Raf kinase inhibitor protein expression in smooth muscle tumours of the uterus: a diagnostic marker for leiomyosarcoma?

RESEARCH QUESTION: What is the expression pattern of Raf kinase inhibitory protein (RKIP) in different subtypes of leiomyoma (usual type, cellular, apoplectic or haemorrhagic leiomyoma, leiomyoma with bizarre nuclei and lipoleiomyoma) and leiomyosarcoma specimens, and what is its biological role in leiomyosarcoma cells? DESIGN: Leiomyoma and leiomyosarcoma specimens underwent immunohistochemistry staining. Leiomyosarcoma SK-LMS-1 cell line was RKIP knocked down and RKIP overexpressed, and cell viability, wound healing migration and clonogenicity assays were carried out. RESULTS: A higher immunohistochemical expression of RKIP was observed in bizarre leiomyomas, than in usual-type leiomyomas. Decreased expression was also found in cellular leiomyoma, with generally absent staining in leiomyosarcomas. Upon RKIP expression manipulation in SK-LMS-1 cell line, no major differences were observed in cell viability and migration capacity over time. RKIP knockout, however, resulted in a significant increase in the cell's ability to form colonies (P = 0.011). CONCLUSION: RKIP distinct expression pattern among leiomyoma histotype and leiomyosarcoma, and its effect on leiomyosarcoma cells on colony formation, encourages further studies of RKIP in uterine smooth muscle disorders.

Uterine Leiomyosarcoma With Osteoclast-like Giant Cells: Report of 2 Cases and Review of Literature.

Leiomyosarcoma (LMS) with osteoclast-like giant cells (OLGCs) is a rare entity with only 18 reported cases thus far. It is not known whether these OLGCs are a reactive or malignant component of LMS. Herein we describe the clinical, histologic, and molecular characteristics of 2 cases of LMS with OLGCs and perform a brief literature review. In 2 of our cases, the OLGCs, marked with CD68, had a low proliferation index with Ki67 and did not show diffuse positivity for smooth muscle markers by immunohistochemistry. By next-generation sequencing, one case harbored a clinically significant TP53 mutation, which has been reported in a significant subset of conventional LMSs. In this case, based on immunohistochemistry, OLGCs showed different molecular alterations as compared with LMS. Although we did not show a distinct immunophenotype or molecular profile for LMS with OLGCs, this study provides additional data on this rare entity.

Molecular Heterogeneity in Leiomyosarcoma and Implications for Personalised Medicine.

OPINION STATEMENT: Leiomyosarcoma (LMS) is one of the more common subtypes of soft tissue sarcomas (STS), accounting for about 20% of cases. Differences in anatomical location, risk of recurrence and histomorphological variants contribute to the substantial clinical heterogeneity in survival outcomes and therapy responses observed in patients. There is therefore a need to move away from the current one-size-fits-all treatment approach towards a personalised strategy tailored for individual patients. Over the past decade, tissue profiling studies have revealed key genomic features and an additional layer of molecular heterogeneity among patients, with potential utility for optimal risk stratification and biomarker-matched therapies. Furthermore, recent studies investigating intratumour heterogeneity and tumour evolution patterns in LMS suggest some key features that may need to be taken into consideration when designing treatment strategies and clinical trials. Moving forward, national and international collaborative efforts to aggregate expertise, data, resources and tools are needed to achieve a step change in improving patient survival outcomes in this disease of unmet need.

Validating the diagnostic accuracy of an MRI-based scoring system for differentiating benign uterine leiomyomas from leiomyosarcomas.

OBJECTIVE: Uterine leiomyomas are the most common benign uterine tumors. They are difficult to distinguish from their malignant counterparts-smooth muscle tumors of unknown malignant potential (STUMP) and leiomyosarcoma. The purpose of this study is to propose and validate the diagnostic accuracy of the MRI-based Oman-Canada Scoring System of Myometrial Masses (OCSSMM) to differentiate uterine leiomyomas from STUMP/leiomyosarcomas. METHODS: This is a retrospective study performed at two tertiary care centers. All patients with a pathology-proven uterine mass who underwent pre-operative pelvic MRI between January 2010 and January 2020 were included. Using a 1.5T MRI machine, sequences included were axial/coronal/sagittal T2 and T1 weighted imaging, axial diffusion weighted and apparent diffusion coefficient map, and axial or sagittal dynamic contrast-enhanced sequences. A scoring system was designed based on previously published worrisome MRI features for uterine leiomyosarcoma. Each feature was allocated a score from 0 to 2 according to the strength of association with malignancy. Subsequently, the MR images were blindly and independently reviewed by a fellowship-trained radiologist and a clinical fellow/senior resident. Each uterine mass was scored according to their imaging features. The scores were divided into five categories according to the sum of scores. Category III and above was considered positive for leiomyosarcoma/STUMP. Sensitivity, specificity, and positive and negative predictive values were calculated. RESULTS: A total of 244 women were included (age range 20-74 years, mean 40). Of these, 218 patients had benign leiomyoma, 13 had STUMP, and 13 had leiomyosarcoma. The sensitivity and specificity of the scoring system were 92.3% and 64.7%, respectively. The negative predictive value was 98.6%. No leiomyosarcoma was missed using this scoring system. The presence of non-cystic T2 hyperintensity or diffusion restriction in a uterine mass were the most sensitive signs of a leiomyosarcoma/STUMP. CONCLUSION: The proposed multi-parametric MRI scoring system may be useful in differentiating benign uterine leiomyomas from leiomyosarcomas/STUMP.

Potential Markers to Differentiate Uterine Leiomyosarcomas from Leiomyomas.

Uterine leiomyomas (ULM) are the most common benign tumors of the female genitalia, while uterine leiomyosarcomas (ULMS) are rare. The sarcoma is diffuse growth, prone to hematogenous metastasis, and has a poor prognosis. Due to their similar clinical symptoms and morphological features, it is sometimes difficult to distinguish them, and the final diagnosis depends on histological diagnosis. Misdiagnosis of ULM as ULMS will lead to more invasive and extensive surgery when it is not needed, while misdiagnosis of ULMS as ULM may lead to delayed treatment and poor prognosis. This review searched and studied the published articles on ULM and ULMS, and summarized the potential markers for the differential diagnosis of ULMS. These markers will facilitate differential diagnosis and personalized treatment, providing timely diagnosis and potentially better prognosis for patients.

Findings of an Extraluminal Leiomyosarcoma of the Urinary Bladder in a Dog.

A 9 yr old male miniature poodle presented with acute diarrhea, vomiting, and a distended abdomen. A large and firm mass was palpated in the caudal abdomen. Radiography showed a large soft-tissue mass in the mid ventral abdomen. The mass was mildly contrast-enhancing and in contact with the right cranial aspect of the bladder on computed tomography. The mass was heterogeneous with minimal blood flow on Doppler examination. Surgery confirmed its origin of the urinary bladder, and it was diagnosed leiomyosarcoma on pathology. This is the first report of extraluminal leiomyosarcoma of the bladder wall with imaging characteristics using various modalities.

[A rare malignant tumor of the renal vein]. / Une tumeur maligne rare de la veine rénale.

The renal vein is an exceptional location for leiomyosarcoma, an aggressive malignant tumor of smooth-muscle origin with a poor prognosis. We report the case of a 55-year-old female patient who consulted for left flank pain that had been present for 6 months. A CT scan revealed a 9.4cm left retroperitoneal mass in contact with the psoas muscle, left kidney, stomach, spleen, left colon and extending up to the pancreas, raising the suspicion of a tumour originating in the retroperitoneal tissues. A biopsy revealed a smooth-muscle cell tumour with a degree of malignancy difficult to define. The patient underwent a monobloc left compartmentectomy, which led to the diagnosis of leiomyosarcoma of the left renal vein. A review of the literature on these rare tumours in this location is presented.

Molecular genetics and research progress of uterine leiomyosarcoma.

Uterine leiomyosarcoma (uLMS) is a type of malignant soft-tissue tumor, which is developed from myometrium in the female reproductive system. This disease is difficult to be distinguished from benign uterine leiomyoma in the early stages, but it progresses aggressively and relentlessly. Hence, uLMS has a dismal prognosis and high rates of both misdiagnosis and missed diagnosis. Unfortunately, current studies of uLMS pathogenesis and disease biology are inadequate. uLMS disease models are also very limited, hindering the development of effective therapeutics. In this review, we focus on the pathological molecular biology of uLMS, and systematically review the molecular genetic features, epigenetic variants, experimental models, and clinical research progress of uLMS. We further discuss the development direction and potential needs of uLMS in the fields of tumor evolution, tumor microenvironment, and tumor therapy, with the aim of providing a better understanding of the pathobiological mechanism of uLMS and providing a reference for the development of potential diagnostic and therapeutic strategies.

POTENTIAL DIAGNOSTIC BIOMARKERS FOR HUMAN MESENCHYMAL TUMORS, ESPECIALLY LMP2/Β1I AND CYCLIN E1/MIB1 DIFFERENTIAL EXPRESSION: PRUM-IBIO STUDY.

Most mesenchymal tumors found in the uterine corpus are benign tumors; however, uterine leiomyosarcoma is a malignant tumor with unknown risk factors that repeatedly recurs and metastasizes. In some cases, the histopathologic findings of uterine leiomyoma and uterine leiomyosarcoma are similar and surgical pathological diagnosis using excised tissue samples is difficult. It is necessary to analyze the risk factors for human uterine leiomyosarcoma and establish diagnostic biomarkers and treatments. Female mice deficient in the proteasome subunit low molecular mass peptide 2 (LMP2)/ß1i develop uterine leiomyosarcoma spontaneously. MATERIAL AND METHODS: Out of 334 patients with suspected uterine mesenchymal tumors, patients diagnosed with smooth muscle tumors of the uterus were selected from the pathological file. To investigate the expression status of biomarker candidate factors, immunohistochemical staining was performed with antibodies of biomarker candidate factors on thin-cut slides of human uterine leiomyosarcoma, uterine leiomyoma, and other uterine mesenchymal tumors. RESULTS AND DISCUSSION: In human uterine leiomyosarcoma, there was a loss of LMP2/ß1i expression and enhanced cyclin E1 and Ki-67/MIB1 expression. In human uterine leiomyomas and normal uterine smooth muscle layers, enhanced LMP2/ß1i expression and the disappearance of the expression of E1 and Ki-67/MIB1 were noted. The pattern of expression of each factor in other uterine mesenchymal tumors was different from that of uterine leiomyosarcoma. CONCLUSIONS: LMP2/ß1i, cyclin E1, and Ki-67/MIB1 may be candidate factors for biomarkers of human uterine leiomyosarcoma. Further large-cohort clinical trials should be conducted to establish treatments and diagnostics for uterine mesenchymal tumors.

Molecular-Based Immunohistochemical Algorithm for Uterine Leiomyosarcoma Diagnosis.

The morphologic assessment of uterine leiomyosarcoma (LMS) may be challenging, and diagnostic immunohistochemical (IHC) analysis is currently lacking. We evaluated the genomic landscape of 167 uterine LMS by targeted next-generation sequencing (NGS) to identify common genomic alterations. IHC analyses corresponding to these genomic landmarks were applied to a test cohort of 16 uterine LMS, 6 smooth muscle tumors of uncertain malignant potential (STUMP), and 6 leiomyomas with NGS data and a validation cohort of 8 uterine LMS, 12 STUMP, 21 leiomyomas and leiomyoma variants, 7 low-grade endometrial stromal sarcomas, and 2 diagnostically challenging uterine smooth muscle tumors. IHC results were individually interpreted by 3 pathologists blinded to NGS data. Overall, 94% of LMS showed ≥1 genomic alteration involving TP53, RB1, ATRX, PTEN, CDKN2A, or MDM2, with 80% showing alterations in ≥2 of these genes. In the test cohort, an initial panel of p53, Rb, PTEN, and ATRX was applied, followed by a panel of DAXX, MTAP, and MDM2 in cases without abnormalities. Abnormal p53, Rb, PTEN, and ATRX IHC expression was seen in 75%, 88%, 44%, and 38% of LMS, respectively, in the test cohort. Two or more abnormal IHC results among these markers were seen in 81% of LMS. STUMPs demonstrated only 1 IHC abnormality involving these markers. No IHC abnormalities were seen in leiomyomas. In the validation cohort, abnormal p53, Rb, and PTEN IHC results were seen in LMS, whereas rare STUMP or leiomyomas with bizarre nuclei showed IHC abnormalities involving only 1 of the markers. Abnormalities in ≥2 markers were present in both diagnostically challenging smooth muscle tumors, confirming LMS. Concordance was excellent among pathologists in the interpretation of IHC (κ = 0.97) and between IHC and NGS results (κ = 0.941). Uterine LMS exhibit genomic landmark alterations for which IHC surrogates exist, and a diagnostic algorithm involving molecular-based IHC may aid in the evaluation of unusual uterine smooth muscle tumors.

Percutaneous Uterine Needle Biopsy with Microscopic and Array-CGH Analyses for Preoperative Sarcoma Diagnosis in Patients with Suspicious Myometrial Tumors on MRI: A Prospective Pilot Study (SARCGYN).

BACKGROUND: Unlike for soft tissue sarcomas, percutaneous biopsy is not validated for uterine myometrial tumors, leading to leiomyosarcoma inadvertent morcellation and overtreatment in childbearing patients. This study aimed to evaluate preoperative percutaneous uterine needle biopsy (PUB) with microscopic examination (M-PUB) and array-comparative genomic hybridization (MCGH-PUB). METHODS: This was a prospective single-center cohort study including all consecutive patients who were candidates for hysterectomy because of suspected uterine leiomyosarcoma on magnetic resonance imaging (MRI) who received PUB. Microscopic and array-CGH analyses with genomic index (GI) counts were performed to guide the therapeutic strategy. Smooth-muscle tumors with suspect features with a GI above 15 were deemed malignant, as were tumors without microscopic malignant features with a complex genomic profile (GI above 30 or malignant profile). Preoperative diagnoses based on M-PUB and MCGH-PUB were compared with the postsurgical pathological specimen or follow-up. RESULTS: From November 2016 to February 2022, 34 patients were included. Based on the surgical specimen (N = 23) or follow-up (N = 11), final diagnoses were 11 sarcomas and 23 non-sarcomas. The median follow-up was 12 months (IQR 6-37). The diagnostic accuracies of M-PUB and MCGH-PUB were 94% and 100%, respectively. The sensitivity, specificity, and negative predictive value of MCGH-PUB were 100%, 100%, and 100%, respectively. A high GI was significantly associated with malignancy (P < 0.001). Genomic analyses allowed malignancy upgrades for four tumors. There were no complications and no dissemination along the biopsy track. CONCLUSION: MCGH-PUB is safe and accurate for preoperatively diagnosing uterine sarcomas and should be used routinely after suspicious MRI to tailor surgery.

Dedifferentiated leiomyosarcoma of the uterus: a clinicopathologic and immunohistochemical analysis of 23 cases.

AIMS: To morphologically and immunophenotypically characterize dedifferentiated uterine leiomyosarcoma (LMS). METHODS AND RESULTS: We identified 23 dedifferentiated uterine LMS, defined as a malignant uterine smooth muscle tumour containing discrete differentiated and dedifferentiated components (i.e. with and without morphologic and immunophenotypic evidence of smooth muscle differentiation, respectively). The differentiated component was leiomyosarcoma in most cases (17/23), though some arose from a leiomyoma (n = 4) or smooth muscle tumour of uncertain malignant potential (n = 2). The dedifferentiated tumour component showed noncohesive polygonal cells with moderate to abundant cytoplasm, pleomorphic nuclei with coarse vesicular to smudged chromatin, one or more macronucleoli, frequent multinucleation, and atypical mitoses. Three cases showed heterologous osteosarcomatous or chondrosarcomatous differentiation. Immunohistochemistry revealed alterations characteristic of uterine LMS, including Rb loss (18/19); strong diffuse p16 (17/19); strong diffuse (9/19) or complete absence of (5/19) p53; and ATRX loss (6/16). Compared to a control cohort of uterine LMS without dedifferentiation, dedifferentiated uterine LMS showed significantly shorter disease-specific (median, 54 versus 20 months; 5-year DSS, 46% versus 36%; P = 0.04) and disease-free (median, 31 versus 8 months; 5-year DFS, 42% versus 8%; P = 0.002) survival. Of 19 dedifferentiated uterine LMS with follow-up, 12 had died of disease at median 14 (range, 2-73) months; four were alive with disease at 4, 12, 44, and 50 months; and three were alive with no evidence of disease at 56, 109, and 114 months. CONCLUSION: Routine prospective recognition of dedifferentiated uterine LMS and distinction from mimics is advocated for accurate prognostication and for further characterisation of these tumours.

A differential diagnosis between uterine leiomyoma and leiomyosarcoma using transcriptome analysis.

BACKGROUND: The objective of this study was to estimate the accuracy of transcriptome-based classifier in differential diagnosis of uterine leiomyoma and leiomyosarcoma. We manually selected 114 normal uterine tissue and 31 leiomyosarcoma samples from publicly available transcriptome data in UCSC Xena as training/validation sets. We developed pre-processing procedure and gene selection method to sensitively find genes of larger variance in leiomyosarcoma than normal uterine tissues. Through our method, 17 genes were selected to build transcriptome-based classifier. The prediction accuracies of deep feedforward neural network (DNN), support vector machine (SVM), random forest (RF), and gradient boosting (GB) models were examined. We interpret the biological functionality of selected genes via network-based analysis using GeneMANIA. To validate the performance of trained model, we additionally collected 35 clinical samples of leiomyosarcoma and leiomyoma as a test set (18 + 17 as 1st and 2nd test sets). RESULTS: We discovered genes expressed in a highly variable way in leiomyosarcoma while these genes are expressed in a conserved way in normal uterine samples. These genes were mainly associated with DNA replication. As gene selection and model training were made in leiomyosarcoma and uterine normal tissue, proving discriminant of ability between leiomyosarcoma and leiomyoma is necessary. Thus, further validation of trained model was conducted in newly collected clinical samples of leiomyosarcoma and leiomyoma. The DNN classifier performed sensitivity 0.88, 0.77 (8/9, 7/9) while the specificity 1.0 (8/8, 8/8) in two test data set supporting that the selected genes in conjunction with DNN classifier are well discriminating the difference between leiomyosarcoma and leiomyoma in clinical sample. CONCLUSION: The transcriptome-based classifier accurately distinguished uterine leiomyosarcoma from leiomyoma. Our method can be helpful in clinical practice through the biopsy of sample in advance of surgery. Identification of leiomyosarcoma let the doctor avoid of laparoscopic surgery, thus it minimizes un-wanted tumor spread.

Not All Leiomyosarcomas Are the Same: How to Best Classify LMS.

OPINION STATEMENT: Leiomyosarcoma arises from smooth muscle and represents one of the most common soft tissue sarcomas. Despite aggressive multimodality care, over half of the patients will ultimately develop metastatic and incurable disease with a median survival of 12-18 months. At present, there is no standard system to classify leiomyosarcoma, which itself is a heterogeneous disease. Classification by tumor location is the most simplistic approach and is most frequently utilized in clinical practice. Tumor location impacts diagnosis (recognition pre-operatively versus at the time of surgery) as well as treatment (ability to completely resect with clear margins with minimal morbidity). While tumor location can impact prognosis, for example, extremity tumors would generally be considered as lower risk than inferior vena cava tumors, leiomyosarcoma can exhibit a heterogeneous behavior irrespective of tumor location. Specifically, some patients have rapidly progressing disease despite aggressive chemotherapy, while others display a more indolent course even in the metastatic setting. The pathogenic drivers of the heterogeneity observed in tumor behavior are not well understood. As we learn more about the molecular composition of leiomyosarcoma, various classification groups have been proposed as discussed here. Ultimately, it is unlikely that one variable will be adequate for tumor classification, and a combination of location and molecular composition will be necessary to develop appropriate risk stratification nomograms and treatment strategies.

Challenges in the diagnosis of the enigmatic primary adrenal leiomyosarcoma: two case reports and review of the literature.

BACKGROUND: Primary adrenal leiomyosarcoma is a rare and aggressive mesenchymal tumor derived from the smooth muscle wall of a central adrenal vein or its tributaries; therefore, tumors tend to invade the inferior vena cava and cause thrombosis. The great majority of tumors grow rapidly, which makes the disease difficult to diagnose in its early clinical stages and needs differentiation from adrenocortical carcinomas for the selection of chemotherapy including mitotane which causes adrenal insufficiency. CASE PRESENTATION: We presented two patients with adrenal leiomyosarcoma who were referred to our hospital with abdominal pain and harboring large adrenal tumors and inferior vena cava thrombosis. The endocrine findings, including serum catecholamine levels, were unremarkable. These two patients were considered clinically inoperable, and CT-guided core needle biopsy was performed to obtain the definitive histopathological diagnosis and determine the modes of therapy. The masses were subsequently diagnosed as primary adrenal leiomyosarcoma based on the histological features and positive immunoreactivity for SMA (smooth muscle actin), desmin, and vimentin. CONCLUSIONS: Adrenal leiomyosarcoma derived from the smooth muscle wall of a central adrenal vein or its tributaries is rare but should be considered a differential diagnosis in the case of nonfunctioning adrenal tumors extending directly to the inferior vena cava. CT-guided biopsy is considered useful for histopathological diagnosis and clinical management of patients with inoperable advanced adrenal tumors without any hormone excess.

First report of primary testicular leiomyosarcoma in two dogs.

BACKGROUND: Testicular tumours are common in dogs and, among them, interstitial cell tumours, seminomas and sustentacular cell tumours are the most reported. Mesenchymal testicular tumours are rarely reported in humans as in veterinary medicine where only three cases of sarcomas (leiomyomas and leomyosarcomas) have been described in two stallions and in a ram. CASE PRESENTATION: The present cases regarded a 12-year-old mixed-breed dog and a 10-year-old American Staffordshire Terrier that underwent bilateral orchiectomy. Formalin fixed testes were referred for histopathological diagnosis. At gross examination, in one of the testes of both dogs, a white, firm and variably cystic testicular mass, effacing and replacing the testicular parenchyma was detected. Samples were collected from both neoplastic and contralateral testes, routinely processed for histology and serial sections were also examined immunohistochemically with primary antibodies against cytokeratins, vimentin, Von Willebrand factor, inhibin-α, α-smooth muscle actin, smooth muscle myosin and desmin. Histopathological features as well as the immunohistochemical results, positive for vimentin, actin, myosin and desmin, confirmed the mesenchymal origin and the myoid phenotype of both testicular tumours supporting the diagnoses of leiomyosarcoma. CONCLUSIONS: To the authors knowledge these are the first cases of primary testicular sarcoma reported in the canine species. However, even rare, these tumours deserve to be considered in routine diagnosis when a testicular spindle cell tumour is observed. The immunohistochemical panel applied was useful to distinguish the present tumours from undifferentiated Sertoli cell tumours confirming the diagnosis of leiomyosarcoma.

Surgical resection of retinoblastoma-associated bladder leiomyosarcoma during pregnancy: a case report.

BACKGROUND: Management of a bladder tumor during pregnancy is an uncommon clinical situation. Leiomyosarcoma of the urinary bladder is a rare histological type of bladder tumor and a rare secondary cancer in survivors of retinoblastoma (RB). However, there has been no report of RB-associated bladder leiomyosarcoma during pregnancy. CASE PRESENTATION: A 37-year-old pregnant woman with a medical history of RB in infancy presented with gross hematuria at the 17th week of gestation. Cystoscopy revealed a 40-mm papillary tumor on the left lateral wall of the urinary bladder. At the 25th week of gestation, she underwent transurethral resection of the bladder tumor, and the pathological diagnosis was bladder leiomyosarcoma with loss of RB1 expression. At the 31st week of gestation, she gave birth by caesarean section. One month after the delivery (to allow for involution of the uterus), she underwent partial cystectomy, and the specimen contained no residual leiomyosarcoma tissue. CONCLUSIONS: We have reported a case of RB-associated bladder leiomyosarcoma that was successfully treated during and after pregnancy.

Cutaneous leiomyosarcoma: a retrospective review of 45 cases.

Primary cutaneous leiomyosarcoma (LMS) is a rare soft tissue tumour type with two subtypes, dermal and subcutaneous. As deeper tumours confer a worse prognosis, they require a more aggressive approach. Conversely, a more conservative surgical approach for dermal LMS has been suggested. Few studies have comprehensively reported both clinical surgical and histological excision margins. Therefore, we sought to provide margin recommendations based on our experience and review of the existing literature. We undertook a retrospective case-note review (1998-2019) of cutaneous LMS management to establish histological/surgical margins using pathology/electronic patient records. The diagnosis was made and classified by an experienced dermatopathologist according to the World Health Organization classification. In the dermal LMS cohort (n = 35), mean peripheral and deep histological margins were 5.4 mm (range 0.5-20) and 5.6 mm (range 0.1-14.5), respectively. The incomplete excision rate was 31% (11 of 35). There were no recurrences. In the subcutaneous LMS cohort (n = 10), mean peripheral and deep histological margins were 5.7 mm (range 0.2-14) and 1.1 mm (range 0.2-1.7), respectively. The incomplete excision rate was 40% (4 of 10). The recurrence rate was 20% (2 of 10) despite achieving histological clearance after 1 year. One lung metastasis occurred 1 year following an adequately excised primary scalp LMS. Thus, for dermal LMS we propose a clinical margin of 5-10 mm (depending on lesion size) at the initial excision or at scar re-excision following involved/close histological peripheral and/or deep margins (i.e. < 1 mm). For subcutaneous LMS, we suggest a clinical margin of 15-20 mm (depending on lesion size) to achieve a peripheral histological clearance of 10 mm and negative deep margin (i.e. > 1 mm), down to the periosteum/fascia/muscle according to anatomical site. If this is not achieved, a re-excision would be recommended. However, prospective studies are needed for optimal guidance.

Pulmonary inflammatory leiomyosarcoma represents a potential diagnostic pitfall of DNA methylation-based classification of sarcomas: a case report.

BACKGROUND: Pulmonary inflammatory leiomyosarcoma (PILMS) is a rare type of myogenic tumor with prominent lymphohistiocytic infiltration. Despite their histological similarities, PILMS is immunohistochemically and genetically distinct from soft tissue inflammatory leiomyosarcoma, and its clinicopathological picture including DNA methylome data remains still unknown. CASE PRESENTATION: Here we present a case of PILMS in an 18-year-old male who underwent lobectomy. As reported previously, the current case demonstrated spindle myoid cell proliferation with smooth muscle differentiation within a prominent lymphohistiocytic infiltration and a diploid genome with a MUC3A gene alteration. DNA methylation analysis predicted this case to be an "inflammatory myofibroblastic tumor" (IMT) according to the Deutsches Krebsforschungszentrum (DKFZ) classifier. The data was analyzed by t-distributed stochastic neighbor embedding, which plotted the case tumor in the vicinity of IMT, however, there were no IMT histological features. These discordant results could be due to background non-neoplastic inflammatory cells. CONCLUSIONS: As the DNA methylation classification of PILMS might be a potential diagnostic pitfall, an integrative histological and genetic approach is required for its accurate diagnosis.

Diagnostic and prognostic value of Bcl-2 in uterine leiomyosarcoma.

BACKGROUND: Uterine leiomyosarcoma (uLMS) may show loss of expression of B-cell lymphoma-2 (Bcl-2) protein. It has been suggested that Bcl-2 loss may both be a diagnostic marker and an unfavorable prognostic marker in uLMS. OBJECTIVE: To define the diagnostic and prognostic value of Bcl-2 loss in uLMS through a systematic review and meta-analysis. METHODS: Electronic databases were searched from their inception to May 2020 for all studies assessing the diagnostic and prognostic value of Bcl-2 loss of immunohistochemical expression in uLMS. Data were extracted to calculate odds ratio (OR) for the association of Bcl-2 with uLMS vs leiomyoma variants and smooth-muscle tumors of uncertain malignant potential (STUMP), and hazard ratio (HR) for overall survival; a p value < 0.05 was considered significant. RESULTS: Eight studies with 388 patients were included. Loss of Bcl-2 expression in uLMS was not significantly associated with a diagnosis of uLMS vs leiomyoma variants and STUMP (OR = 2.981; p = 0.48). Bcl-2 loss was significantly associated with shorter overall survival in uLMS (HR = 3.722; p = 0.006). High statistical heterogeneity was observed in both analyses. CONCLUSION: Loss of Bcl-2 expression appears as a significant prognostic but not diagnostic marker in uLMS. The high heterogeneity observed highlights the need for further research and larger studies.