Pulmonary "Inflammatory Leiomyosarcomas" Are Indolent Tumors With Diploid Genomes and No Convincing Rhabdomyoblastic Differentiation.

Inflammatory leiomyosarcoma is a rare myogenic tumor with striking inflammatory infiltrates and a specific genomic pattern of near-haploidization despite exception(s). Recent studies demonstrated that inflammatory leiomyosarcoma shares substantially overlapping features with histiocyte-rich rhabdomyoblastic tumor, including expression of rhabdomyoblastic markers such as myogenin, MyoD1, and PAX7 and a high prevalence of genomic near-haploidization, suggesting that they represent a unifying entity, for which the term inflammatory rhabdomyoblastic tumor was coined. In this study, we identified 4 pulmonary tumors histologically typical of inflammatory leiomyosarcomas, all in men (aged 26 to 49), presented as slow-growing well-defined nodules ranging from 1.4 to 3.5 cm, and following uneventful postoperative courses. All tumors were positive for desmin immunostaining, while only 1 and 2 were focally positive for smooth muscle actin and smooth muscle myosin heavy chain, respectively. They showed no expression of myogenin, MyoD1, or PAX7 by immunohistochemistry or RNA sequencing. Copy number analyses by whole-exome sequencing (N=1), OncoScan single-nucleotide polymorphism array (2), and fluorescence in situ hybridization (1) revealed/suggested diploid genomes. Together with a previously reported case, all these pulmonary "inflammatory leiomyosarcomas" seemed clinically, pathologically, and genomically alike. Despite a superficial resemblance to conventional inflammatory leiomyosarcoma in somatic soft tissues (now preferably termed inflammatory rhabdomyoblastic tumor), they differ in the lack of convincing rhabdomyoblastic differentiation and genomic near-haploidization. Therefore, we propose that these pulmonary tumors probably represent a distinct entity, for which the exact line of differentiation, and perhaps the most suitable terminology to better reflect its nature, remains to be determined. The term inflammatory rhabdomyoblastic tumor seems inappropriate for this group of tumors.

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.

Multiple cutaneous pleomorphic leiomyosarcoma in a dog.

A male dog developed multiple cutaneous masses at 15 different sites between the ages of 11.5 and 13-years. The masses were surgically removed and histopathologically examined. In gross appearance, the cut surfaces of the masses were white with partially red areas. Microscopy revealed that the tumors were located at the dermis and were composed of spindle cells and pleomorphic cells with abundant eosinophilic cytoplasm, accompanying giant cells. These cells were occasionally arranged in bundles with minimal stromal collagen. Immunohistochemical analysis revealed that the neoplastic cells were strongly positive for vimentin, partially positive for smooth muscle actin and desmin, and negative for cytokeratin. Based on these pathological findings, the tumor was diagnosed as multiple cutaneous pleomorphic leiomyosarcoma.

Loss of succinate dehydrogenase B immunohistochemical expression distinguishes pulmonary chondromas from hamartomas.

AIMS: Pulmonary chondromas, which are rare cartilaginous neoplasms that often arise in the setting of Carney triad, are morphologically similar to pulmonary hamartomas, which are much more common. There is evidence that succinate dehydrogenase (SDH) deficiency drives neoplasia in patients with Carney triad, and SDHB immunohistochemistry can be used as a surrogate marker to detect SDH deficiency. The aim of this study was to investigate the utility of SDHB immunohistochemistry in distinguishing pulmonary chondromas from hamartomas. METHODS AND RESULTS: Immunohistochemistry for SDHB (clone 21A11AE7) was performed on histological sections from six cases of pulmonary chondroma and 33 cases of pulmonary hamartoma. SDHB expression was retained in all 33 pulmonary hamartomas, and lost in the majority of evaluable chondromas (five of six). Of the five patients with chondromas showing SDHB loss, four had definitive Carney triad. Most patients with pulmonary hamartomas were older males with small solitary masses, whereas chondromas often presented as multiple masses in young females. CONCLUSION: Loss of SDHB immunohistochemical expression can be useful for differentiating pulmonary chondromas from hamartomas, and potentially identifying patients with Carney triad.

Leiomiosarcoma cutáneo: la importancia de la localización histológica / Cutaneous Leiomyosarcoma: On the Importance of Histologic Location

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Leiomiosarcoma cutáneo: características clínicas, histopatológicas y correlación pronóstica en 12 pacientes / Clinical and Histopathologic Findings of Cutaneous Leiomyosarcoma: Correlation with Prognosis in 12 Patients

INTRODUCCIÓN: El leiomiosarcoma de piel es una neoplasia maligna de estirpe muscular cuya baja incidencia dificulta el desarrollo de protocolos específicos de diagnóstico y manejo terapéutico. OBJETIVOS: Describir las características clínicas e histopatológicas de una serie de leiomiosarcomas cutáneos primarios y secundarios, junto con su correlación pronóstica. MATERIAL Y MÉTODOS: Se realizó un estudio retrospectivo, descriptivo y observacional. Se seleccionaron 17 casos de leiomiosarcoma cutáneo en 12 pacientes, diagnosticados entre el 1 de enero de 2000 y el 31 de diciembre de 2015. Se recogieron sus datos demográficos, características clínicas e histopatológicas, evolución y respuesta al tratamiento. RESULTADOS: Se reclutaron 5 varones y 7 mujeres, todos ellos mayores de 50 años al diagnóstico. Se recogieron 4 leiomiosarcomas dérmicos (4/17, 23%) en 4 pacientes, 2 leiomiosarcomas hipodérmicos (2/17, 11,5%) en 2 pacientes, y 11 metástasis cutáneas de leiomiosarcoma (11/17, 65%) en 6 pacientes. Las localizaciones más frecuentes fueron cuero cabelludo (7/17, 41%), miembros inferiores (3/17, 17%) y tronco (3/17, 17%). Durante el seguimiento, un 50% de leiomiosarcomas dérmicos recidivaron, un 50% de leiomiosarcomas hipodérmicos presentaron metástasis a distancia y 5/6 pacientes con metástasis cutáneas de leiomiosarcoma (83%) fallecieron a causa de su enfermedad. Limitaciones: Este estudio es una revisión retrospectiva de una serie de casos de tamaño limitado en un centro único. CONCLUSIONES: El leiomiosarcoma cutáneo es una neoplasia maligna poco frecuente. A la hora de adoptar una actitud diagnóstico-terapéutica en estos pacientes debemos tener en cuenta la marcada heterogeneidad pronóstica entre sus diferentes subtipos

INTRODUCTION: Cutaneous leiomyosarcoma is a malignant neoplasm derived from smooth muscle cells. Its low incidence hampers the development of specific protocols for diagnosis and treatment. OBJECTIVES: To describe the clinical and histopathologic characteristics of a series of primary and secondary cutaneous leiomyosarcomas and to determine how these characteristics correlate with prognosis. MATERIAL AND METHODS: We performed an observational, descriptive, retrospective study based on 17 cutaneous leiomyosarcomas in 12 patients diagnosed between January 1, 2000 and December 31, 2015. We recorded demographic data, clinical and histopathologic characteristics, outcome, and response to treatment. RESULTS: We included 5 men and 7 women, all aged more than 50 years at diagnosis. There were 4 cutaneous leiomyosarcomas (23%) in 4 patients, 2 subcutaneous leiomyosarcomas (11.5%) in 2 patients, and 11 skin metastases of leiomyosarcoma (65%) in 6 patients. The most frequently affected sites were the scalp (41%), lower limbs (17%), and trunk (17%). During follow-up, 50% of the cutaneous leiomyosarcomas recurred, 50% of the subcutaneous leiomyosarcomas presented distant metastases, and 83% of the patients with skin metastases of leiomyosarcoma died of their disease. Limitations: Ours was a retrospective review of a small case series at a single center. CONCLUSIONS: Cutaneous leiomyosarcoma is an uncommon malignant neoplasm. Our approach to diagnosis and therapy must take into account the marked heterogeneity in the prognosis of the various subtypes

Distinct molecular subtypes of uterine leiomyosarcoma respond differently to chemotherapy treatment.

BACKGROUND: Uterine leiomyosarcoma (ULMS) is an aggressive form of soft tissue tumors. The molecular heterogeneity and pathogenesis of ULMS are not well understood. METHODS: Expression profiling data were used to determine the possibility and optimal number of ULMS molecular subtypes. Next, clinicopathological characters and molecular pathways were analyzed in each subtype to prospect the clinical applications and progression mechanisms of ULMS. RESULTS: Two distinct molecular subtypes of ULMS were defined based on different gene expression signatures. Subtype I ULMS recapitulated low-grade ULMS, the gene expression pattern of which resembled normal smooth muscle cells, characterized by overexpression of smooth muscle function genes such as LMOD1, SLMAP, MYLK, MYH11. In contrast, subtype II ULMS recapitulated high-grade ULMS with higher tumor weight and invasion rate, and was characterized by overexpression of genes involved in the pathway of epithelial to mesenchymal transition and tumorigenesis, such as CDK6, MAPK13 and HOXA1. CONCLUSIONS: We identified two distinct molecular subtypes of ULMS responding differently to chemotherapy treatment. Our findings provide a better understanding of ULMS intrinsic molecular subtypes, and will potentially facilitate the development of subtype-specific diagnosis biomarkers and therapy strategies for these tumors.

Current Concepts in Non-Gastrointestinal Stromal Tumor Soft Tissue Sarcomas: A Primer for Radiologists.

Non-gastrointestinal stromal tumor (GIST) soft tissue sarcomas (STSs) are a heterogeneous group of neoplasms whose classification and management continues to evolve with better understanding of their biologic behavior. The 2013 World Health Organization (WHO) has revised their classification based on new immunohistochemical and cytogenetic data. In this article, we will provide a brief overview of the revised WHO classification of soft tissue tumors, discuss in detail the radiology and management of the two most common adult non-GIST STS, namely liposarcoma and leiomyosarcoma, and review some of the emerging histology-driven targeted therapies in non-GIST STS, focusing on the role of the radiologist.

Gene expression profiling identifies distinct molecular subgroups of leiomyosarcoma with clinical relevance.

BACKGROUND: Soft tissue sarcomas are heterogeneous and a major complication in their management is that the existing classification scheme is not definitive and is still evolving. Leiomyosarcomas, a major histologic category of soft tissue sarcomas, are malignant tumours displaying smooth muscle differentiation. Although defined as a single group, they exhibit a wide range of clinical behaviour. We aimed to carry out molecular classification to identify new molecular subgroups with clinical relevance. METHODS: We used gene expression profiling on 20 extra-uterine leiomyosarcomas and cross-study analyses for molecular classification of leiomyosarcomas. Clinical significance of the subgroupings was investigated. RESULTS: We have identified two distinct molecular subgroups of leiomyosarcomas. One group was characterised by high expression of 26 genes that included many genes from the sub-classification gene cluster proposed by Nielsen et al. These sub-classification genes include genes that have importance structurally, as well as in cell signalling. Notably, we found a statistically significant association of the subgroupings with tumour grade. Further refinement led to a group of 15 genes that could recapitulate the tumour subgroupings in our data set and in a second independent sarcoma set. Remarkably, cross-study analyses suggested that these molecular subgroups could be found in four independent data sets, providing strong support for their existence. CONCLUSIONS: Our study strongly supported the existence of distinct leiomyosarcoma molecular subgroups, which have clinical association with tumour grade. Our findings will aid in advancing the classification of leiomyosarcomas and lead to more individualised and better management of the disease.

Myxoid Leiomyosarcoma of the Uterus: A Clinicopathologic Analysis of 30 Cases and Review of the Literature With Reappraisal of Its Distinction From Other Uterine Myxoid Mesenchymal Neoplasms.

Myxoid leiomyosarcoma (mLMS) of the uterus is a rare neoplasm; thus, knowledge of its clinical behavior and morphology remains limited. We therefore reviewed 30 cases initially diagnosed as uterine mLMS to better characterize its clinicopathologic features. Diagnosis was confirmed in 25 subjects (average age 51.5 y), of whom 80% were stage 1 at presentation. The average tumor size was 10.8 cm. An infiltrative tumor border was observed microscopically in 24 cases (96%); the border in 1 case could not be assessed. Fourteen cases (56%) had >10 mitoses per 10 high-power fields, 8 (32%) had between 2 and 10, and 3 cases (12%) had <2 mitoses. Geographic tumor necrosis and moderate to severe nuclear pleomorphism were seen concurrently in 12 cases (48%). All tumors expressed smooth muscle markers. Estrogen receptor was expressed in 29.4% of cases. Eighteen of 21 cases (85.7%) were negative for ALK by immunohistochemistry. Follow-up information was available in 18 subjects: 8 died of disease, 6 were alive with local and/or distant recurrence, and 4 were alive with no evidence of disease. Individuals who died of disease tended to have tumors with >10 mitoses per 10 high-power fields. Among cases with ≥5-year follow-up, overall survival was 11.1%, significantly worse compared with reported survival rates for conventional LMS. The initial diagnosis of mLMS was revised in 5 cases. Four had a distinctive loose myxoid appearance, nuclei with vesicular chromatin, and ALK positivity by immunohistochemistry, suggesting, suggesting inflammatory myofibroblastic tumor. This diagnosis was confirmed by in situ hybridization in 2 cases. One additional myxoid tumor lacked smooth muscle or myofibroblastic features and could not be classified further. mLMS is an aggressive neoplasm characterized by infiltrative tumor borders and variability of other features (mitotic count, atypia, and necrosis). The differential diagnosis includes myxoid leiomyoma and inflammatory myofibroblastic tumor. Attention to distinguishing morphologic features and immunohistochemistry will aid in the interpretation. An illustrated algorithm with criteria for diagnosis is proposed.

An immunohistochemical analysis of stathmin 1 expression in uterine smooth muscle tumors: differential expression in leiomyosarcomas and leiomyomas.

The oncogenic phosphatidylinositol 3-kinase-AKT-mammlian target of rapamycin pathway (PI3K-AKT-mTOR) pathway is known to be activated in uterine smooth muscle tumors, and Stathmin 1 (STMN1) expression has been identified as a marker of PI3K-AKT-mTOR pathway activation. We hypothesized that STMN1 may have some diagnostic utility and explored how well STMN1 expression correlated with histologic classifications of uterine smooth muscle tumors into benign and malignant groupings. 84 smooth muscle tumors were assessed for STMN1 expression by immunohistochemistry. These included spindle cell leiomyosarcoma (n=32), conventional spindle cell leiomyomas (n=30), atypical (symplastic) leiomyoma (n=5), cellular leiomyoma (n=7), smooth muscle tumor of uncertain malignant potential (n=4), mitotically active leiomyomas (n=2), benign metastasizing leiomyoma (n=3), and cotyledonoid dissecting leiomyoma (n=1). All spindle cell leiomyosarcomas were positive (32/32 positive; 100%) as compared with conventional leiomyomata (11/30; 37%) (P<0.0001). The average immunohistochemical score (0-12+, reflective of intensity and extent) for leiomyosarcomas was 8.7 (±1.43) whereas the conventional leiomyomata average score was 1.6 (±1.07) (P<0.0001). This difference in scores was reflected in the patterns of expression: leiomyosarcomas were predominantly strongly and diffusely positive whereas leiomyomata were predominantly weakly, albeit diffusely positive when expression was present. The sensitivity of STMN1 expression for leiomyosarcomas was 100%. However, the specificity was found to be only 55% (CI=43-68%). The negative and positive predictive values for leiomyosarcomas were 100% and 52% respectively. The odds ratio (OR) for any STMN1 expression in predicting a spindle cell leiomyosarcoma diagnosis from this dataset was highly significant (OR=144, P=0.0006). Thirteen non-smooth muscle tumors that involved the uterus all showed at least focal STMN1 immunoreactivity. In summary, STMN1 is a highly sensitive marker for leiomyosarcoma but is suboptimally specific for diagnostic purposes. The 100% negative predictive value for leiomyosarcoma may offer some diagnostic utility in a small sample, since the absence of STMN1 immunoreactivity in a putative leiomyosarcoma is a strong argument against this diagnostic possibility.

Clinically Relevant Molecular Subtypes in Leiomyosarcoma.

PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.

Progressive loss of myogenic differentiation in leiomyosarcoma has prognostic value.

AIMS: Well-differentiated leiomyosarcomas show morphologically recognizable smooth muscle differentiation, whereas poorly differentiated tumours may form a spectrum with a subset of undifferentiated pleomorphic sarcomas. The expression of certain muscle markers has been reported to have prognostic impact. We investigated the correlation between the morphological spectrum and the muscle marker expression profile of leiomyosarcoma, and the impact of these factors on patient outcomes. METHODS AND RESULTS: Tissue microarrays including 202 non-uterine and 181 uterine leiomyosarcomas with a spectrum of tumour morphologies were evaluated for expression of immunohistochemical markers of muscle differentiation. Poorly differentiated tumours frequently lost one or more conventional smooth muscle markers [smooth muscle actin, desmin, h-caldesmon, and smooth muscle myosin (P < 0.0001)], as well as the more recently described markers SLMAP, MYLK, and ACTG2 (P < 0.0001). In primary tumours, both desmin and CFL2 expression predicted improved overall survival in multivariate analyses (P = 0.0111 and P = 0.043, respectively). Patients with muscle marker-enriched tumours (expressing all four conventional markers or any three of ACTG2, CFL2, CASQ2, MYLK, and SLMAP) had improved overall survival (P < 0.05) in univariate analyses. CONCLUSIONS: Morphologically and immunohistochemically, poorly differentiated leiomyosarcomas can masquerade as undifferentiated pleomorphic sarcomas with progressive loss of muscle markers. The expression of muscle markers has prognostic significance in primary leiomyosarcomas independently of tumour morphology.

Contemporary management and classification of hepatic leiomyosarcoma.

BACKGROUND: Hepatic 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. METHODS: Patients 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. RESULTS: Eight 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. CONCLUSIONS: Hepatic 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.

[Gastrointestinal stromal tumor (GIST): advances in 2013]. / Gastrointestinální stromální tumor (GIST): pokroky do roku 2013.

Gastrointestinal stromal tumors (GIST) are currently regarded as a heterogenous group of tumors sharing common histological appearance, KIT immunopositivity and supposed origin from tissue progenitor cells capable of differentiation into the phenotype of Cajal interstitial cells. GISTs can be divided according to immunoexpression of the beta subunit of mitochondrial enzyme succinate dehydrogenase (SDHB) to SDHB-positive (encompassing KIT, PDGFRA and NF1 mutated GISTs), and SDHB-deficient GISTs (including Carney-Stratakis syndrome, Carney triad, sporadic pediatric GISTs, and a small subset of sporadic adult GISTs). The individual molecular subtypes differ in biological behavior and in their response to systemic targeted therapy, which is indicated in metastatic GISTs or in tumors with high risk of recurrence. Although several risk-stratification classifications have been developed, strictly defined criteria to identify patients at risk are still lacking. Pharmacogenomics have been successful in designing drugs to overcome not only the primary resistance of GISTs to the action of imatinib (e.g. GISTs with a substitution of Asp842Val in exon 18 PDGFRA or SDHB-deficient GISTs), but also the secondary resistance caused by secondary mutation of a gene encoding either the receptor tyrosine kinase or other molecules involved in the respective signalling cascade. Future directions concentrate on rational molecular targeting for systemic therapy based on complex genetic investigation of the tumor. Peripheral blood is planned to be used as a source of information for genetic events responsible for the secondary resistance of metastatic tumors.

Smooth muscle tumors of soft tissue and non-uterine viscera: biology and prognosis.

Smooth muscle tumors are here considered an essentially dichotomous group composed of benign leiomyomas and malignant leiomyosarcomas. Soft tissue smooth muscle tumors with both atypia and mitotic activity are generally diagnosed leiomyosarcomas acknowledging potential for metastasis. However, lesions exist that cannot be comfortably placed in either category, and in such cases the designation 'smooth muscle tumor of uncertain biologic potential' is appropriate. The use of this category is often necessary with limited sampling, such as needle core biopsies. Benign smooth muscle tumors include smooth muscle hamartoma and angioleiomyoma. A specific category of leiomyomas are estrogen-receptor positive ones in women. These are similar to uterine leiomyomas and can occur anywhere in the abdomen and abdominal wall. Leiomyosarcomas can occur at any site, although are more frequent in the retroperitoneum and proximal extremities. They are recognized by likeness to smooth muscle cells but can undergo pleomorphic evolution ('dedifferentiation'). Presence of smooth muscle actin is nearly uniform and desmin-positivity usual. This and the lack of KIT expression separate leiomyosarcoma from GIST, an important problem in abdominal soft tissues. EBV-associated smooth muscle tumors are a specific subcategory occurring in AIDS or post-transplant patients. These tumors can have incomplete smooth muscle differentiation but show nuclear EBER as a diagnostic feature. In contrast to many other soft tissue tumors, genetics of smooth muscle tumors are poorly understood and such diagnostic testing is not yet generally applicable in this histogenetic group. Leiomyosarcomas are known to be genetically complex, often showing 'chaotic' karyotypes including aneuploidy or polyploidy, and no recurrent tumor-specific translocations have been detected.

Diagnosis, prognosis, and management of leiomyosarcoma: recognition of anatomic variants.

PURPOSE OF REVIEW: The purpose of this review is to present the most recent advances in the diagnosis of the more common leiomyosarcoma (LMS) anatomic variants, potentially useful prognostic markers that have recently been identified and the systemic approaches currently used or under evaluation to improve the outcome of patients with this disease. RECENT FINDINGS: Over the last few years emphasis has been placed on incorporating effective imaging tools and using pathological biomarkers in the diagnostic workup of LMS. Moreover, efforts are being made to identify meaningful prognostic and predictive parameters that will aid the development of effective novel therapeutics. The number of systemic therapies available to treat LMS has increased over the last decade, but the selection of systemic therapy is not based on the anatomic origin of LMS. SUMMARY: Currently, the only curative option in LMS is surgery and despite progress in systemic therapy the outcome of patients with advanced/metastatic disease remains poor. Better understanding of the underlying biology of the LMS variants, improved diagnostics and more effective, less toxic therapeutic agents are required.

Genetic profiling identifies two classes of soft-tissue leiomyosarcomas with distinct clinical characteristics.

PURPOSE: Data about the prognostic factors of soft-tissue leiomyosarcomas and their correlation with molecular profile are limited. EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSION: 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.

Recent developments in uterine mesenchymal neoplasms.

Smooth muscle and endometrial stromal tumours represent the two most common uterine mesenchymal neoplasms that may present diagnostic dilemmas for the practising surgical pathologist. Recent changes in morphological and staging criteria, as well as the discovery of new immunohistochemical markers, have improved the diagnosis and classification of these tumours. We highlight the difficulty in distinguishing tumour cell necrosis from infarct-type necrosis and the limited utility of p16 immunohistochemical expression in the diagnosis of leiomyosarcoma. We also discuss the controversial use of mitotic activity and necrosis as prognostic factors in endometrial stromal sarcomas. Emerging genetic information has also greatly expanded our understanding of 'sarcomagenesis' in both tumour types and may provide insight into potential therapeutic targets for the treatment of leiomyosarcoma and endometrial stromal sarcomas, harboring MED12 (mediator complex subunit 12) mutations and recurrent gene rearrangements, respectively. In this review, we discuss the core updates in the diagnosis and classification of uterine leiomyosarcomas and endometrial stromal sarcomas, highlighting new and important molecular genetic findings that may drive pathogenesis.