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Medicina (Kaunas, Lithuania) Jul 2023: The uterine smooth muscle tumors of uncertain malignant potential (STUMP) are tumors with pathological characteristics similar to leiomyosarcoma, but that do not... (Review)
Review
: The uterine smooth muscle tumors of uncertain malignant potential (STUMP) are tumors with pathological characteristics similar to leiomyosarcoma, but that do not satisfy histological criteria for leiomyoma. These are problematic lesions with intermediate morphologic features; thus, diagnosis and treatment are difficult. This narrative review aims to review data in the literature about STUMPs, particularly focusing on management and therapeutic options and strategies for women who desire to preserve fertility. : authors searched for "uterine smooth muscle tumor of uncertain malignant potential" in PubMed and Scopus databases, from 2000 to March 2023. Pertinent articles were obtained in full-text format and screened for additional references. Only articles in English language were included. Studies including full case description of patients with histopathological diagnosis of STUMP in accordance with Stanford criteria were included. : The median age was 43 years old. Symptoms are similar to those of leiomyomas, with a mean diameter of 8.0 cm. Total hysterectomy with or without bilateral salpingo-oophorectomy is the standard care for women if fertility desire is satisfied. Myomectomy alone can be considered for young patients. Although these tumors have not a high malignant potential, several studies described recurrence and metastases. : STUMPs are complex uterine smooth muscle tumors, with a rare but reasoned clinical-diagnostic management. Considering the high clinical and histological complexity of these tumors, high level of expertise is mandatory.
Topics: Adult; Female; Humans; Databases, Factual; Leiomyoma; Smooth Muscle Tumor; Uterine Myomectomy; Uterus
PubMed: 37629661
DOI: 10.3390/medicina59081371 -
Head and Neck Pathology Dec 2021This report describes a case of an adult rhabdomyoma (ARM) occurring in the oral cavity. A 47-year-old man was referred for the diagnosis of a painless,...
This report describes a case of an adult rhabdomyoma (ARM) occurring in the oral cavity. A 47-year-old man was referred for the diagnosis of a painless, well-circumscribed, submucous nodule located on the floor of the mouth, measuring approximately 6.0 cm in length. Computed tomography revealed a well-defined, solid, and hypodense mass. A benign salivary gland or mesenchymal tumor were the main diagnostic hypotheses. Under local anesthesia, the patient underwent surgical excision. Microscopically, the tumor comprised large polygonal well-defined cells with abundant, eosinophilic granular cytoplasm with cross striations. No atypia or mitosis was observed. The cells were positive for muscle-specific actin, desmin, and sarcomeric alpha-actin. Based on these features, a diagnosis of ARM was established. No recurrence was observed after 48 months. Although rare, ARM should be considered in the differential diagnosis of oral submucosal nodules, especially those located on the floor of the mouth.
Topics: Humans; Male; Middle Aged; Mouth Neoplasms; Rhabdomyoma
PubMed: 34378165
DOI: 10.1007/s12105-021-01371-z -
Japanese Journal of Clinical Oncology Nov 2023Alveolar soft part sarcoma is a rare neoplasm of uncertain histogenesis that belongs to a newly defined category of ultra-rare sarcomas. The neoplasm is characterized by... (Review)
Review
Alveolar soft part sarcoma is a rare neoplasm of uncertain histogenesis that belongs to a newly defined category of ultra-rare sarcomas. The neoplasm is characterized by a specific chromosomal translocation, der (17) t(X; 17)(p11.2;q25), that results in ASPSCR1-TFE3 gene fusion. The natural history of alveolar soft part sarcoma describes indolent behaviour with slow progression in deep soft tissues of the extremities, trunk and head/neck in adolescents and young adults. A high rate of detection of distant metastasis at presentation has been reported, and the most common metastatic sites in decreasing order of frequency are the lung, bone and brain. Complete surgical resection remains the standard treatment strategy, whereas radiotherapy is indicated for patients with inadequate surgical margins or unresectable tumours. Although alveolar soft part sarcoma is refractory to conventional doxorubicin-based chemotherapy, monotherapy or combination therapy using tyrosine kinase inhibitors and immune checkpoint inhibitors have provided antitumor activity and emerged as new treatment strategies. This article provides an overview of the current understanding of this ultra-rare sarcoma and recent advancements in treatments according to the clinical stage of alveolar soft part sarcoma.
Topics: Adolescent; Young Adult; Humans; Sarcoma, Alveolar Soft Part; Oncogene Proteins, Fusion; Soft Tissue Neoplasms; Translocation, Genetic; Combined Modality Therapy
PubMed: 37626447
DOI: 10.1093/jjco/hyad102 -
Clinical Cancer Research : An Official... Jan 2023PAX-fusion negative rhabdomyosarcoma (FN RMS) is driven by alterations in the RAS/MAP kinase pathway and is partially responsive to MEK inhibition. Overexpression of...
PURPOSE
PAX-fusion negative rhabdomyosarcoma (FN RMS) is driven by alterations in the RAS/MAP kinase pathway and is partially responsive to MEK inhibition. Overexpression of IGF1R and its ligands is also observed in FN RMS. Preclinical and clinical studies have suggested that IGF1R is itself an important target in FN RMS. Our previous studies revealed preclinical efficacy of the MEK1/2 inhibitor, trametinib, and an IGF1R inhibitor, BMS-754807, but this combination was not pursued clinically due to intolerability in preclinical murine models. Here, we sought to identify a combination of an MEK1/2 inhibitor and IGF1R inhibitor, which would be tolerated in murine models and effective in both cell line and patient-derived xenograft models of RAS-mutant FN RMS.
EXPERIMENTAL DESIGN
Using proliferation and apoptosis assays, we studied the factorial effects of trametinib and ganitumab (AMG 479), a mAb with specificity for human and murine IGF1R, in a panel of RAS-mutant FN RMS cell lines. The molecular mechanism of the observed synergy was determined using conventional and capillary immunoassays. The efficacy and tolerability of trametinib/ganitumab was assessed using a panel of RAS-mutated cell-line and patient-derived RMS xenograft models.
RESULTS
Treatment with trametinib and ganitumab resulted in synergistic cellular growth inhibition in all cell lines tested and inhibition of tumor growth in four of six models of RAS-mutant RMS. The combination had little effect on body weight and did not produce thrombocytopenia, neutropenia, or hyperinsulinemia in tumor-bearing SCID beige mice. Mechanistically, ganitumab treatment prevented the phosphorylation of AKT induced by MEK inhibition alone. Therapeutic response to the combination was observed in models without a mutation in the PI3K/PTEN axis.
CONCLUSIONS
We demonstrate that combined trametinib and ganitumab is effective in a genomically diverse panel of RAS-mutated FN RMS preclinical models. Our data also show that the trametinib/ganitumab combination likely has a favorable tolerability profile. These data support testing this combination in a phase I/II clinical trial for pediatric patients with relapsed or refractory RAS-mutated FN RMS.
Topics: Humans; Animals; Mice; Child; Cell Line, Tumor; Mice, SCID; Rhabdomyosarcoma; Protein Kinase Inhibitors; Mitogen-Activated Protein Kinase Kinases
PubMed: 36322002
DOI: 10.1158/1078-0432.CCR-22-1646 -
Journal of the American Veterinary... Nov 2019
Topics: Animals; Female; Granular Cell Tumor; Hyraxes; Liver Neoplasms
PubMed: 31687898
DOI: 10.2460/javma.255.10.1121 -
JCO Precision Oncology Jan 2023Total cell-free DNA (cfDNA) and tumor-derived cfDNA (ctDNA) can be used to study tumor-derived genetic aberrations. We analyzed the diagnostic and prognostic potential...
PURPOSE
Total cell-free DNA (cfDNA) and tumor-derived cfDNA (ctDNA) can be used to study tumor-derived genetic aberrations. We analyzed the diagnostic and prognostic potential of cfDNA and ctDNA, obtained from pediatric patients with rhabdomyosarcoma.
METHODS
cfDNA was isolated from diagnostic plasma samples from 57 patients enrolled in the EpSSG RMS2005 study. To study the diagnostic potential, shallow whole genome sequencing (shWGS) and cell-free reduced representation bisulphite sequencing (cfRRBS) were performed in a subset of samples and all samples were tested using droplet digital polymerase chain reaction to detect methylated (M). Correlation with outcome was studied by combining cfDNA M detection with analysis of our rhabdomyosarcoma-specific RNA panel in paired cellular blood and bone marrow fractions and survival analysis in 56 patients.
RESULTS
At diagnosis, ctDNA was detected in 16 of 30 and 24 of 26 patients using shallow whole genome sequencing and cfRRBS, respectively. Furthermore, 21 of 25 samples were correctly classified as embryonal by cfRRBS. -M was detected in 21 of 57 patients. The presence of -M was significantly correlated with poor outcome (the 5-year event-free survival [EFS] rate was 46.2% for 21 -Mpositive patients, compared with 84.9% for 36 -Mnegative patients [ < .001]). -M positivity had the highest prognostic effect among patients with metastatic disease. Patients both negative for -M and the rhabdomyosarcoma-specific RNA panel (28 of 56 patients) had excellent outcome (5-year EFS 92.9%), while double-positive patients (11/56) had poor outcome (5-year EFS 13.6%, < .001).
CONCLUSION
Analyzing ctDNA at diagnosis using various techniques is feasible in pediatric rhabdomyosarcoma and has potential for clinical use. Measuring M in plasma at initial diagnosis correlated significantly with outcome, particularly when combined with paired analysis of blood and bone marrow using a rhabdomyosarcoma-specific RNA panel.
Topics: Humans; Child; Cell-Free Nucleic Acids; Prognosis; Rhabdomyosarcoma; RNA; Biomarkers
PubMed: 36652664
DOI: 10.1200/PO.22.00113 -
Archives of Pathology & Laboratory... Nov 2019Leiomyosarcoma of bone is a rare primary osseous sarcoma characterized by smooth muscle differentiation and absence of malignant osteoid formation. Leiomyosarcoma of... (Review)
Review
CONTEXT.—
Leiomyosarcoma of bone is a rare primary osseous sarcoma characterized by smooth muscle differentiation and absence of malignant osteoid formation. Leiomyosarcoma of bone is diagnostically challenging; this can be improved with greater awareness of this entity and the ability to differentiate it from its histologic mimics. Because of its rarity, only a small number of studies are available in the literature. These factors contribute to our limited understanding of its pathology, prognosis, and treatment.
OBJECTIVE.—
To review the clinicopathologic features of leiomyosarcoma of bone and present the most up-to-date understanding of its behavior and management in accordance with the current literature.
DATA SOURCES.—
Review of pertinent literature on the major features, current knowledge thereof, and the authors' experience in the diagnosis and management of leiomyosarcoma of bone.
CONCLUSIONS.—
Leiomyosarcoma of bone is a rare but well-recognized primary osseous sarcoma that may arise de novo or in association with radiation. Although it is diagnostically challenging, awareness of this rare sarcoma and knowledge of its key histomorphologic and immunohistochemical features allow for accurate diagnosis.
Topics: Bone Neoplasms; Bone and Bones; Humans; Leiomyosarcoma; Prognosis
PubMed: 31661313
DOI: 10.5858/arpa.2019-0375-RA -
JCO Precision Oncology Jun 2023Extremity rhabdomyosarcoma (RMS) is associated with a very poor outcome compared with other sites, mainly because of its high incidence of alveolar histology and...
PURPOSE
Extremity rhabdomyosarcoma (RMS) is associated with a very poor outcome compared with other sites, mainly because of its high incidence of alveolar histology and regional lymph node involvement. To better define prognostic markers in this clinical subset, we investigated our experience of 61 patients with extremity RMS treated at our tertiary cancer center for the past 2 decades.
PATIENTS AND METHODS
The patients had a median age of 8 years at diagnosis, equal gender distribution, and two-thirds occurred in the lower extremity. Most (85%) patients had fusion-positive alveolar RMS (ARMS), with 70% having a transcript. Remaining were seven patients with fusion-negative embryonal RMS (ERMS) and two with mutant spindle cell/sclerosing RMS (SRMS). In 40% of the patients, material was available for DNA-based targeted sequencing using MSK-IMPACT cancer gene panel.
RESULTS
One-third of patients presented with localized disease at diagnosis while the remaining had regional nodal (18%) or distant metastases (51%). Metastatic disease, high-risk group, and age 10 years or older significantly affected the overall survival (OS; hazard ratio [HR], 2.68 [ = .004], 2.78 [ = .010] and 2.26 [ .034], respectively). Although the presence of metastatic disease had a dismal impact on 5-year EFS and OS (19% and 29%, respectively), nodal involvement had a comparatively lower impact on 5-year EFS and 5-year OS (43% and 66%, respectively). ARMS had worse prognosis and afflicted older children compared with (HR = 3.45, .016). The most common events in the ARMS group included alterations, amplifications, and deletions (8%-17%). The latter two abnormalities were mutually exclusive, enriched for acral and high-risk lesions, and correlated with poor outcome on OS ( = .02).
CONCLUSION
Our data provide rationale for considering the integration of molecular abnormalities to refine risk stratification in extremity RMS.
Topics: Child; Humans; Adolescent; Genomics; Rhabdomyosarcoma; Extremities; Oncogenes; Risk Assessment
PubMed: 37315267
DOI: 10.1200/PO.22.00705 -
Cells Apr 2021Uterine fibroids represent the most common benign tumors of the uterus. They are considered a typical fibrotic disorder. In fact, the extracellular matrix (ECM)... (Review)
Review
Uterine fibroids represent the most common benign tumors of the uterus. They are considered a typical fibrotic disorder. In fact, the extracellular matrix (ECM) proteins-above all, collagen 1A1, fibronectin and versican-are upregulated in this pathology. The uterine fibroids etiology has not yet been clarified, and this represents an important matter about their resolution. A model has been proposed according to which the formation of an altered ECM could be the result of an excessive wound healing, in turn driven by a dysregulated inflammation process. A lot of molecules act in the complex inflammatory response. Macrophages have a great flexibility since they can assume different phenotypes leading to the tissue repair process. The dysregulation of macrophage proliferation, accumulation and infiltration could lead to an uncontrolled tissue repair and to the consequent pathological fibrosis. In addition, molecules such as monocyte chemoattractant protein-1 (MCP-1), granulocyte macrophage-colony-stimulating factor (GM-CSF), transforming growth factor-beta (TGF-β), activin A and tumor necrosis factor-alfa (TNF-α) were demonstrated to play an important role in the macrophage action within the uncontrolled tissue repair that contributes to the pathological fibrosis that represents a typical feature of the uterine fibroids.
Topics: Animals; Humans; Immunity; Leiomyoma; Macrophages
PubMed: 33922329
DOI: 10.3390/cells10050982 -
British Journal of Cancer Nov 2022Rhabdomyosarcoma (RMS) is a paediatric cancer driven either by fusion proteins (e.g., PAX3-FOXO1) or by mutations in key signalling molecules (e.g., RAS or FGFR4)....
BACKGROUND
Rhabdomyosarcoma (RMS) is a paediatric cancer driven either by fusion proteins (e.g., PAX3-FOXO1) or by mutations in key signalling molecules (e.g., RAS or FGFR4). Despite the latter providing opportunities for precision medicine approaches in RMS, there are currently no such treatments implemented in the clinic.
METHODS
We evaluated biologic properties and targeting strategies for the FGFR4 V550L activating mutation in RMS559 cells, which have a high allelic fraction of this mutation and are oncogenically dependent on FGFR4 signalling. Signalling and trafficking of FGFR4 V550L were characterised by confocal microscopy and proteomics. Drug effects were determined by live-cell imaging, MTS assay, and in a mouse model.
RESULTS
Among recently developed FGFR4-specific inhibitors, FGF401 inhibited FGFR4 V550L-dependent signalling and cell proliferation at low nanomolar concentrations. Two other FGFR4 inhibitors, BLU9931 and H3B6527, lacked potent activity against FGFR4 V550L. Alternate targeting strategies were identified by RMS559 phosphoproteomic analyses, demonstrating that RAS/MAPK and PI3K/AKT are essential druggable pathways downstream of FGFR4 V550L. Furthermore, we found that FGFR4 V550L is HSP90-dependent, and HSP90 inhibitors efficiently impeded RMS559 proliferation. In a RMS559 mouse xenograft model, the pan-FGFR inhibitor, LY2874455, did not efficiently inhibit growth, whereas FGF401 potently abrogated growth.
CONCLUSIONS
Our results pave the way for precision medicine approaches against FGFR4 V550L-driven RMS.
Topics: Humans; Mice; Animals; Phosphatidylinositol 3-Kinases; Receptor, Fibroblast Growth Factor, Type 4; Rhabdomyosarcoma; Rhabdomyosarcoma, Embryonal; Protein Kinase Inhibitors; Cell Proliferation; Cell Line, Tumor
PubMed: 36097178
DOI: 10.1038/s41416-022-01973-6