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Seminars in Diagnostic Pathology May 2022Leiomyoma with nuclear atypia describes a group of uterine smooth muscle tumors with a wide range of histologic and clinical presentations and remarkable nuclear atypia.... (Review)
Review
Leiomyoma with nuclear atypia describes a group of uterine smooth muscle tumors with a wide range of histologic and clinical presentations and remarkable nuclear atypia. These include fumarate hydratase-deficient leiomyoma (FH-LM), intravenous leiomyomatosis (IV-LM), and leiomyoma with bizarre nuclei (LM-BN). Other uterine mesenchymal tumors, such as perivascular epithelioid tumor (PEComa) and inflammatory myofibroblastic tumors (IMFT) are the mimickers of leiomyoma with nuclear atypia. LM-BN is the primary tumor model with a long history in gynecologic pathology, but the histogenesis of LM-BN remains largely unknown. Differentiating LM-BN from other benign variants, tumors with uncertain malignant potential (STUMP), or fully malignant leiomyosarcoma (LMS) can be diagnostically challenging. Recent progress has improved the diagnosis of many types of leiomyoma with nuclear atypia based on their specific histology and molecular alterations. LM-BN is now a diagnosis of exclusion. In this article, I review the history of leiomyoma with nuclear atypia and compare the clinical, histologic, and molecular features of LM-BN with those of its mimics. In particular, I highlight the current progress made in molecular genetics and pitfalls in the diagnosis of different myogenic tumors with nuclear atypia.
Topics: Biomarkers, Tumor; Female; Humans; Leiomyoma; Leiomyosarcoma; Rare Diseases; Uterine Neoplasms
PubMed: 35144823
DOI: 10.1053/j.semdp.2022.01.006 -
Cancer Sep 2019
Topics: Child; Cyclophosphamide; Humans; Rhabdomyosarcoma; Rhabdomyosarcoma, Embryonal
PubMed: 31174230
DOI: 10.1002/cncr.32205 -
Archives of Gynecology and Obstetrics Feb 2023Uterine 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... (Meta-Analysis)
Meta-Analysis Review
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.
Topics: Female; Humans; Leiomyosarcoma; Prognosis; Uterine Neoplasms; Leiomyoma; Pelvic Neoplasms
PubMed: 35344084
DOI: 10.1007/s00404-022-06531-2 -
Revista de La Facultad de Ciencias... Sep 2022Primary skin leiomyosarcomas are infrequent neoplasms. They correspond to 2-3% of skin sarcomas and are most frequently located on the lower extremities, trunk and...
INTRODUCTION
Primary skin leiomyosarcomas are infrequent neoplasms. They correspond to 2-3% of skin sarcomas and are most frequently located on the lower extremities, trunk and genitals.
METHODS
We present a case of a 73-year-old man with a 4-month evolution of foreskin leiomyosarcoma. The lesion was biopsied for histopathological study with HE and immunohistochemistry with smooth muscle actin, specific muscle actin, CD34, p63 and S-100 (-).
RESULTS
We observed a leiomyosarcoma of high histological grade and mitotic count. It was positive by immunohistochemistry for smooth muscle actin, while the other markers were negative. Surgical limits were compromised so a reoperation with wide margins of healthy tissue was necessary.
CONCLUSION
The skin lesions should be removed all, without exception, since they can be neoplasms of variable biological behavior. The histological study must be complemented with immunohistochemistry to differentiate them from other neoplasms. For the prognosis, the histological grade, size, location and the possibility of resection with wide margins must be taken into account.
Topics: Actins; Aged; Foreskin; Humans; Immunohistochemistry; Leiomyosarcoma; Male; Prognosis
PubMed: 36149076
DOI: 10.31053/1853.0605.v79.n3.34628 -
Journal of Clinical Oncology : Official... May 2023Novel biomarkers are needed to differentiate outcomes in intermediate-risk rhabdomyosarcoma (IR RMS). We sought to evaluate strategies for identifying circulating tumor...
PURPOSE
Novel biomarkers are needed to differentiate outcomes in intermediate-risk rhabdomyosarcoma (IR RMS). We sought to evaluate strategies for identifying circulating tumor DNA (ctDNA) in IR RMS and to determine whether ctDNA detection before therapy is associated with outcome.
PATIENTS AND METHODS
Pretreatment serum and tumor samples were available from 124 patients with newly diagnosed IR RMS from the Children's Oncology Group biorepository, including 75 patients with fusion-negative rhabdomyosarcoma (FN-RMS) and 49 with fusion-positive rhabdomyosarcoma (FP-RMS) disease. We used ultralow passage whole-genome sequencing to detect copy number alterations and a new custom sequencing assay, Rhabdo-Seq, to detect rearrangements and single-nucleotide variants.
RESULTS
We found that ultralow passage whole-genome sequencing was a method applicable to ctDNA detection in all patients with FN-RMS and that ctDNA was detectable in 13 of 75 serum samples (17%). However, the use of Rhabdo-Seq in FN-RMS samples also identified single-nucleotide variants, such as , previously associated with prognosis. Identification of pathognomonic translocations between or and by Rhabdo-Seq was the best method for measuring ctDNA in FP-RMS and detected ctDNA in 27 of 49 cases (55%). Patients with FN-RMS with detectable ctDNA at diagnosis had significantly worse outcomes than patients without detectable ctDNA (event-free survival, 33.3% 68.9%; = .0028; overall survival, 33.3% 83.2%; < .0001) as did patients with FP-RMS (event-free survival, 37% 70%; = .045; overall survival, 39.2% 75%; = .023). In multivariable analysis, ctDNA was independently associated with worse prognosis in FN-RMS but not in the smaller FP-RMS cohort.
CONCLUSION
Our study demonstrates that baseline ctDNA detection is feasible and is prognostic in IR RMS.
Topics: Humans; Child; Prognosis; Circulating Tumor DNA; Rhabdomyosarcoma; Nucleotides; Rhabdomyosarcoma, Alveolar; Biomarkers, Tumor
PubMed: 36724417
DOI: 10.1200/JCO.22.00409 -
Pediatric Blood & Cancer Sep 2021Rhabdomyosarcoma (RMS) is characterized by the expression of the myogenic regulatory protein MYOD1. Histologic types include alveolar, embryonal (ERMS), and spindle cell...
BACKGROUND/OBJECTIVES
Rhabdomyosarcoma (RMS) is characterized by the expression of the myogenic regulatory protein MYOD1. Histologic types include alveolar, embryonal (ERMS), and spindle cell sclerosing RMS (SRMS). SRMS harbors MYOD1 mutations in a subset of adult cases in association with poor prognosis.
DESIGN/METHODS
To study the level of MYOD1 protein expression and its clinical significance, we have analyzed variable numbers of pediatric (<18 years of age) and adult (age range ≥18 to 35 years) ERMS and SRMS cases for presence or absence of MYOD1 immunoreactivity in correlation with clinical outcome and MYOD1 L122R mutations.
RESULTS
Lack of MYOD1 immunoreactivity, identified in 23.8% of nonalveolar RMS (non-ARMS) cases, was more prevalent in SRMS (44%) than ERMS (17.2%) and was significantly associated with low overall survival and unfavorable tumor sites (p < .05). Lack of MYOD1 immunoreactivity was not associated with MYOD1 L122R mutations, which were identified in 3/37 (8%) cases including only two of 31 (6.5%) pediatric cases, one of 11 or 9% pediatric SRMS, and one case of infant ERMS.
CONCLUSION
These studies highlight the prognostic role of MYOD1 in non-ARMS. Lack of MYOD1 immunoreactivity is associated with poor prognosis in ERMS and SRMS. MYOD1 gene mutations are generally infrequent in pediatric RMS. Although mutations are predominant in SRMS, they may exceptionally occur in infantile ERMS.
Topics: Adolescent; Adult; Child; Humans; Infant; Mutation; MyoD Protein; Prognosis; Rhabdomyosarcoma; Rhabdomyosarcoma, Alveolar; Rhabdomyosarcoma, Embryonal; Young Adult
PubMed: 33913590
DOI: 10.1002/pbc.29085 -
Clinics (Sao Paulo, Brazil) 2024The present study aimed to investigate FOXO3a deregulation in Uterine Smooth Muscle Tumors (USMT) and its potential association with cancer development and prognosis.
OBJECTIVE
The present study aimed to investigate FOXO3a deregulation in Uterine Smooth Muscle Tumors (USMT) and its potential association with cancer development and prognosis.
METHODS
The authors analyzed gene and protein expression profiles of FOXO3a in 56 uterine Leiomyosarcomas (LMS), 119 leiomyomas (comprising conventional and unusual leiomyomas), and 20 Myometrium (MM) samples. The authors used techniques such as Immunohistochemistry (IHC), FISH/CISH, and qRT-PCR for the present analyses. Additionally, the authors conducted an in-silico analysis to understand the interaction network involving FOXO3a and its correlated genes.
RESULTS
This investigation revealed distinct expression patterns of the FOXO3a gene and protein, including both normal and phosphorylated forms. Expression levels were notably elevated in LMS, and Unusual Leiomyomas (ULM) compared to conventional Leiomyomas (LM) and Myometrium (MM) samples. This upregulation was significantly associated with metastasis and Overall Survival (OS) in LMS patients. Intriguingly, FOXO3a deregulation did not seem to be influenced by EGF/HER-2 signaling, as there were minimal levels of EGF and VEGF expression detected, and HER-2 and EGFR were negative in the analyzed samples. In the examination of miRNAs, the authors observed upregulation of miR-96-5p and miR-155-5p, which are known negative regulators of FOXO3a, in LMS samples. Conversely, the tumor suppressor miR-let7c-5p was downregulated.
CONCLUSIONS
In summary, the outcomes of the present study suggest that the imbalance in FOXO3a within Uterine Smooth Muscle Tumors might arise from both protein phosphorylation and miRNA activity. FOXO3a could emerge as a promising therapeutic target for individuals with Unusual Leiomyomas and Leiomyosarcomas (ULM and LMS), offering novel directions for treatment strategies.
Topics: Humans; Female; Forkhead Box Protein O3; Uterine Neoplasms; Middle Aged; Leiomyoma; Adult; Immunohistochemistry; Gene Expression Regulation, Neoplastic; Leiomyosarcoma; Smooth Muscle Tumor; Up-Regulation; MicroRNAs; Prognosis; Aged; Myometrium
PubMed: 38636197
DOI: 10.1016/j.clinsp.2024.100350 -
Cellular and Molecular Life Sciences :... Aug 2023The stage, when tissues and organs are growing, is very vulnerable to environmental influences, but it's not clear how exposure during this time causes changes to the...
BACKGROUND
The stage, when tissues and organs are growing, is very vulnerable to environmental influences, but it's not clear how exposure during this time causes changes to the epigenome and increases the risk of hormone-related illnesses like uterine fibroids (UFs).
METHODS
Developmental reprogramming of myometrial stem cells (MMSCs), the putative origin from which UFs originate, was investigated in vitro and in the Eker rat model by RNA-seq, ChIP-seq, RRBS, gain/loss of function analysis, and luciferase activity assays.
RESULTS
When exposed to the endocrine-disrupting chemical (EDC) diethylstilbestrol during Eker rat development, MMSCs undergo a reprogramming of their estrogen-responsive transcriptome. The reprogrammed genes in MMSCs are known as estrogen-responsive genes (ERGs) and are activated by mixed lineage leukemia protein-1 (MLL1) and DNA hypo-methylation mechanisms. Additionally, we observed a notable elevation in the expression of ERGs in MMSCs from Eker rats exposed to natural steroids after developmental exposure to EDC, thereby augmenting estrogen activity.
CONCLUSION
Our studies identify epigenetic mechanisms of MLL1/DNA hypo-methylation-mediated MMSC reprogramming. EDC exposure epigenetically targets MMSCs and leads to persistent changes in the expression of a subset of ERGs, imparting a hormonal imprint on the ERGs, resulting in a "hyper-estrogenic" phenotype, and increasing the hormone-dependent risk of UFs.
Topics: Animals; Rats; Endocrine Disruptors; Estrogens; Biological Assay; Leiomyoma; Myeloid-Lymphoid Leukemia Protein; DNA
PubMed: 37650943
DOI: 10.1007/s00018-023-04919-0 -
Clinical Cancer Research : An Official... Jan 2023Rhabdomyosarcoma (RMS) is an aggressive soft-tissue sarcoma, which primarily occurs in children and young adults. We previously reported specific genomic alterations in...
PURPOSE
Rhabdomyosarcoma (RMS) is an aggressive soft-tissue sarcoma, which primarily occurs in children and young adults. We previously reported specific genomic alterations in RMS, which strongly correlated with survival; however, predicting these mutations or high-risk disease at diagnosis remains a significant challenge. In this study, we utilized convolutional neural networks (CNN) to learn histologic features associated with driver mutations and outcome using hematoxylin and eosin (H&E) images of RMS.
EXPERIMENTAL DESIGN
Digital whole slide H&E images were collected from clinically annotated diagnostic tumor samples from 321 patients with RMS enrolled in Children's Oncology Group (COG) trials (1998-2017). Patches were extracted and fed into deep learning CNNs to learn features associated with mutations and relative event-free survival risk. The performance of the trained models was evaluated against independent test sample data (n = 136) or holdout test data.
RESULTS
The trained CNN could accurately classify alveolar RMS, a high-risk subtype associated with PAX3/7-FOXO1 fusion genes, with an ROC of 0.85 on an independent test dataset. CNN models trained on mutationally-annotated samples identified tumors with RAS pathway with a ROC of 0.67, and high-risk mutations in MYOD1 or TP53 with a ROC of 0.97 and 0.63, respectively. Remarkably, CNN models were superior in predicting event-free and overall survival compared with current molecular-clinical risk stratification.
CONCLUSIONS
This study demonstrates that high-risk features, including those associated with certain mutations, can be readily identified at diagnosis using deep learning. CNNs are a powerful tool for diagnostic and prognostic prediction of rhabdomyosarcoma, which will be tested in prospective COG clinical trials.
Topics: Child; Humans; Young Adult; Deep Learning; Eosine Yellowish-(YS); Hematoxylin; Paired Box Transcription Factors; Prospective Studies; Rhabdomyosarcoma; Rhabdomyosarcoma, Alveolar
PubMed: 36346688
DOI: 10.1158/1078-0432.CCR-22-1663 -
Medicina (Kaunas, Lithuania) Dec 2023Uterine myomas represent one of the most prevalent pathologies affecting the female population. These benign neoplasms originate from the smooth muscular cells of the... (Review)
Review
Uterine myomas represent one of the most prevalent pathologies affecting the female population. These benign neoplasms originate from the smooth muscular cells of the uterus, and they can be either single or multiple. Often associated with debilitating symptoms such as pelvic heaviness, pain, constipation, and urinary dysfunctions, the surgical management of myomectomy exhibits considerable variability. This diversity in approaches is influenced by factors such as the number and size of myomas, the patient's age, and overall clinical conditions. This study aims to elucidate and compare the advantages and disadvantages of different surgical approaches, specifically endoscopic procedures versus open surgery, providing valuable insights for clinical decision making. A comprehensive bibliographic search spanning from 2013 to 2023 was systematically conducted across databases including Medline, Embase, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov. The search utilized keywords such as "myomectomy laparoscopic and open", "myomectomy open and minimally invasive", "myomectomy open and laparoscopic", and "myomectomy open vs. laparoscopic." The research methodology, along with predetermined inclusion and exclusion criteria, was established prior to the search, ensuring a systematic and rigorous approach. Subsequently, data analysis was carried out. Following the study selection process, 25 articles met the eligibility criteria for inclusion in this analysis. The average numbers of myomas were 3.7 (ranging from 1 to 13.7) and 5.4 (ranging from 1 to 13.5) for the minimally invasive surgery and open surgery groups, respectively. In terms of myoma size, the total averages across studies were 7 cm (ranging from 4.8 to 14) for the minimally invasive group and 8 cm (ranging from 3.9 to 11.2) for the open surgery group. The average pregnancy and delivery rates were 29.7% (ranging from 1.8 to 100) for the minimally invasive group and 28.5% (ranging from 1.8 to 100) for the open surgery group. Regarding complications, the average rate was 14.2% (ranging from 0 to 50) for the endoscopic group and 22.3% (ranging from 0 to 60.3) for the laparotomic group. In conclusion, a critical factor influencing the choice of surgical approach is primarily the size and quantity of fibroids. The mini-laparotomic approach emerges as a viable alternative to endoscopy, demonstrating favorable surgical outcomes and aesthetic results. Interestingly, the type of surgical procedure appears to have no significant impact on the pregnancy rate.
Topics: Pregnancy; Female; Humans; Systematic Reviews as Topic; Leiomyoma; Uterine Myomectomy; Laparoscopy; Myoma
PubMed: 38256325
DOI: 10.3390/medicina60010064