For this article, 80 papers were finally selected. The vast majority of the articles were clinical case reports. Despite single mentions of new potential pharmacological treatments, surgery (radical or fertility-sparing) is definitely the mainstay of treatment. There are currently no treatment guidelines for these tumors. A review of the literature has revealed the use of various adjuvant treatments. We, therefore, believe that a more detailed understanding of the biology of these tumors is necessary in order to find new target points for treatment. We would like to emphasize the importance of creating an international database of rare ovarian tumors which would make it possible to gather data from various oncological centers and enable further research into these neoplasms.