Soft Tissue Leiomyosarcoma Research Articles

Abstract 5196: Different miRNAs expression in leiomyosarcoma and undifferentiated pleomorphic sarcoma

Abstract Rare and highly aggressive adult soft tissue sarcomas, leiomyosarcoma (LMS) and undifferentiated pleomorphic sarcoma (UPS), contain complex genomics characterized by a multitude of rearrangements, amplifications and deletions. Since differential diagnosis between the two sarcoma histotypes continues to remain a challenge, we attempted to identify a specific signature useful for improving the differential diagnosis, and we performed miRNA profiling on series of LMS and UPS samples stored at Rizzoli biobank. First, we investigated the different miRNA expression profile in 20 primary sarcoma samples, 10 high-grade LMS and 10 UPS, MFH-like, using miRNA array technique. The top 5 differentially expressed (p<0.01) miRNAs (miR-199b-5p, miR-320a, miR-199a-3p, miR-126, miR-22) were validated by RT-PCR on a series of further 27 UPS and 21 LMS. Confirming our microarray data, an higher expression of miR-199-5p and a lower expression of miR-320a was seen in UPS when compared to LMS. To evaluate the potential role of the above selected miRNAs, the gene targets recognized by three different target prediction databases (miRBase, TargetScan , miRanda) were combined with a list of LMS- and UPS-associated genes reported in literature. From an integrated analysis, IMP3, ROR2, MDM2, CDK4, and UPA genes were identified. By immunohistochemistry analysis, most of them showed strong protein expression in LMS group. Our data suggest a potential role of miR-320a and miR-199-5p in LMS and UPS development and expand our knowledge about these complex sarcoma histotypes. Association analysis between expression and chromosomal locations of miRNAs are ongoing to identify chromosomal regions involved in these tumors. Citation Format: Laura Pazzaglia, Mohamed Guled, Ioana Borze, Maria Serena Benassi, Piero Picci, Sakari Knuutila. Different miRNAs expression in leiomyosarcoma and undifferentiated pleomorphic sarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5196. doi:10.1158/1538-7445.AM2014-5196

Microcirculation density and maturity in uterine and soft tissue leiomyosarcomas: an immunohistochemical study.

The role of angiogenesis as a hallmark of tumor progression has been poorly explored in leiomyosarcoma, a rare but aggressive mesenchymal malignancy. We aimed to characterize microvessel distribution and morphology - including pericyte coverage - in a retrospective series of leyomiosarcomas of the soft tissues and the uterus. 41 whole-block tumor slides from formalin-fixed paraffin-embedded tissues were immunostained for endothelial-specific marker CD31 and microvessel density was quantified by assigning a grade to the frequency of CD31 positive microvessels. Vessel morphology and pericyte coverage were investigated by double-labeling for CD31 and either PDGFRβ, αSMA, desmin, CD90, or CD146. We found that microvessel density correlated with tumor grade in leiomyosarcoma of soft tissues, in analogy with what has been established in several types of carcinoma. This did not apply to uterine leiomyosarcoma, possibly due to the abundant myometrial vascularization. The evaluation of perivascular cell markers related to vessel stability revealed immature microvascular networks with aberrant pericyte coverage, irrespective of tumor origin or grade. Our observations substantiate the role of angiogenesis in the progression of soft tissue leiomyosarcoma. A multiple-marker approach to the assessment of pericyte coverage can identify different profiles of vessel immaturity correlated with tumor grade.

Cutaneous scalp metastases from retroperitoneal leiomyosarcoma: a case report

A 71-year-old woman presented with five scalp nodules that were clinically suspicious for pilar cysts. Histopathologic examination showed a proliferation of mitotically active pleomorphic spindle cells arranged into intersecting fascicles in the dermis and subcutis. Tumor cells displayed deeply eosinophilic cytoplasm and expressed desmin but were negative for S100 protein by immunohistochemistry. Before 10 years, the patient was diagnosed with high-grade retroperitoneal leiomyosarcoma and underwent resection with intraoperative radiation. Metastatic disease involving the lungs, liver and soft tissue developed, requiring treatment with resections, radiation and chemotherapy. Owing to the presentation of multiple scalp nodules with microscopic features of leiomyosarcoma in conjunction with the clinical history of retroperitoneal leiomyosarcoma, a diagnosis of metastatic leiomyosarcoma was made. Scalp metastasis from retroperitoneal leiomyosarcoma is extremely rare and portends a poor prognosis. To our knowledge, only two other cases have been reported in the English literature, and a further search discovered only nine additional cases of scalp metastasis from soft tissue leiomyosarcoma of any non-gynecologic anatomic site. This case highlights the striking microscopic similarity between primary cutaneous and metastatic leiomyosarcoma and illustrates the necessity of adequate clinical information and an appropriate index of suspicion in excluding the possibility of cutaneous metastases of leiomyosarcoma from somatic soft tissue.

Differentiating soft tissue leiomyosarcoma and undifferentiated pleomorphic sarcoma: A miRNA analysis.

The rare and highly aggressive adult soft tissue sarcomas leiomyosarcoma (LMS) and undifferentiated pleomorphic sarcoma (UPS) contain complex genomes characterized by a multitude of rearrangements, amplifications, and deletions. Differential diagnosis remains a challenge. MicroRNA (miRNA) profiling was conducted on a series of LMS and UPS samples to initially investigate the differential expression and to identify specific signatures useful for improving the differential diagnosis. Initially, 10 high-grade LMS and 10 high-grade UPS were profiled with a miRNA microarray. Two cultured human mesenchymal stem cell samples were used as controls. 38 and 46 miRNAs classified UPS and LMS samples, respectively, into separate groups compared to control samples. When comparing the two profiles, miR-199b-5p, miR-320a, miR-199a-3p, miR-126, miR-22 were differentially expressed. These were validated by RT-PCR on a further series of 27 UPS and 21 LMS for a total of 68 cases. The levels of miR-199-5p and miR-320a, in particular, confirmed the microarray data, the former highly expressed in UPS and the latter in LMS. Immunohistochemistry was performed on all 68 cases to confirm original diagnosis. Recently reported LMS- and UPS-associated genes were correlated with miRNA targets based on target algorithms of three databases. Several genes including IMP3, ROR2, MDM2, CDK4, and UPA, are targets of differentially expressed miRNAs. We identified miRNA expression patterns in LMS and UPS, linking them to chromosomal regions and mRNA targets known to be involved in tumor development/progression of LMS and UPS.

MRI, MDCT features, and clinical outcome of extremity leiomyosarcomas: experience in 47 patients

To describe MRI, MDCT features, and clinical outcome of extremity leiomyosarcomas (LMS). In this IRB-approved, HIPAA-compliant retrospective study, we included 47 patients (23 women, 24 men; mean age: 55.3years, range: 17-85years) with pathologically confirmed extremity LMS seen at our adult tertiary cancer center between 2000 and 2012. MRI/MDCT of primary tumors in 23 patients and follow-up in all patients were reviewed by two radiologists in consensus. Clinical data were extracted from electronic medical records. Primary tumors were distributed in bones (6 out of 47), deep soft tissues (24 out of 47), and superficial soft tissues (17 out of 47). On imaging (bone = 4, deep soft tissue =11, superficial soft tissue = 8), compared with skeletal muscle, they were T1 iso-hypointense and T2 hyperintense. Bone LMS were metaphyseal tumors with cortical destruction (3 out of 4). Deep soft-tissue LMS were large with hemorrhage (7 out of 11) and necrosis (10 out of 11). Superficial soft-tissue LMS were relatively smaller, homogeneously enhancing (6 out of 8) tumors. Distant metastases developed in 32 out of 47 patients (bone LMS [6 out of 6], deep soft-tissue LMS [18 out of 24], superficial soft-tissue LMS [8 out of 17]), commonly to lung (29 out of 47) and bone (14 out of 47). At the time of writing, 22 out of 36 patients (bone LMS [4 out of 6], deep soft-tissue LMS [15 out of 24], superficial soft-tissue LMS [4 out of 17]) have died. There was no statistically significant correlation between metastatic disease and tumor size or grade. Extremity LMS arise in bones and in the deep and superficial soft tissues, frequently metastasize to the lungs, and have a poor prognosis. Superficial LMS tend to have a better prognosis than bone or deep soft-tissue LMS.

Mediator complex subunit 12 exon 2 mutation analysis in different subtypes of smooth muscle tumors confirms genetic heterogeneity

Recently, heterozygous mutations in exon 2 of the mediator complex subunit 12 gene have been described in 50% to 70% of uterine leiomyomas; the recurrent nature of these mutations suggests an important role in their pathogenesis. Mediator complex subunit 12 is involved in regulation of transcription and Wnt signaling. So far, little is known about the pathogenesis of the different subtypes of extrauterine leiomyomas and leiomyosarcomas. We performed mutation analysis of mediator complex subunit 12 and immunohistochemistry for β-catenin, using 69 tumors of 64 patients including 19 uterine leiomyomas, 6 abdominal leiomyomas, 9 angioleiomyomas, 5 piloleiomyomas, and 7 uterine and 23 soft tissue leiomyosarcomas. In line with previous observations, 58% of uterine leiomyomas carried a mediator complex subunit 12 mutation. However, all other extrauterine leiomyomas were negative with the exception of 1 abdominal leiomyoma with a likely primary uterine origin. Of the 30 leiomyosarcomas, only 1 uterine tumor harbored a mutation. A new observation is the identification of 3 tumors with a homozygous mutation; a monosomy X or interstitial deletion was excluded. β-Catenin immunohistochemistry showed nuclear positivity in only 55% of the mediator complex subunit 12-mutated uterine leiomyomas, suggesting the involvement of pathways other than canonical Wnt signaling in tumorigenesis. Interestingly, 80% of mediator complex subunit 12 wild-type sporadic piloleiomyomas displayed nuclear β-catenin positivity, indicating its involvement in this leiomyoma subtype. The lack of mediator complex subunit 12 mutations in extrauterine leiomyomas and leiomyosarcomas indicates that these tumors arise through a different pathway, emphasizing the genetic heterogeneity of smooth muscle tumors.

Genetic Profiling Identifies Two Classes of Soft-Tissue Leiomyosarcomas with Distinct Clinical Characteristics

Data about the prognostic factors of soft-tissue leiomyosarcomas and their correlation with molecular profile are limited. From 1990 to 2010, 586 adult patients with a primary soft-tissue leiomyosarcoma were included in the French Sarcoma Group (GSF) database after surgery of the primary tumor. Multivariate analyses were conducted by Cox regression model in a backward stepwise procedure. Genetic profiling was conducted for 73 cases. Median age was 59 years (range, 21-98 years). The median follow-up of patients alive was 46 months. The 5-year metastasis-free survival (MFS) rate was 51% (95% location and grade > I were independent adverse prognostic factors for MFS). The 5-year overall survival (OS) rate was 63% [95% confidence interval (CI), 59-67]. On multivariate analysis, age ≥ 60 years old, tumor size > 5 cm, deep location, and grade > I were independent adverse prognostic factors for OS. Molecular profiling identified specific clusters with activation of different biologic pathways: retroperitoneal leiomyosarcomas are characterized by overexpression of genes involved in muscle differentiation and nonretroperitoneal leiomyosarcomas characterized by overexpression of genes mainly involved in extracellular matrix, wounding, and adhesion pathways. The CINSARC signature but not comparative genomic hybridization (CGH) profiling was predictive of outcome. Soft-tissue leiomyosarcomas represent a heterogeneous group of tumors with at least two categories, retroperitoneal and extremities leiomyosarcomas, having specific clinical outcome and molecular features. Future clinical trials should consider this heterogeneity for a better stratification of patients.

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.

Leiomyosarcoma Leptomeningeal Brain Metastases

Brain metastases from soft tissue sarcomas (STS) occur late and relatively rarely, most commonly after lung metastases have developed. Furthermore, they are most commonly intraparenchymal in distribution. We describe two cases of histologically confirmed intracranial metastatic soft tissue leiomyosarcomas. In both cases all the nodular metastases measuring 10 mm in diameter or less could be easily detected in the leptomeningeal spaces by MRI. However, as the lesion enlarges it is difficult to recognize the site of origin, and the mass appears and behaves as intra-axial. Lesions located in the leptomeningeal spaces and in the perivascular space can be extremely small, which makes their detection problematic. For this reason we believe that in this context, MRI global gadolinium enhanced imaging using contiguous 1 mm slice thickness acquisition (TR 23 ms,TE 8 ms 512×512 matrix) is preferable, since the patient's management may vary depending on the multiplicity and location of the lesions.

Phosphorylation of signal transducer and activator of transcription 3 in soft tissue leiomyosarcoma is associated with a better prognosis

Signal transducer and activator of transcription (STAT) 3 mediates a broad range of biological processes, including cell survival and proliferation, and STAT3 has generally been regarded as a pro-oncogenic transcription factor. We investigated the phosphorylation status of STAT3 and the protein expression of the suppressor of cytokine signaling 3 (SOCS3) by immunohistochemistry in 145 formalin-fixed, paraffin-embedded samples of soft tissue leiomyosarcoma (LMS), including 129 primary tumors. Eight benign soft tissue smooth muscle tumors were also examined. Thirteen frozen LMS samples, which were paired with normal tissue samples, were assessed by Western blot analysis for the phosphorylation of STAT3 and SOCS3 expression. Immunohistochemical study showed that the phosphorylation of STAT3 was not a major event in LMS (37%). Moreover, phosphorylated STAT3 (pSTAT3) expression was significantly correlated with a better prognosis. Overexpression of SOCS3 was recognized in 52% of the cases and negatively correlated with pSTAT3 expression. Among the benign tumors, 63 and 25% were positive for pSTAT3 and SOCS3, respectively. Immunoblotting detected pSTAT3 in all tumor samples, but at lower levels than in non-neoplastic tissue. SOCS3 was detected in 92% (12 out of 13) of tumor tissues, but in none of the normal tissues. Contrary to the previous investigations of many other malignant tumors, STAT3 was inactivated in most LMS cases, likely owing to SOCS3 overexpression. STAT3 might not contribute to the progression of soft tissue LMS, and the phosphorylation status of STAT3 has the potential to be a favorable prognostic marker of LMS.

Characterization of giant marker and ring chromosomes in a pleomorphic leiomyosarcoma of soft tissue by spectral karyotyping

Pleomorphic leiomyosarcoma of soft tissue is relatively rare and its cytogenetic and molecular genetic data are scarce. We present a case of pleomorphic leiomyosarcoma arising in the left thigh of a 60-year-old man. Fluorine-18-deoxyglucose positron emission tomography imaging showed a homogenously high uptake within the mass in the proximal left thigh (maximum standardized uptake value, 20.9). Following a core needle biopsy, wide resection of the tumor was performed. Histologically, the tumor was composed of a mixture of spindle cells, polygonal cells and bizarre giant cells forming interlacing bundles and a storiform pattern. Immunohistochemically, the tumor cells were positive for vimentin, smooth muscle actin and desmin. The MIB-1 labeling index was 19.7% in the highest spot. Cytogenetic analysis exhibited a complex karyotype with several numerical and structural alterations, including giant marker and ring chromosomes. Spectral karyotyping demonstrated that giant marker and ring chromosomes were composed of material from the X chromosome. Metaphase-based comparative genomic hybridization analysis showed high-level amplifications of 1q21-q25 and 12q13-q21 and gains of 1p31-p32, 10p11-p13, 17p11 and 19p13. The patient received postoperative adjuvant radiotherapy and doxorubicin-based chemotherapy. No local recurrence or distant metastasis was detected during a follow-up period of 19 months. The clinicopathological, cytogenetic and molecular genetic features of pleomorphic soft tissue leiomyosarcoma are discussed.

Outcomes and Prognostic Factors for a Consecutive Case Series of 115 Patients with Somatic Leiomyosarcoma

Leiomyosarcoma is an uncommon tumor that affects 500 to 1000 patients in the United States annually. The purpose of our study was to further define survival rates as well as to identify multivariable predictors of disease-specific mortality, local recurrence, and development of distant metastasis following surgical resection. We studied a consecutive series of patients treated for leiomyosarcoma at our institution (a tertiary-care referral center) over a ten-year period. Only patients with leiomyosarcoma of soft tissues, vasculature, or bone were included. Those with uterine, gastrointestinal, or cutaneous forms of the disease were excluded. This yielded a cohort of 115 patients with complete follow-up data on which statistical analysis was performed. One-year, five-year, and ten-year disease-specific survival rates were 87%, 57%, and 19%, respectively. Tumor depth (p < 0.01), histological grade (p < 0.01), and metastasis at presentation (p = 0.03) were found to be multivariable predictors of mortality. Both retroperitoneal location (p = 0.01) and mitotic rate (p < 0.001) were predictive of distant metastasis. Resection margin was the only multivariable significant predictor of local recurrence in the group treated with surgical resection (p < 0.001). Leiomyosarcoma is an aggressive disease, with a generally poor prognosis. Depth of tumor and high histological grade are indicators of a poor prognosis. Retroperitoneal tumors have a particularly high potential to metastasize.

Oncofetal protein IMP3: a useful diagnostic biomarker for leiomyosarcoma

An accurate diagnosis between leiomyoma and leiomyosarcoma is essential for patient management. IMP3 is a member of the insulin-like growth factor (IGF-II) mRNA binding protein (IMP) family that consist of IMP1, IMP2, and IMP3. IMP3 is an oncofetal protein associated with aggressive and advanced tumors and is specifically expressed in malignant tumors but not found in benign tissues. The aim of this study was to determine the expression and diagnostic value of IMP3 in leiomyoma and leiomyosarcoma. A total of 216 cases (resection, n = 183; biopsy, n = 33) consisting of 82 leiomyosarcomas (uterine, n = 15; soft tissue, n = 67), 62 leiomyomas (uterine, n = 50; soft tissue, n = 12), and 72 uterine-variant leiomyomas (atypical, n = 19 [14%]; cellular, n = 21 [16%]; mitotically active, n = 12 [9%]; myxoid, n = 11 [8%]; vascular, n = 3 [2%]; epithelioid, n = 1 [1%]; benign metastasizing, n = 1 [1%]; and smooth muscle tumors of uncertain malignant potential, n = 4) were examined by immunohistochemistry for IMP3 expression. IMP3 showed strong cytoplasmic staining in 43 (52%) of 82 leiomyosarcomas, regardless of histologic grades. There was no difference in IMP3 expression between uterine and soft tissue leiomyosarcomas. In contrast to malignant tumors, IMP3 expression was not found in any of the typical leiomyomas (0/62 cases). All uterine-variant leiomyomas were negative, except for 3 cases (atypical variant, n = 2; cellular variant, n = 1) for IMP3 staining. In summary, we are the first to describe IMP3 expression in smooth muscle tumors. Our findings indicate that the expression of IMP3 in both uterine and soft tissue leiomyosarcomas can be used as a positive biomarker to increase the level of confidence in establishing a definitive diagnosis of a malignant smooth muscle tumor.

Immunohistochemical analysis of the endoribonucleases Drosha, Dicer and Ago2 in smooth muscle tumours of soft tissues

The aims of the present study were to determine the protein levels and cellular distribution of the endoribonucleases Drosha, Dicer and Ago2, major components of the microRNA-processing machinery, in benign and malignant soft tissue smooth muscle tumours, and to correlate the cellular levels of these enzymes with clinicopathological parameters including tumour histopathological grade. Cellular levels of Drosha, Dicer and Ago2 were evaluated in 110 soft tissue leiomyosarcomas (LMS), 31 leiomyomas (LM) and normal smooth muscle (NSM) using immunohistochemistry. Drosha and Dicer were barely detectable in NSM, while augmented levels of these enzymes were observed in LM and LMS. This finding suggests that Drosha and Dicer are implicated in the development of smooth muscle neoplasms. Notably, cellular levels of Dicer were significantly greater in high-grade compared to low-grade LMS, implying its participation in the progression of these neoplasms. Ago2 was detected in NSM, as well as LM and LMS; its cellular levels were not associated with tumour grade. Our results provide novel evidence that Drosha, Dicer and Ago2 are probably involved in the pathobiology of human smooth muscle neoplasms and that Dicer could serve as potentially significant biomarker for LMS progression.

Leiomyosarcoma of the Somatic Soft Tissues

Leiomyosarcomas of the somatic soft tissues are tumors of smooth muscle origin that occur in the extremities. These lesions are commonly high-grade tumors that carry a poor prognosis. Recommended treatment often includes wide excision and chemotherapy or radiation therapy. Sixty-five patients were followed for a mean of 4.1 years. The mean maximum tumor diameter was 7 cm, and approximately 70% of all patients had tumors deep to fascia. Including all stages of disease, the overall 1-, 2-, and 5-year survival rates were 91%, 87%, and 68%, respectively. Mitotic rate and tumor depth were significant predictors of development of recurrent disease and metastatic disease. Tumor size was another predictor of recurrent disease. The mitotic rate and AJCC stage were also important predictors of overall survival. Patients with deep lesions, histologic grade 3 disease/higher mitotic rates, and advanced stage of disease had a poorer prognosis and thus were more likely to undergo adjuvant chemotherapy. Future clinical studies may help determine if knowledge of these predictors can help guide treatment and improve clinical outcomes.

The Akt/mammalian target of rapamycin pathway is activated and associated with adverse prognosis in soft tissue leiomyosarcomas

The Akt/mammalian target of rapamycin (mTOR) pathway mediates cell survival and proliferation and contributes to tumor progression. Soft tissue leiomyosarcoma continues to show poor prognosis, and little is known about its mechanisms of tumor progression. Here the authors investigated the significance of activation of the Akt/mTOR pathway in soft tissue leiomyosarcomas. The phosphorylation status of Akt, mTOR, S6, and the eukaryotic translation initiation factor 4E-binding protein (4E-BP1) and the protein expression of phosphatase and tensin homologue (PTEN) were assessed by immunohistochemistry in 145 formalin-fixed paraffin-embedded samples of soft tissue leiomyosarcoma including 129 primary tumors. The expression of phosphorylated Akt and mTOR in comparison with their total forms was assessed by Western blot analysis in 13 frozen samples, which were paired with normal tissue samples. Moreover, 39 frozen tumor samples were analyzed for PIK3CA and AKT1 gene mutation. Immunohistochemically, phosphorylated forms of Akt, mTOR, S6, and 4E-BP1 were positive in 78.3%, 72.6%, 74.5%, and 70.5% of the samples, respectively. These results were correlated with each other, and associated with higher mitotic activity and adverse prognosis. Decreased expression of PTEN was recognized in only 19.7% and had no statistically significant correlation with Akt or other molecules. Immunoblotting showed a high degree of Akt and mTOR phosphorylation in tumor samples compared with that in non-neoplastic tissue. Mutational analysis failed to reveal any PIK3CA or AKT1 mutations around the hot spots. The Akt/mTOR pathway was activated in most cases of soft tissue leiomyosarcoma and associated with worse clinical behavior and aggressive pathological findings.

Local recurrence and assessment of sentinel lymph node biopsy in deep soft tissue leiomyosarcoma of the extremities

BackgroundLeiomyosarcoma of deep soft tissues of the extremities is a rare malignant tumour treated primarily by surgery. The incidence of local recurrence and lymph node metastasis is uncertain and it is not known whether a sentinel lymph node biopsy is indicated in these tumours.MethodsA retrospective review of patients treated for extremity deep soft tissue leiomyosarcoma at our institution over a 10-year period was conducted. Patients developing local recurrence or lymph node metastasis were identified. The presence or absence of lymphatics in the primary tumours was assessed by immunohistochemical expression of LYVE-1 and podoplanin.Results27 patients (mean age 62 years) were included in the study. 15 were female and 12 male. Lymph node metastasis was seen in only two cases (7%); intratumoural lymphatics were identified in the primary tumours of both these cases. Local recurrence occurred in 25.9% of cases despite complete excision and post-operative radiotherapy; the mean time to recurrence was 10.1 months.ConclusionOn the basis of this study, we do not advocate sentinel lymph node biopsy in this group of patients except in those cases in which intratumoural lymphatics can be demonstrated. Close follow up is important especially for high grade leiomyosarcomas, particularly in the first year, as these tumours have a high incidence of local recurrence.

Inguinal Smooth Muscle Tumors In Women—A Dichotomous Group Consisting of Müllerian-Type Leiomyomas and Soft Tissue Leiomyosarcomas

Assessment of the biological potential of smooth muscle tumors can be difficult and depends primarily on tumor site, stage, and histologic parameters. In this study, we examined the clinicopathologic and immunohistochemical features of 55 noncutaneous inguinal smooth muscle tumors of women (age range, 20 to 82 y; median, 57 y). Histologically, 23 tumors were considered as leiomyomas. They showed low mitotic activity (range, 0 to 6 mitoses/10 high-power fields, without atypical mitotic figures), minimal cytologic atypia, and absence of coagulative necrosis. Fifteen of these tumors histologically resembled conventional uterine leiomyomas and 8 resembled their variants: lipoleiomyomas (n = 2) and epithelioid variants (n = 6). The mean size was 7.8 cm, and half of the tumors with specified location arose in association with the round ligament. Immunohistochemical expression of estrogen receptor (ER) and/or Wilms tumor protein (WT1) was detected in most cases (83%), supporting Müllerian derivation. Follow-up data (range, 10 to 29 y; median, 13 y) on 11 patients showed that all were alive without disease or death from unrelated causes. The second group, classified as leiomyosarcomas, consisted of 32 mitotically active smooth muscle tumors, almost invariably with atypical mitotic figures, and exhibiting significant cytologic atypia. These patients were older than those with leiomyomas, and their tumors were mostly subcutaneous with a mean tumor size of 5.4 cm. Two leiomyosarcomas showed a femoral vein origin, but none were associated with the round ligament. All but 3 leiomyosarcomas were negative for ER. Follow-up data on 13 patients (range, 2 mo to 30 y; median, 4.5 y) showed that 5 died of metastatic sarcoma. Six individuals were alive without disease (median, 16 y), and 2 died of unrelated causes. In conclusion, inguinal smooth muscle tumors in women are a dichotomous group. They consist of ER/WT1-positive Müllerian-type leiomyomas resembling uterine leiomyomas with an excellent prognosis and conventional LMSs that are usually ER/WT1-negative and show a variable malignant course. Separation of these 2 categories is important for prognostication and optimal patient management, and is aided by immunohistochemical studies for ER and WT1.

Soft tissue tumors: Soft tissue leiomyosarcoma

Review on Soft tissue tumors: Soft tissue leiomyosarcoma, with data on clinics, and the genes involved.

The Dependence Receptor UNC5H2/B Triggers Apoptosis via PP2A-Mediated Dephosphorylation of DAP Kinase

The UNC5H dependence receptors promote apoptosis in the absence of their ligand, netrin-1, and this is important for neuronal and vascular development and for limitation of cancer progression. UNC5H2 (also called UNC5B) triggers cell death through the activation of the serine-threonine protein kinase DAPk. While performing a siRNA screen to identify genes implicated in UNC5H-induced apoptosis, we identified the structural subunit PR65β of the holoenzyme protein phosphatase 2A (PP2A). We show that UNC5H2/B recruits a protein complex that includes PR65β and DAPk and retains PP2A activity. PP2A activity is required for UNC5H2/B-induced apoptosis, since it activates DAPk by triggering its dephosphorylation. Moreover, netrin-1 binding to UNC5H2/B prevents this effect through interaction of the PP2A inhibitor CIP2A to UNC5H2/B. Thus we show here that, in the absence of netrin-1, recruitment of PP2A to UNC5H2/B allows the activation of DAPk via a PP2A-mediated dephosphorylation and that this mechanism is involved in angiogenesis regulation.