Leiomyosarcoma Subtypes Research Articles

Demystifying primary bone leiomyosarcoma: A case study and literature overview

Primary leiomyosarcoma of the bone (LMSB). It's indeed an extremely rare and challenging condition, and case reports like the one you mentioned are valuable in increasing awareness and understanding among clinicians and researchers. LMSB is a subtype of leiomyosarcoma that originates in the bone, specifically the primary bone tissue, and it's distinct from more common bone tumors like osteosarcoma or chondrosarcoma. Given its rarity, diagnosing and treating LMSB can be quite complex, and histopathological examination is often essential to confirm the diagnosis. Treatment options for LMSB are generally limited, and the approach may involve a combination of surgery, radiation therapy, and chemotherapy, although the optimal treatment strategy may vary from case to case. The prognosis for LMSB is generally poor, but early diagnosis and timely intervention can make a difference in patient outcomes. Case reports like the one you mentioned are essential for improving our knowledge of rare diseases like LMSB. They can help clinicians and researchers better understand the condition, its clinical features, and potential treatment strategies. Sharing such cases within the medical community can lead to the development of more effective diagnostic and treatment approaches and potentially improve the prognosis for affected individuals in the future.

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.

Molecular subtypes of leiomyosarcoma: Moving toward a consensus

Molecular subtypes of leiomyosarcoma: Moving toward a consensus

Lineage-defined leiomyosarcoma subtypes emerge years before diagnosis and determine patient survival

Leiomyosarcomas (LMS) are genetically heterogeneous tumors differentiating along smooth muscle lines. Currently, LMS treatment is not informed by molecular subtyping and is associated with highly variable survival. While disease site continues to dictate clinical management, the contribution of genetic factors to LMS subtype, origins, and timing are unknown. Here we analyze 70 genomes and 130 transcriptomes of LMS, including multiple tumor regions and paired metastases. Molecular profiling highlight the very early origins of LMS. We uncover three specific subtypes of LMS that likely develop from distinct lineages of smooth muscle cells. Of these, dedifferentiated LMS with high immune infiltration and tumors primarily of gynecological origin harbor genomic dystrophin deletions and/or loss of dystrophin expression, acquire the highest burden of genomic mutation, and are associated with worse survival. Homologous recombination defects lead to genome-wide mutational signatures, and a corresponding sensitivity to PARP trappers and other DNA damage response inhibitors, suggesting a promising therapeutic strategy for LMS. Finally, by phylogenetic reconstruction, we present evidence that clones seeding lethal metastases arise decades prior to LMS diagnosis.

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.

A Retrospective Analysis of the Efficacy of Immunotherapy in Metastatic Soft-Tissue Sarcomas.

Although checkpoint inhibitors have been approved in multiple cancers, they are still under investigation in soft tissue sarcoma (STS). We conducted a retrospective review to report the safety, efficacy, and prognostic factors related to checkpoint inhibitors in STS. A sequential cohort of metastatic STS patients from four institutions treated with checkpoint inhibitors was assembled. Logistic and Cox regression models were applied to determine the effect of patient characteristics, prior treatment, and baseline factors on achieving the best overall response of complete response (CR), partial response (PR), or stable disease (SD) as determined by the treating physician. Eighty-eight patients with two median prior therapies received checkpoint inhibitors. Treatments included pembrolizumab in 47, nivolumab in 6, ipilimumab in 1, combination ipilimumab/nivolumab in 27, and other combination immunotherapies in 7 patients. Immunotherapy was discontinued in 54 patients—72.2% for progression, 16.7% for toxicity, and 11.1% for other reasons. Median progression-free survival (PFS) was 4.1 months and median overall survival was 19.1 months. One patient with undifferentiated pleomorphic sarcoma (UPS) achieved a CR, while 20 patients had a PR, including 7 UPS, 9 leiomyosarcoma (LMS), and 1 each with alveolar soft part sarcoma, fibroblastic sarcoma, sclerosing epithelioid fibrosarcoma, and myxofibrosarcoma. Forty-five percent (9 of 20) of LMS patients achieved a PR. Twenty-eight patients had SD. Our results confirm the activity and safety of anti-PD-1 therapy in metastatic STS. A notable response rate was observed in UPS and LMS subtypes. This study expands the knowledge base beyond what is currently available from clinical trials involving checkpoint inhibitors in metastatic STS.

Leiomyosarcoma of the Inferior Vena Cava with Hepatic and Pulmonary Metastases: Case Report

Sarcomas are connective tissue tumors accounting for only 1% of all adult malignancies. Leiomyosarcoma (LMS) is a sarcoma arising from smooth muscle cells, and accounts for 10-20% of all sarcomas. A subtype of LMS are those originating from the smooth muscle of blood vessels. Leiomyosarcoma of the inferior vena cava is a sarcomatous tumor, with less than 350 cases described in the literature. It carries a poor prognosis, with 5- and 10-year survival rates of 31.4% and 7.4%, respectively. We present a case of a 46-year-old female with no significant past medical history presented to the emergency department with mild abdominal pain and distention, early satiety, and weight loss for three weeks, found to have unresectable metastatic leiomyosarcoma of the inferior vena cava.

Practical issues in uterine pathology from banal to bewildering: the remarkable spectrum of smooth muscle neoplasia

Among mesenchymal tumors of the uterus, smooth muscle neoplasms are most common. The wide morphologic spectrum, especially within the category of leiomyomas, is responsible for diagnostic problems more frequently with leiomyosarcoma (including mitotically active, apoplectic, and leiomyoma with bizarre nuclei) but also with endometrial stromal tumors. In the former scenario, clinical information, gross appearance as well as strict utilization of morphologic criteria including cytologic atypia, mitotic activity, and tumor cell necrosis are clues in establishing the correct diagnosis. It is important to keep in mind that mitotic rate thresholds vary for the different subtypes of leiomyosarcoma. Of note, p16 should be used with caution in supporting a diagnosis of leiomyosarcoma as it is often positive in leiomyomas with bizarre nuclei and leiomyomas with apoplectic change (in the latter most frequently and more intense near areas of necrosis). MED12 mutations have also a very limited role in this differential diagnosis. Endometrial stromal tumors are by far, less common than smooth muscle tumors, but can be confused with leiomyosarcomas if they are associated with an undifferentiated uterine sarcoma and the low-grade component is overlooked or they have a myxoid/fibroblastic morphology. The differential diagnosis may be confounded if the latter is associated with a high-grade endometrial stromal sarcoma. It is important to highlight that CD10 is not a reliable marker in these differentials and should be used as a part of a panel of antibodies that also includes desmin and h-caldesmon. Two other recently categorized tumors in the uterus that merit special mention are PEComa and inflammatory myofibroblastic tumor as they enter in the differential diagnosis of smooth muscle tumors. PEComa may be part of the tuberous sclerosis syndrome and may show either a predominantly epithelioid or spindle morphology or combination thereof. Rarely, it may contain melanin pigment. There is variable positivity for HMB-45, MelanA, MiTF, and CathepsinK, and some tumors have been shown to express TFE-3 especially when associated with "clear cell" morphology. Patients with adverse outcome have tumors with ≥2 of the following features: ≥5 cm, infiltration, high-grade cytologic features, mitotic rate ≥1/50 high-power fields, necrosis, or lymphovascular invasion. Inflammatory myofibroblastic tumor is important to recognize as it often mimics myxoid smooth muscle tumors, either benign or malignant. The presence of an associated lymphoplasmacytic infiltrate should alert to that possibility and ALK studies (immunostain or FISH) are helpful in establishing this diagnosis. These tumors can behave in a malignant manner if large, associated with abundant myxoid change, brisk mitotic rate or show tumor cell necrosis.

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.

Recent advances in understanding and managing leiomyosarcomas.

Leiomyosarcomas are malignant mesenchymal tumours that derive from the smooth muscle lineage. They are studied and frequently treated as if they are the same as other soft tissue sarcomas. Recent developments suggest that a different approach may be more appropriate. Their underlying genetic mechanisms remain unclear, and complex. Unbalanced karyotypic defects are the only shared features observed across different leiomyosarcoma subtypes. Unlike other soft tissue sarcomas, leiomyosarcomas are particularly sensitive to the combination of gemcitabine and docetaxel. Furthermore, treatment with trabectedin has shown a good efficacy in leiomyosarcomas, mainly in the form of chronic disease stabilisation.

Contemporary management and classification of hepatic leiomyosarcoma

BackgroundHepatic leiomyosarcomas are rare soft-tissue tumours. The majority of lesions previously considered as leiomyosarcomas have been identified as gastrointestinal stromal tumours (GISTs). Consequently, understanding of the role of liver resection for true leiomyosarcoma is limited, a fact that is exacerbated by the increasing recognition of leiomyosarcoma subtypes. This study presents data on the outcomes of liver resection for leiomyosarcoma and suggests an algorithm for its pathological assessment and treatment. MethodsPatients were identified from a prospectively collected departmental database. All tumours were negative for c-kit expression. Immunohistochemistry was performed to identify the presence of oestrogen or progesterone receptor (OR/PR) expression or Epstein–Barr virus (EBV) and patients were stratified according to this profile. ResultsEight patients (of whom seven were female) underwent a total of 11 liver resections over a 12-year period. One patient had a primary hepatic leiomyosarcoma. Of those with metastatic leiomyosarcomas, the primary tumours were located in the mesentery, gynaecological organs and retroperitoneum in four, two and one patient, respectively. Both leiomyosarcomas of gynaecological origin stained positive for OR/PR expression. One patient had previously undergone renal transplantation; this leiomyosarcoma was associated with EBV expression. Median survival was 56 months (range: 22–132 months) and eight, six and four patients remained alive at 1, 3 and 5 years, respectively. ConclusionsHepatic resection for leiomyosarcoma is associated with encouraging rates of 5-year overall and disease-free survival. The worse outcome that had been expected based on data derived from historical cohorts (partly comprising subjects with GIST) was not observed. An algorithm for pathological classification and treatment is suggested.

Trabectedin in Soft Tissue Sarcomas

Soft tissue sarcomas are a group of rare tumors derived from mesenchymal tissue, accounting for about 1% of adult cancers. There are over 60 different histological subtypes, each with their own unique biological behavior and response to systemic therapy. The outcome for patients with metastatic soft tissue sarcoma is poor with few available systemic treatment options. For decades, the mainstay of management has consisted of doxorubicin with or without ifosfamide. Trabectedin is a synthetic agent derived from the Caribbean tunicate, Ecteinascidia turbinata. This drug has a number of potential mechanisms of action, including binding the DNA minor groove, interfering with DNA repair pathways and the cell cycle, as well as interacting with transcription factors. Several phase II trials have shown that trabectedin has activity in anthracycline and alkylating agent-resistant soft tissue sarcoma and suggest use in the second- and third-line setting. More recently, trabectedin has shown similar progression-free survival to doxorubicin in the first-line setting and significant activity in liposarcoma and leiomyosarcoma subtypes. Trabectedin has shown a favorable toxicity profile and has been approved in over 70 countries for the treatment of metastatic soft tissue sarcoma. This manuscript will review the development of trabectedin in soft tissue sarcomas.

Rare Occurrence of an Epithelioid Leiomyosarcoma in a Uterine Leiomyoma

Leiomyosarcoma of the uterus is a malignant tumor arising from the smooth muscle of the uterus. It is a rare tumor with an incidence as low as 2%-5% of all uterine malignancies. Besides the conventional type, one of the important variants includes the epithelioid leiomyosarcoma which is by itself a rare subtype of leiomyosarcoma. The precise diagnosis of leiomyosarcoma is essential since it has an aggressive behaviour. We present a rare case of Leiomyosarcoma of the epithelioid variant arising in a leiomyoma.

Prognostic role of E-cadherin and Vimentin expression in various subtypes of soft tissue leiomyosarcomas

The gain of E-cadherin and loss of Vimentin known as "Cadherin switching" resulting in epithelial differentiation play an important role in tumor cell invasion and metastasis. In soft tissue leiomyosarcoma (LMS), aberrant expression of E-cadherin and down-regulation of Vimentin-related Mesenchymal to Epithelial Reverting Transition was defined, but the role of these proteins in various subtypes of LMS have not been well demonstrated yet. The aim of this study was to evaluate the prognostic role of E-cadherin and Vimentin expression in 45 soft tissue leiomyosarcoma samples by Immunohistochemistry analysis. E-cadherin was positive in a small proportion of LMS, accounting for 15.6 % (7/45). All LMS samples expressed Vimentin, concluding 20 patients as strong positive group (44.4 %), 25 patients as week positive group (55.6 %). Although the aberrant expression of E-cadherin had no differences among various subtypes of LMS, it was significantly associated with early clinical stages. The patients with strong positive expression of Vimentin suffered significant high risk of recurrence and metastasis and also had significant worse overall survival. These data suggest that the epithelial differentiation of LMS evaluated by E-cadherin expression does not belong to certain subtypes in LMS. The patients with the gain of E-cadherin and loss of Vimentin expression represent favorable trend of survival. They might serve as good biomarkers of the LMS clinical outcome after further investigations.

Comparative Gene Expression Profiling of Benign and Malignant Lesions Reveals Candidate Therapeutic Compounds for Leiomyosarcoma

Leiomyosarcoma (LMS) is a malignant, soft-tissue tumor for which few effective therapies exist. Previously, we showed that there are three molecular subtypes of LMS. Here, we analyzed genes differentially expressed in each of the three LMS subtypes as compared to benign leiomyomas and then used the Connectivity Map (cmap) to calculate enrichment scores for the 1309 cmap drugs in order to identify candidate molecules with the potential to induce a benign, leiomyoma-like phenotype in LMS cells. 11 drugs were selected and tested for their ability to inhibit the growth of three human LMS cell lines. We identified two drugs with in vitro efficacy against LMS, one of which had a strongly negative enrichment score (Cantharidin) and the other of which had a strongly positive enrichment score (MG-132). Given MG-132's strong inhibitory effect on LMS cell viability, we hypothesized that LMS cells may be sensitive to treatment with other proteasome inhibitors and demonstrated that bortezomib, a clinically-approved proteasome inhibitor not included in the original cmap screen, potently inhibited the viability of the LMS cell lines. These findings suggest that systematically linking LMS subtype-specific expression signatures with drug-associated expression profiles represents a promising approach for the identification of new drugs for LMS.

Analysis of differential diagnostic gene expression profiles in uterine leiomyoma and leiomyosarcoma

Objective: Smooth muscle tumors are the most frequent mesenchymal tumors of the uterus, the majority of which are readily classifiable as benign or malignant. However, when unusual features are seen in some leiomyoma (fibroid) variants, the differential diagnosis with a leiomyosarcoma may become challenging. Moreover, diagnostic criteria for the different subtypes of leiomyosarcoma are not uniform. Correct diagnosis has important prognostic and therapeutic implications. We examined the transcriptomes of normal myometrium, benign uterine fibroids and uterine leiomyosarcoma in search of a molecular signature that would aid in differentiating between benign and malignant lesions of the myometrium.

Smooth Muscle Tumors of the Uterus: A Practical Approach

Smooth muscle tumors (SMTs) are the most frequent mesenchymal tumors of the uterus. The majority of the uterine SMTs are readily classificable as benign or malignant based on their gross and microscopic appearances. However, when unusual features are seen in some leiomyoma variants, the differential diagnosis with a leiomyosarcoma may become challenging. Moreover, diagnostic criteria for the different subtypes of leiomyosarcoma are not uniform. Finally, non-smooth muscle tumors that originate in the uterus may show overlapping histologic and even immunohistochemical features with uterine SMTs, more commonly with the spindle and epithelioid variants, complicating their correct classification. The diagnosis of malignant uterine SMTs has important prognostic and therapeutic implications. This review provides a practical approach to the diagnosis of uterine leiomyosarcoma based on a systematic assessment of histologic parameters as well as a systematic approach to its differential diagnosis based on histologic and immunohistochemical features.

Spindle Cell Tumor With EWS-WT1 Transcript and a Favorable Clinical Course: A Variant of DSCT, a Variant of Leiomyosarcoma, or a New Entity? Report of 2 Pediatric Cases

We report 2 intra-abdominal tumors originally diagnosed as leiomyosarcomas, occurring in adolescents, one as a second malignancy after a Hodgkin lymphoma. Both tumors exhibited unusual morphologic features characterized by spindle cells arranged in sheets or in fascicles, devoid of the typical desmoplastic stroma. Cytokeratins and mesenchymal markers, including smooth muscle actin, desmin, and muscle specific actin, were coexpressed in the tumor cells, whereas EMA was negative. Reverse transcription-polymerase chain reaction analysis showed an EWS-WT1 fusion transcript. Both patients are alive and in complete remission at 3 and 13 years after diagnosis, respectively. These tumors raise a variety of diagnostic possibilities. They could represent intra-abdominal desmoplastic small round cell tumor, with histologic features of epithelioid leiomyosarcoma or an unusual subtype of leiomyosarcoma with an EWS-WT1 transcript. Alternatively, they could represent an unrecognized subgroup of tumors with spindle cell morphology, bearing the same translocation as desmoplastic small round cell tumor, but characterized by a more favorable clinical course.