Extrauterine Leiomyosarcomas Research Articles

Feasibility of Longitudinal ctDNA Assessment in Patients with Uterine and Extra-Uterine Leiomyosarcoma.

Background: Leiomyosarcomas (LMS) are aggressive malignancies with a propensity for early relapse. Current surveillance modalities include physical exam and imaging; however, radiological response to therapy may only manifest after 4-6 cycles of treatment. Herein, we evaluated the feasibility of longitudinal circulating tumor DNA (ctDNA) assessment in LMS patients to identify disease progression. Methods: We performed a retrospective review of patients with LMS who underwent treatment at Stanford Cancer Center between September 2019 and May 2022. ctDNA detection was performed using a personalized, tumor-informed ctDNA assay. Genomic analysis was conducted to characterize tumor mutation burden (TMB) and known driver mutations. Results: A total of 148 plasma samples were obtained from 34 patients with uterine (N = 21) and extrauterine (N = 13) LMS (median follow-up: 67.2 (19-346.3) weeks] and analyzed for ctDNA presence. Nineteen patients had metastatic disease. The most frequently mutated driver genes across sub-cohorts were TP53, RB1, and PTEN. Patients were stratified into four sub-cohorts (A-D) based on ctDNA kinetics. ctDNA levels tracked longitudinally with progression of disease and response to therapy. Conclusion: Our results indicate that while undetectable ctDNA may suggest a lower likelihood of relapse, ctDNA positivity may indicate progressive disease, enabling closer monitoring of patients for early clinical intervention.

Differential outcome of females with uterine versus extra-uterine leiomyosarcomas, a retrospective analysis.

e23557 Background: Leiomyosarcomas, are aggressive sarcomas with survival rates among the lowest of all soft tissue sarcomas. Patients with uterine leiomyosarcoma (ULMS) have worse overall survival (OS) than those with extra-uterine leiomyosarcoma (EULMS). The effect of several clinical factors on OS have been investigated, including age, tumor size, grade, stage, and use of chemotherapy. Looking at the epigenetics of the 2 diseases, differentially methylated regions (DMRs) were statistically significant between the 2 groups. Methods: The 2004-2016 National Cancer Database was queried for females with ULMS and EULMS. We investigated several factors as predictors of binary survival status (alive or dead): patient’s age, race, year at diagnosis, tumor grade, size and stage, receipt of surgical treatment, chemotherapy, palliative care, surgical margins and time to treatment in days. Univariate and backward stepwise multivariate logistic regression models were used to determine prognostic factors associated with survival in each group. Kaplan-Meier (KM) method with log-rank test was used to compare OS rates between the 2 groups. All analyses were conducted using Stata/SE 15.1. Results: The total number of subjects was 16883. The median OS was 36.7 months in ULMS vs 57.2 in EULMS (P < 0.001). Older age was associated with a lower likelihood of survival in both groups (OR = 0.95, P = 0.018 in ULMS; OR = 0.97, P < 0.001 in EULMS). Lymphovascular invasion and receipt of palliative care were associated with a relatively large decrease in survival in ULMS only (OR = 0.25, P < 0.001; OR = 0.13, P = 0.015 respectively). In the EULMS group, increased likelihood of survival was associated with later years of diagnosis (OR = 1.27; P < 0.001). Larger tumor size (OR = 0.39; P = 0.001), stages II-IV or unstageable disease (OR = 0.56; P < 0.001), positive surgical margins or margins that were unevaluable (OR = 0.87; P = 0.009) and receipt of systemic therapy (OR = 0.85; P = 0.016) were associated with a lower likelihood of survival. Conclusions: Our study reiterated that females with ULMS had worse OS than those with EULMS. this difference can be attributed to certain clinical risk factors, however, it may also be secondary to genetic and epigenetic factors. Surprisingly, the use of palliative care in this study was associated with poorer OS in the EULMS group. Further studies are needed to investigate the genetic map of these diseases and highlight certain potentially targetable prognostic and predictive factors. Study limitations: Our study did not stratify ULMS and EULMS according to the stage to examine if the aforementioned factors would still be relevant in the limited versus metastatic setting.

A retrospective analysis of gender disparities in clinical outcomes of patients diagnosed with non-uterine leiomyosarcoma.

e23547 Background: The effect of gender in sarcoma patients in various organ systems has been the subject of several studies, many of which show no overall survival (OS) difference between male and female genders. Tumor size and grade have been noted to be independent predictors of local recurrence and disease specific survival in a prospective study of patients with non-uterine leiomyosarcoma by Gaddy et. al. however, gender had no effect on OS. Methods: The 2004-2016 National Cancer Database (NCDB) was queried for males with leiomyosarcoma (LMS) and females with extrauterine leiomyosarcoma (EULMS) using topographical codes C490-C496, and C498-C499. Data included: patient’s age, race, year at diagnosis, tumor grade, size and stage, lymph node involvement, receipt of surgical treatment, chemotherapy or palliative care treatment, surgical margins, time to treatment in days, OS (months between the date of diagnosis and date of death or censored at last contact), and long-term survival defined as survival for 60 months or more. Univariate analysis was used to determine significant predictors of binary survival status (i.e. alive or dead), significant factors were then included in a multivariate analysis. Using Stata/SE 15.1, Kaplan-Meier (KM) method with log-rank test was used to compare and estimate OS rates between the 2 groups. Results: The total number of patients was 13537, with 6311 males (46.6%) and 7226 females (53.4%). The OS in females was 57.2 months compared to 72.0 months in males (P < 0.001). Men were also more likely to achieve long-term survival (36.1%) compared to females (34.4%, P < 0.001). Men with LMS had a lower percentage of chemotherapy use compared to females (18.7% vs 25% respectively, P < 0.001) and palliative care use (3.0% vs 3.5%; P = 0.013). Lower likelihood of survival among both groups was noted in older age (OR = 0.96; P < 0.001 in males; OR = 0.97, P < 0.001 in females), tumor stage > I (OR = 0.64, P = 0.005 in males; OR = 0.56, P < 0.001 in females) and positive surgical margins (OR = 0.76, P = 0.013 in males; OR = 0.87, P = 0.009 in females). Contrarily, increasing year of diagnosis was associated with an increased likelihood of survival (OR = 1.51, P < 0.001 in males; OR = 1.27, P < 0.001 in females). Larger tumor size was also associated with decreased likelihood of survival, but only in the female group (OR = 0.39, P = 0.001). Conclusions: Our analysis shows that males with LMS had a higher OS and higher percentage of long-term survival compared to females. The only factor affecting survival that was different between the 2 groups was the tumor size, which was associated with significantly decreased likelihood of survival in females. No clear explanation for this different survival could be extrapolated from the clinical data collected. Further studies are recommended to investigate the genetic, epigenetic, and possibly hormonal factors that may affect survival in LMS.

Impact of Surgery and Chemotherapy on Metastatic Extrauterine Leiomyosarcoma.

Background: Few studies have described the characteristics and prognostic factors of patients with metastatic extrauterine leiomyosarcoma (euLMS). Therefore, we retrospectively investigated the clinicopathological features, clinical outcomes, and prognostic factors of patients with euLMS. Methods: We recruited 61 patients with metastatic euLMS treated from 2006 to 2020 and collected and statistically analyzed information on patient-, tumor-, and treatment-related factors. The median follow-up period was 21.1 months. Results: Sixty-one patients with euLMS and a median age of 59 years were included. Furthermore, their five-year overall survival (OS) rate was 38.3%. Univariate analysis revealed that primary tumor size >10 cm, synchronous metastasis, initial metastatic sites >1, and no metastasectomy with curative intent were significantly associated with poor OS rate. Multivariate analysis identified primary tumor size >10 cm as an independent prognostic factor for poor OS. Among 24 patients who received metastasectomy with curative intent, the interval from the initial diagnosis to development of metastasis ≤6 months was significantly correlated with unfavorable OS. Among 37 patients who did not receive metastasectomy, chemotherapy after metastasis development was significantly related to better OS. Conclusions: Complete metastasectomy should be considered for metastatic euLMS treatment. Moreover, chemotherapy could prolong survival in patients with metastasis who are ineligible for metastasectomy.

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 alarge antibody panel, and to determine whether they potentially play arole 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.

Prognostic relevance of the hexosamine biosynthesis pathway activation in leiomyosarcoma

Metabolic reprogramming of tumor cells and the increase of glucose uptake is one of the hallmarks of cancer. In order to identify metabolic pathways activated in leiomyosarcoma (LMS), we analyzed transcriptomic profiles of distinct subtypes of LMS in several datasets. Primary, recurrent and metastatic tumors in the subtype 2 of LMS showed consistent enrichment of genes involved in hexosamine biosynthesis pathway (HBP). We demonstrated that glutamine-fructose-6-phosphate transaminase 2 (GFPT2), the rate-limiting enzyme in HBP, is expressed on protein level in a subset of LMS and the expression of this enzyme is frequently retained in patient-matched primary and metastatic tumors. In a new independent cohort of 327 patients, we showed that GFPT2 is associated with poor outcome of uterine LMS but not extra-uterine LMS. Based on the analysis of a small group of patients studied by 18F-FDG-PET imaging, we propose that strong expression of GFPT2 in primary LMS may be associated with high metabolic activity. Our data suggest that HBP is a potential new therapeutic target in one of the subtypes of LMS.

The Use of Smoothelin and Other Antibodies in the Diagnosis of Uterine and Soft Tissue Smooth Muscle Tumors.

Smoothelin is a cytoplasmic protein expressed in differentiated smooth muscle cells. Immunohistochemical evaluation of smoothelin has previously been reported in gastrointestinal (GI) smooth muscle tumors, but has yet to be studied in smooth muscle tumors of uterine and other soft tissue origin. DOG1 expression is reported to be specific for GI stromal tumors; however, variable expression has been reported in leiomyosarcomas (LMS) depending on site of origin. Overexpression of p16 is common in LMS of uterine and other sites of origin, but has not been correlated with tumor grade. This study explores the differential expression of these markers, as well as caldesmon, in LMS cases to assess diagnostic utility. Using tissue microarrays and cases from Tulane Medical Center and Medical College of Wisconsin, expression of smoothelin, DOG1, caldesmon, and p16 was evaluated by immunohistochemistry in 87 cases of LMS. The cases were subdivided by location of origin into uterine (N=31) and nonuterine (N=56) with 10 of the nonuterine of GI origin, as well as by grade into low grade (N=27) and intermediate and high grade (N=60). Differential expression among different grades and locations was evaluated. The same markers were evaluated in atypical leiomyoma cases (N=4) and 1 smooth muscle tumor of uncertain malignant potential case (N=1). Smoothelin expression was also assessed in 20 benign uterine leiomyomas. Weak DOG1 expression is rare but possible in extrauterine LMS. Expression of p16 is common in both uterine and extrauterine LMS, and more frequent in higher grades. Expression of smoothelin in this study differed depending on tumor type, grade, and site of origin. All leiomyomas and most atypical leiomyomas showed cytoplasmic positivity for smoothelin, whereas only 5% of LMS had cytoplasmic expression. The study suggests smoothelin may be downregulated in the cytoplasm of malignant smooth muscle tumor cells and may serve as a supportive aid in the distinction of LMS from benign smooth muscle tumors in cases where it is difficult by morphology alone.

Detection of Circulating Tumor DNA in Patients With Leiomyosarcoma With Progressive Disease.

Leiomyosarcoma (LMS) is a soft tissue sarcoma characterized by multiple copy number alterations (CNAs) and without common recurrent single nucleotide variants. We evaluated the feasibility of detecting circulating tumor DNA (ctDNA) with next-generation sequencing in a cohort of patients with LMS whose tumor burden ranged from no evidence of disease to metastatic progressive disease. Cell-free DNA in plasma samples and paired genomic DNA from resected tumors were evaluated from patients with LMS by ultra-low passage whole genome sequencing (ULP-WGS). Sequencing reads were aligned to the human genome and CNAs identified in cell-free DNA and tumor DNA by ichorCNA software to determine the presence of ctDNA. Clinical data were reviewed to assess disease burden and clinicopathologic features. We identified LMS ctDNA in eleven of sixteen patients (69%) with disease progression and total tumor burden over 5 cm. Sixteen patients with stable disease or low disease burden at the time of blood draw were found to have no detectable ctDNA. Higher ctDNA fraction of total cell-free DNA was associated with increasing tumor size and disease progression. Conserved CNAs were found between primary tumors and ctDNA in each case, and recurrent CNAs were found across LMS samples. ctDNA levels declined following resection of progressive disease in one case and became detectable upon disease relapse in another individual patient. These results suggest that ctDNA, assayed by a widely available sequencing approach, may be useful as a biomarker for a subset of uterine and extrauterine LMS. Higher levels of ctDNA correlate with tumor size and disease progression. Liquid biopsies may assist in guiding treatment decisions, monitoring response to systemic therapy, surveying for disease recurrence and differentiating benign and malignant smooth muscle tumors.

CDK8 Expression in Extrauterine Leiomyosarcoma Correlates With Tumor Stage and Progression.

Mediator is a multiprotein complex that acts as a versatile transcription coactivator in eukaryotes. CDK8 kinase complex is a 4-protein subunit of the mediator complex that can act as a transcriptional repressor or coactivator, depending on the specific pathways involved. Although the role of MED12 exon 2 mutations is documented in the pathogenesis of uterine leiomyomas, its role in extrauterine smooth muscle tumorigenesis is less clear. Similarly, there is a paucity of data on the role of CDK8 in extrauterine smooth muscle tumorigenesis and progression. Our study correlates immunohistochemical expression of CDK8 and MED12 with clinical and pathologic parameters in extrauterine leiomyosarcomas. Immunohistochemical expression of CDK8 and MED12 in leiomyosarcomas was correlated with the tumor grade, stage, and the presence of local recurrence or metastasis. MED12 was expressed in the majority of leiomyosarcomas regardless of their stage or grade. CDK8 expression was lost in 1 of 6 pT1 tumors, compared with 9 of 10 pT2 tumors (P=0.0076). When the second group was expanded to include those tumors that did not have a recorded pathologic stage but had local recurrence and distant metastases, the difference in CDK8 expression was also statistically significant. Loss of CDK8 expression by immunohistochemistry is more prevalent in somatic leiomyosarcomas presenting at a higher histopathologic stage, as well as with local and distant recurrence, and can be used to enhance the current predictive parameters.

A Phase I/II Study Targeting Angiogenesis Using Bevacizumab Combined with Chemotherapy and a Histone Deacetylase Inhibitor (Valproic Acid) in Advanced Sarcomas.

Epigenetic events and genetic alterations under the control of the tumor microenvironment potentially mediate tumor induced angiogenesis involved in soft tissue sarcoma (STS) metastasis. Addition of antiangiogenic agent, such as bevacizumab, to standard chemotherapy in treatment of sarcoma has been studied in clinical trials, but most of the findings have not supported its use. We hypothesized the existence of an epigenetically mediated “angiogenic switch”, and the tumor microenvironment, prevents bevacizumab from truly blocking angiogenesis. The addition of valproic acid (VPA), a weak histone deacetylase inhibitor, and bevacizumab, a monoclonal antibody against vascular endothelial growth factor, together with the cytotoxic effects of gemcitabine and docetaxel, may enhance responses and alter chemoresistance. This was designed as a phase I/II trial with primary endpoints including safety of the treatment combination and tumor response. Unresectable or metastatic sarcoma patients >18 years of age, irrespective of number of prior treatments, received VPA 40 mg/kg orally for 5 days prior to day 1, bevacizumab at 15 mg/kg IV on day 1, gemcitabine 900 mg/m2 (day 1, day 8), and docetaxel 75 mg/m2 (day 8). Cycles were of 28 day duration. Bevacizumab and VPA were continued as maintenance after 6 cycles, until disease progression. A standard 3 + 3 phase I dose de-escalation design was utilized to evaluate safety. Gain of function p53 gene mutation testing was performed on available archival tissue specimens. A total of 46 patients (30 female, 16 male) with median age of 60 (range 24–81) years were enrolled; 34 (73.9%) patients received prior chemotherapy, 14 (30%) of which received prior gemcitabine and docetaxel. Patients received a median of 5.5 cycles (range 0–24 of treatment (min 0, one patient died prior to completing the first cycle; max: 24, one patient received 6 cycles and 18 maintenance cycles before progressing). Seventeen patients underwent dose reduction, of which VPA was reduced in 6 patients. Forty-one patients were evaluable for response. There was a confirmed complete response in 1 (epithelioid sarcoma), and a partial response (PR) in 6 (1 carcinosarcoma, 2 extrauterine leiomyosarcoma (LMS), 2 undifferentiated pleomorphic sarcoma, and 1 uterine LMS) patients. Stable disease (SD) was seen in 21 patients for at least 2 months. One subject with prior gemcitabine and docetaxel had PR, and 7 had SD. Median progression-free survival (PFS) was 5.7 months (95% CI: 2.1–8.0), and overall survival (OS) was 12.9 months (95% CI: 8.3–14.5). Three patients died due to tumor progression while on the study. The combination of VPA, bevacizumab, gemcitabine, and docetaxel appears to be moderately safe and well tolerated. Given that there are very limited options for patients with relapsed refractory STS, this drug combination may be an important therapy to consider. This combination treatment deserves further investigation in epithelioid and carcinosarcoma subtypes.

Abstract B23: A pilot study targeting angiogenesis using bevacizumab combined with gemcitabine/docetaxel and valproic acid (VPA), a histone deacetylase inhibitor (HDACi), in advanced soft tissue sarcomas (STS)

Abstract Introduction: Many of the signaling pathways involved in angiogenesis also drive STS tumor cell growth. Autocrine and paracrine vascular endothelial growth factor (VEGF) and platelet-derived growth factor mediated growth plays a role in the pathogenesis of several STS subtypes. Relatively few clinical trials have evaluated the role of combining angiogenesis inhibitors, like bevacizumab, with chemotherapy in sarcoma with mostly negative results. We hypothesized that the microenvironment may prevent bevacizumab from truly blocking angiogenesis and that there may exist an “angiogenic switch” that is epigenetically mediated. Epigenetically modifying the tumor microenvironment prior to chemotherapy has been shown to improve cytotoxic cell kill and response rates. Gain-of-function p53 mutant tumors are poor chemotherapy responders and cause genome-wide increase in histone methylation and acetylation. VPA is a known HDACi with antitumor effects and suppresses neovascularization. Herein we combined pulse dose of VPA with bevacizumab and standard chemotherapy (gemcitabine/docetaxel) to better modulate the cytotoxic effects against STS. Materials and Methods: Subjects with locally advanced, unresectable, or metastatic STS of any site and all subtypes with measurable disease were enrolled. GIST, bone, and Kaposi's sarcomas were excluded. VPA at 40-mg/kg dosage was given for 5 days prior to each cycle and was repeated before each cycle. Gemcitabine 900 mg/m2 on days 1 and 8 and docetaxel 75 mg/m2 on day 8 were administered on a 28-day schedule. Bevacizumab 15 mg/kg every 4 weeks was administered on day 1 throughout chemotherapy and after chemotherapy was completed. Subjects were treated for a total of 6 cycles and assessed every 2 cycles for progression. Treatment was terminated on disease progression or with unacceptable toxicity. All pathologic diagnoses were confirmed by a pathologist with subspecialty training in bone and soft-tissue pathology. Results: 46 subjects (30 female, 16 male) with median age of 60 (range 24-81) years and a median of 1 (range 0-6) prior line of chemotherapy were enrolled. Sarcoma subtypes included extrauterine leiomyosarcoma (LMS) (9), uterine LMS (8), undifferentiated pleomorphic (7), angiosarcoma, carcinosarcoma, liposarcoma (4 each), and other types (10). 34 (73.9%) subjects received prior chemotherapy, 14 (30%) of whom received prior gemcitabine and docetaxel. 16 (34.8%) received prior radiation and 44 (95.7%) had prior surgery. 5 (12%) of 41 subjects had gain-of-function p53 mutation. Subjects received a median of 5.5 cycles (0-15) of treatment. 17 subjects underwent dose reduction of which VPA was reduced in 6 subjects. 42 subjects were evaluable for response. There was a complete response in 1 (epithelioid) and a partial response (PR) in 6 (1 carcinosarcoma, 2 extrauterine LMS, 2 undifferentiated pleomorphic, and 1 uterine LMS) subjects. Stable disease (SD) was seen in 21 subjects. One subject with prior gemcitabine and docetaxel had PR and 7 had SD. Median progression-free survival (PFS) was 5.7 months (95% CI: 2.1-8) and overall survival (OS) was 12.9 months (95% CI: 8.3-14.5). In LMS subgroup median PFS was 8.4 months (95% CI: 2-8.6) and median OS was 16.3 months (95% CI: 8.1-26.5). Grade 3/4 bevacizumab and VPA-related hematologic toxicities were observed in 2% and 13% and nonhematological toxicities in 9% and 13% of subjects, respectively. Conclusions: Addition of VPA and bevacizumab to gemcitabine and docetaxel showed a clinical benefit rate of 61.54 % in subjects with prior gemcitabine and docetaxel. This regimen is safe and toxicities are manageable. The overall response rate in the study was 16.67%. The combination deserves further investigation in epithelioid and carcinosarcoma subgroups. Citation Format: Umang Swami, Varun Monga, Munir Tanas, Aaron Bossler, Sarah Mott, Brian Smith, Mohammed Milhem. A pilot study targeting angiogenesis using bevacizumab combined with gemcitabine/docetaxel and valproic acid (VPA), a histone deacetylase inhibitor (HDACi), in advanced soft tissue sarcomas (STS) [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr B23.

Omnipresent, omnipotent - extra-uterine leiomyosarcoma with varied presentation - case series of a dozen!!

Background: Leiomyosarcoma (LMS), accounting for 7-10% of all soft tissue tumors, is derived from smooth muscles and arises most commonly from uterus, retroperitoneum, extremities, but can potentially involve any site of the body. Through this case series of 12 extra-uterine LMSs, we highlight the wide variety of clinical presentations of this tumor. Methods: Retrospective analysis of clinical details, histopathological examination (HPE) and immunohistochemistry (IHC) of LMSs diagnosed in the extra uterine sites from 2012-2016 in our tertiary care institute. Result: The mean age of presentation was 55.8 years, with male: female ratio 2:1. The site distribution was: stomach (3), non visceral soft tissue-thigh (2), breast (2), cutaneous (2), ileum(1), esophagus(1), and larynx (1). Conclusion: The variable presentations of LMS at extra-uterine sites, makes it a challenging diagnosis for the unsuspecting clinicians and histopathologists. Thus, any soft tissue tumor in similar clinical scenarios may turn out to be LMS. DOI:10.21276/APALM.1588

Uterine leiomyosarcomas exhibit distinct drug resistance molecular profiles compared to extrauterine leiomyosarcomas: A comprehensive analysis of 1,023 leiomyosarcomas

Uterine leiomyosarcomas exhibit distinct drug resistance molecular profiles compared to extrauterine leiomyosarcomas: A comprehensive analysis of 1,023 leiomyosarcomas

Overall Survival and Response to Systemic Therapy in Metastatic Extrauterine Leiomyosarcoma.

Background. Leiomyosarcomas (LMS) represent a heterogeneous subset of soft tissue sarcomas. Factors influencing prognosis for patients with metastatic extrauterine LMS (euLMS) are not well described. Limited data are available regarding responses to systemic therapy. Methods. We collected clinical and pathologic information for all patients with metastatic euLMS seen at Memorial Sloan Kettering Cancer Center between 1989 and 2012. Objective responses to first-line therapy were analyzed for a subset of patients with available baseline and on-treatment imaging using RECIST 1.1. Results. 215 patients with metastatic euLMS had a median overall survival (OS) of 2.6 years from the time of metastasis. Older age, male sex, and ≥3 initial sites of metastasis were associated with worse OS on multivariate analysis. Objective response rate (ORR) in N = 113 was 19% overall and 25%, 26%, and 25% for gemcitabine, gemcitabine plus docetaxel, and anthracycline-alkylator combinations. Patients whose tumors objectively responded to first-line therapy had a lower risk of death versus those who did not (Hazard Ratio 0.46; 95% CI: 0.26–0.79, p = 0.005). Conclusions. Anthracycline- and gemcitabine-based regimens have similar activity in this cohort of euLMS. Prognostic factors for OS include older age, male sex, and ≥3 initial sites.

Clinically Relevant Molecular Subtypes in Leiomyosarcoma.

Leiomyosarcoma is a malignant neoplasm with smooth muscle differentiation. Little is known about its molecular heterogeneity and no targeted therapy currently exists for leiomyosarcoma. Recognition of different molecular subtypes is necessary to evaluate novel therapeutic options. In a previous study on 51 leiomyosarcomas, we identified three molecular subtypes in leiomyosarcoma. The current study was performed to determine whether the existence of these subtypes could be confirmed in independent cohorts. Ninety-nine cases of leiomyosarcoma were expression profiled with 3'end RNA-Sequencing (3SEQ). Consensus clustering was conducted to determine the optimal number of subtypes. We identified 3 leiomyosarcoma molecular subtypes and confirmed this finding by analyzing publically available data on 82 leiomyosarcoma from The Cancer Genome Atlas (TCGA). We identified two new formalin-fixed, paraffin-embedded tissue-compatible diagnostic immunohistochemical markers; LMOD1 for subtype I leiomyosarcoma and ARL4C for subtype II leiomyosarcoma. A leiomyosarcoma tissue microarray with known clinical outcome was used to show that subtype I leiomyosarcoma is associated with good outcome in extrauterine leiomyosarcoma while subtype II leiomyosarcoma is associated with poor prognosis in both uterine and extrauterine leiomyosarcoma. The leiomyosarcoma subtypes showed significant differences in expression levels for genes for which novel targeted therapies are being developed, suggesting that leiomyosarcoma subtypes may respond differentially to these targeted therapies. We confirm the existence of 3 molecular subtypes in leiomyosarcoma using two independent datasets and show that the different molecular subtypes are associated with distinct clinical outcomes. The findings offer an opportunity for treating leiomyosarcoma in a subtype-specific targeted approach.

MED12 exon 2 mutations in uterine and extrauterine smooth muscle tumors

Mutations in exon 2 of the MED12 gene have been reported in 50% to 70% of uterine leiomyomas. To determine the frequency of MED12 mutations in various types of smooth muscle tumors as well as normal uterine myometrium adjacent to a leiomyoma, we selected a total of 143 cases for analysis of MED12 exon 2 mutations by polymerase chain reaction and Sanger sequencing. MED12 mutations were detected in 54% of classical uterine leiomyomas (15/28) and in 15% of cases in myometrium adjacent to leiomyomas (2/13); 34% of leiomyoma/leiomyomatosis in pelvic/retroperitoneal sites (10/29); 0% of extrauterine leiomyomas (0/29); 8% of smooth muscle tumor of uncertain malignant potential (1/12); 30% of uterine leiomyosarcomas (6/20); and 4% of extrauterine leiomyosarcomas (1/25). Mutations were clustered around codons 44, 40, 41, and 36, and consisted primarily of single nucleotide substitutions and small in-frame deletions. Our results confirm the findings of similar recent studies and further show that pelvic and retroperitoneal leiomyomas harbor an increased frequency of MED12 mutations (34%) as compared with other extrauterine sites (0%; P = 0.0006), and that histologically unremarkable adjacent myometrium can harbor similar MED12 mutations. These findings suggest that smooth muscle tumors in pelvic/retroperitoneal sites are subject to the same mutational changes as those of uterine myometrium, and that these mutations may precede the gross or histological development of a leiomyoma.

Bilateral Renal Metastases In Oral Leiomyosarcoma: A Case Report

A primary leiomyosarcoma in the oral cavity with bilateral renal metastasis in a 22-year-old female is reported. The tumour started during pregnancy and progressed to form a large unresectable mass post delivery. CT scan showed an extensive soft tissue lesion in the maxilla extending to the floor of the middle cranial fossa, oral cavity, parapharyngeal space and facial soft tissue. FNA and biopsy from maxilla showed a spindle cells lesion, which expressed smooth muscle actin and desmin in immunohistochemistry and was diagnosed as leiomyosarcoma. The tumour did not express estrogen and progesterone receptors, which have been reported in some uterine and extrauterine leiomyosarcomas. CT scan abdomen showed bilateral heterogeneously enhancing masses in right and left kidneys. CT guided FNA showed clusters of malignant spindle cells. The patient is being treated with chemotherapy consisting of Adriamycin 60mg (Day1) and Ifosfamide 2g (Day1 to Day3) to be given in 6 courses at an interval of 21 days. The case is interesting due its presentation in association with pregnancy and the presence of bilateral renal metastases. Renal metastases from sarcomas are very rare and have not been reported in primary leiomyosarcoma of oral cavity, which in turn is a rare tumor.

Leiomyosarcoma of the inferior vena cava

We describe 3 cases of leiomyosarcoma of the inferior vena cava (IVC) and review the literature describing clinicopathologic features of 211 cases and the outcome. Of these, 74% of the cases affected women with median age of 52 years. The most common symptoms were abdominal pain or mass (57%), Budd-Chiari syndrome (17%), and deep vein thrombosis (4%). The most frequent site of tumor origin is the middle segment of the IVC (33%). Tumor size ranged from 2 to 38 cm (mean, 12 cm). Of the tumors with an assigned grade, 46% were high grade, 17% were intermediate grade, and 36% were low grade. Of all patients, 47% underwent complete resection, 24% had complete resection with preoperative or postoperative chemotherapy and/or radiation, and 5% had palliative surgery. Tumor recurrence occurred in 40% of the patients (11% had local recurrence and 29% had metastasis). Perioperative mortality occurred in 4% of the cases. Of those patients who died, 42% died of the disease, 2% died of other causes, 26% were alive and free of the disease, 14% were alive with recurrent disease, and 11% were lost to follow-up. Tumors involving level 2 of the IVC have the best prognosis and tumors of level 1 have the worse prognosis. Although there is no standardized criteria for the grading of extrauterine leiomyosarcoma, we propose to grade based on mitotic activity as follows: high grade, 10 or more mitoses per 10 high-power field (HPF); intermediate grade, 5 to 9 mitoses per 10 HPF; and low grade, 1 to 4 mitoses per 10 HPF.

Loss of DNA copy number of 10q is associated with aggressive behavior of leiomyosarcomas: a comparative genomic hybridization study

Leiomyosarcomas (LMS) account for 10–20% of all soft tissue sarcomas. We analyzed 10 primary, 5 metastatic, and 2 recurrent extrauterine LMS. Genomic imbalances were detected in 15 out of the 17 tumors. The most common regions of loss were 13q (59%, 10 of 17), 10q (59%, 10 of 17), 2q (35%, 6 of 17), and 16q (29%, 5 of 17). The most common region of gain was 5p (35%, 6 of 17). High-level gain of DNA copy number was detected in 6p and 17p. Loss of function of tumor suppressor genes or the activation of oncogenes (or both of these factors) resulting from these copy number changes might play an important role in the development of extrauterine LMS. Large tumors and tumors with metastasis showed 10q deletions. Gain of 5p was detected only in G3 tumors. These findings are consistent with our earlier study on uterine LMS and indicate that loss of 10q and gain of 5p are associated with an aggressive behavior of LMS. A larger series of cases is needed to confirm these results.

Estrogen and Progesterone Receptor Expression in Uterine and Extrauterine Leiomyosarcomas

The authors have noted anecdotal cases of extrauterine leiomyosarcomas (LMS) with estrogen receptor (ER) and progester-one receptor (PR) immunoreactivity. However, there are few studies that have compared ER and PR immunoexpression in LMS of uterine and extrauterine origin. The authors obtained a representative formalin-fixed, paraffin-embedded tissue block from cases of uterine LMS (n = 15) and extrauterine LMS (n = 16) from the archives of the Cleveland Clinic Foundation and performed immunohistochemical staining for ER and PR. Staining was evaluated by 2 observers in a semiquantitative manner using the following scale: 0, no nuclear staining; 1+, 1 to 25% of nuclei stained; 2+, 26 to 50% of nuclei stained; 3+, 51 to 75% of nuclei stained; 4+, 76 to 100% of nuclei stained. The majority of uterine LMS stained for ER (13 of 15, 87%), PR (12 of 15, 80%), or both ER and PR (12 of 15, 80%), with most cases showing 3+ or 4+ positive staining. For the extrauterine LMS cases, staining for ER was seen in 4 of 16 cases (25%), staining for PR was observed in 2 of 16 cases (13%), and staining for both ER and PR was seen in 2 of 16 cases (13%). One extrauterine LMS showed 4+ coexpression of ER and PR, but the remaining extrauterine cases showed only 1+ ER and/or PR immunoreactivity. These data suggest that most uterine LMS coexpress ER and PR, and most extrauterine LMS do not stain for these antigens. However, a subset of extrauterine LMS are ER and/or PR immunoreactive. This raises the possibility that hormonal manipulation may be beneficial in the treatment of these therapeutically recalcitrant tumors.