USP5 Promotes Ripretinib Resistance in Gastrointestinal Stromal Tumors by MDH2 Deubiquition.

Ripretinib, a broad-spectrum inhibitor of the KIT and PDGFRA receptor tyrosine kinases, is designated as a fourth-line treatment for gastrointestinal stromal tumor (GIST). It is tailored for patients resistant to imatinib, sunitinib, and regorafenib. As its increasing use, instances of resistance to ripretinib are becoming more frequent. Unfortunately, there are currently no scientifically mature treatment options available for patients resistant to ripretinib. Posttranslational modifications (PTMs) such as ubiquitination, in conjunction with its interplay with other modifications, play a collective role in regulating tumor initiation and progression. However, the specific association between ubiquitination and ripretinib resistance is not reported. Through proteome-ubiquitinome sequencing, increased levels of the USP5 protein and decreased ubiquitination in ripretinib-resistant GISTs are detected. Subsequent examination of the mass spectrometry findings validated the interaction through which TRIM21 governs USP5 expression via ubiquitination, and USP5 regulates MDH2 expression through deubiquitination, consequently fostering ripretinib resistance in GIST. Moreover, ZDHHC18 can palmitoylate MDH2, preventing its ubiquitination and further increasing its protein stability. The research underscores the correlation between posttranslational modifications, specifically ubiquitination, and drug resistance, emphasizing the potential of targeting the USP5-MDH2 axis to counteract ripretinib resistance in GIST.

Clinical and pathological analyses of 14 cases of angiomatoid fibrous histiocytoma.

Angiomatoid fibrous histiocytoma (AFH) is a soft tissue tumor of uncertain differentiation. Although its prognosis is good, its diagnosis and differential diagnosis remain a challenge, particularly for tumors with an atypical morphology. We evaluated the clinicopathological characteristics of 14 AFH cases and examined the key factors in its diagnosis or differential diagnosis. The cohort comprised 6 men and 8 women aged 9-65 years (average age: 31.2 years). Most of the tumors (11/14, 79%) were located in soft tissues, whereas 3/14 (21%) were located in the lung (1 case) and brain (2 cases). Tumor cells were spindle-shaped to epithelioid, with a visible fibrous capsule (9/14, 64%), hemorrhagic gap (9/14, 64%), lymphocyte sleeve (7/14, 50%), necrosis (3/14, 21%), and infiltrative boundary (4/14, 29%). The tumors expressed desmin (10/14, 71%) and exhibited low levels of Ki-67. 13 cases (93%) displayed ESWSR1 gene rearrangement. At follow-up, 1 case (7%) experienced local tumor recurrence. AFH is a rare intermediate tumor. Its pathological diagnosis requires a comprehensive analysis of histological, immunophenotypic, and molecular genetic features to avoid misdiagnosis. Our study has further enriched the histological features of AFH, emphasizing the importance of differential diagnosis and providing a reference for clinical practice.

World Health Organization Reporting System for Soft Tissue Cytopathology: Risk of malignancy and reproducibility of categories among observers.

INTRODUCTION: In 2024, the World Health Organization (WHO) is scheduled to publish the WHO Reporting System for Soft Tissue Cytopathology (WHORSSTC). This system establishes categories with well-defined definitions, criteria, and estimated risks of malignancy (ROMs) for soft tissue tumors. The estimates of ROM are based on a relatively small number of published studies. Interobserver reproducibility is not addressed in the reporting system even though reproducibility of a reporting system is highly important. METHODS: A manual search of one authors personal consultation files and teaching set (L.J.L.) was conducted for all cytologic specimens of soft tissue tumors accessioned between January 1, 1985 and December 31, 2022. Only cases with documented surgical pathology follow-up were included in the study. Slides from each case were evaluated independently by three cytopathologists with each case assigned to one of the WHORSSTC categories. A ROM for each of the WHORSSTC categories was calculated. Interobserver agreement was evaluated by the kappa and weighted kappa statistics. RESULTS: Risk for malignancy by category were: Category 1: 0%, Category 2: 28%, Category 3: 57%, Category 4: 47%, Category 5: 63%, and Category 6: 88%. Kappa statistics for agreement between raters varied from 0.2183 to 0.3465 and weighted kappa varied from 0.3778 to 0.5217. CONCLUSIONS: The WHORSSTC showed a progression of malignancy risk from the category "benign" (28%) to the category "malignant" (88%). Interobserver agreement was only fair.

Histological diagnostic discrepancy and its clinical impact in bone and soft tissue tumors referred to a sarcoma center.

Histological diagnosis of sarcomas (malignant bone and soft tissue tumors) is challenging due to their rarity, morphological diversity, and constantly evolving diagnostic criteria. In this study, we aimed to assess the concordance in histological diagnosis of bone and soft tissue tumors between referring hospitals and a tertiary sarcoma center and analyzed the clinical impact of the diagnostic alteration. We analyzed 628 consecutively accessioned specimens from 624 patients who visited a specialized sarcoma center for treatment. The diagnoses at referring hospitals and those at the sarcoma center were compared and classified into four categories: agreed, disagreed, specified, and de-specified. Of the 628 specimens, the diagnoses agreed in 403 (64.2%) specimens, whereas some changes were made in 225 (35.8%) specimens: disagreed in 153 (24.3%), specified in 52 (8.3%), and de-specified in 20 (3.2%) cases. The benign/intermediate/malignant judgment changed for 92 cases (14.6%). The diagnostic change resulted in patient management modification in 91 cases (14.5%), including surgical and medical treatment changes. The main inferred reason for the diagnostic discrepancies was a different interpretation of morphological findings of the tumor, which accounted for 48.9% of the cases. This was followed by the unavailability of specialized immunohistochemical antibodies and the unavailability of genetic analysis. In summary, our study clarified the actual clinical impact of diagnostic discrepancy in bone and soft tissue tumors. This may underscore the value of pathology consultation, facilitating access to specialized diagnostic tools, and continued education. These measures are expected to improve diagnostic precision and ultimately benefit patients.

Diagnosis and Management of Desmoid Fibromatosis of the Breast.

Desmoid fibromatosis of the breast (also known as desmoid tumor of the breast) is a rare entity infrequently encountered by oncologists and surgeons caring for patients with breast disease. The current body of literature is highly reliant on case series and extrapolations from other sites of desmoid tumor-related disease. Much remains unclear regarding the pathological origins, natural history, and response to treatment of this condition. Traditional treatment strategies have centered on surgical resection, which may result in significantly disfiguring cosmetic and functional outcomes, frequent need for re-operation, and associated morbidity. There are limited data to support the superiority of upfront surgical resection when compared to medical therapy or watchful waiting strategies. Current treatment guidelines for desmoid tumors do not focus on the breast as a site of disease and are purposefully ambiguous due to the paucity of evidence available. We aim to review the literature concerning desmoid fibromatosis of the breast and propose an algorithm for current evidence-based management of this rare disease in the context of our experience with this pathology at a high-volume quaternary referral center.

Surgical Treatment of Multiple Large Tuberous and Tendinous Xanthoma Secondary to Familial Hypercholesterolaemia: A Case Report.

Xanthomas are well-circumscribed skin lesions that are commonly seen in patients with familial hypercholesterolemia (FH). The aim of this report is to present a rare case of multiple large tuberous and tendinous xanthomas. A 17-year-old female patient in this report presented with multiple asymptomatic and papulo-nodular masses in both sides of palms, elbows, buttocks, knees, and Achilles tendons. Surgical removal of the masses was carried out in combination with lipid-lowering therapy. A following up of 3 months showed all wounds were healing well, and no recurrence of masses was observed. Therefore, for patients with xanthomas related with familial hypercholesterolaemia, lipid-lowering therapy has reportedly reduced the size of masses, but surgical treatment may be essential for large xanthomas caused pain or limitation of daily activities.

A Population-Based Long-Term Follow-Up of Soft Tissue Angiosarcomas: Characteristics, Treatment Outcomes, and Prognostic Factors.

Angiosarcoma is a rare aggressive and understudied soft tissue sarcoma with pending evidence-based treatment guidelines due to varying study cohorts and inconsistent outcome measures. Surgery with wide resection is currently considered to be the cornerstone in management. In a population-based cohort identified from Danish National Health Registers between 2000 and 2017, this study aimed to define prognostic factors in patients with newly diagnosed soft tissue angiosarcoma. Kaplan-Meier survival analysis demonstrated 5-year overall survival of 28%. Competing risk analysis demonstrated cumulative incidence of local recurrence of 30% and metastasis of 43%. Multivariable Cox models among 154 included patients demonstrated age above 60 years and metastasis to be independently associated with worse overall survival. Cutaneous tumors, surgery, and negative resection margin were independently associated with improved overall survival. Adjuvant oncological treatment did not improve overall survival, risk of metastasis, or recurrence. Negative margin was not associated with lower risk of recurrence and metastasis. We conclude that, despite demonstrated improved survival after surgery with wide resection, overall survival remains poor.

Applying dynamic contrast-enhanced MRI tracer kinetic models to differentiate benign and malignant soft tissue tumors.

BACKGROUND: To explore the potential of different quantitative dynamic contrast-enhanced (qDCE)-MRI tracer kinetic (TK) models and qDCE parameters in discriminating benign from malignant soft tissue tumors (STTs). METHODS: This research included 92 patients (41females, 51 males; age range 16-86 years, mean age 51.24 years) with STTs. The qDCE parameters (Ktrans, Kep, Ve, Vp, F, PS, MTT and E) for regions of interest of STTs were estimated by using the following TK models: Tofts (TOFTS), Extended Tofts (EXTOFTS), adiabatic tissue homogeneity (ATH), conventional compartmental (CC), and distributed parameter (DP). We established a comprehensive model combining the morphologic features, time-signal intensity curve shape, and optimal qDCE parameters. The capacities to identify benign and malignant STTs was evaluated using the area under the curve (AUC), degree of accuracy, and the analysis of the decision curve. RESULTS: TOFTS-Ktrans, EXTOFTS-Ktrans, EXTOFTS-Vp, CC-Vp and DP-Vp demonstrated good diagnostic performance among the qDCE parameters. Compared with the other TK models, the DP model has a higher AUC and a greater level of accuracy. The comprehensive model (AUC, 0.936, 0.884-0.988) demonstrated superiority in discriminating benign and malignant STTs, outperforming the qDCE models (AUC, 0.899-0.915) and the traditional imaging model (AUC, 0.802, 0.712-0.891) alone. CONCLUSIONS: Various TK models successfully distinguish benign from malignant STTs. The comprehensive model is a noninvasive approach incorporating morphological imaging aspects and qDCE parameters, and shows significant potential for further development.

Case report: Rapidly progressive desmoid tumor after surgery for esophagogastric junction cancer and slowly progressive primary desmoid tumor: a report of two cases and literature review.

Background: Desmoid tumor (DT) is a rare locally aggressive but non-metastatic mesenchymal soft tissue neoplasm that predominantly occurs in the abdominal wall, abdominal cavity, and extremities. Its occurrence in the mesentery is relatively uncommon. Case reports: This article reports two cases of desmoid tumor treated at the Department of Gastrointestinal Surgery, Weifang People's Hospital. The first case was a 59-year-old male patient who had previously undergone surgery for esophagogastric junction cancer. Postoperatively, he developed an intra-abdominal mass that rapidly increased in size within three months. The second case was a 60-year-old male patient who incidentally discovered a mass in the left lower abdomen. Both patients underwent surgical treatment, and the postoperative pathological diagnosis was mesenteric desmoid tumor. Conclusion: The treatment of desmoid tumor remains challenging. Simple surgical resection often yields unsatisfactory outcomes, and the efficacy of adjuvant radiotherapy and chemotherapy is also limited. Further research and clinical practice are necessary to improve diagnostic and therapeutic strategies, aiming to enhance patient survival and quality of life.

Diagnostic Performance of Radiomics and Deep Learning to Identify Benign and Malignant Soft Tissue Tumors: A Systematic Review and Meta-analysis.

RATIONALE AND OBJECTIVES: To systematically evaluate the application value of radiomics and deep learning (DL) in the differential diagnosis of benign and malignant soft tissue tumors (STTs). MATERIALS AND METHODS: A systematic review was conducted on studies published up to December 11, 2023, that utilized radiomics and DL methods for the diagnosis of STTs. The methodological quality and risk of bias were evaluated using the Radiomics Quality Score (RQS) 2.0 system and Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool, respectively. A bivariate random-effects model was used to calculate the summarized sensitivity and specificity. To identify factors contributing to heterogeneity, meta-regression and subgroup analyses were performed to assess the following covariates: diagnostic modality, region/volume of interest, imaging examination, study design, and pathology type. The asymmetry of Deeks' funnel plot was used to assess publication bias. RESULTS: A total of 21 studies involving 3866 patients were included, with 13 studies using independent test/validation sets included in the quantitative statistical analysis. The average RQS was 21.31, with substantial or near-perfect inter-rater agreement. The combined sensitivity and specificity were 0.84 (95% CI: 0.76-0.89) and 0.88 (95% CI: 0.69-0.96), respectively. Meta-regression and subgroup analyses showed that study design and the region/volume of interest were significant factors affecting study heterogeneity (P < 0.05). No publication bias was observed. CONCLUSION: Radiomics and DL can accurately distinguish between benign and malignant STTs. Future research should concentrate on enhancing the rigor of study designs, conducting multicenter prospective validations, amplifying the interpretability of DL models, and integrating multimodal data to elevate the diagnostic accuracy and clinical utility of soft tissue tumor assessments.

A Rare Coexistence of Hybrid Tumor Low-grade Fibromyxoid Sarcoma/Sclerosing Epithelioid Fibrosarcoma and Hibernoma in the Same Thigh: A Case Report.

Introduction: We encountered a unique case of a patient with two distinct tumors coexisting in the same thigh. To the best of our knowledge, this combination of tumors in the same anatomical region has not been previously described in the literature. Case Report: This case report describes a 38-year-old Caucasian male with a painless mass in his right thigh, which was later diagnosed as a hybrid tumor composed of low-grade fibromyxoid sarcoma and sclerosing epithelioid fibrosarcoma, as well as a second tumor, which was diagnosed as a hibernoma. The patient underwent neoadjuvant chemotherapy and surgical excision, followed by adjuvant radiotherapy and treatment for metastatic recurrence. Conclusion: The rarity of this case highlights the need for interdisciplinary collaboration and further investigations into the behavior and management of hybrid tumors. This case also underscores the importance of an accurate histological diagnosis aided by immunohistochemistry and molecular analyses.

Subcutaneous fibroblastoma resembling hemangioma: A case of benign tumor of the chest wall.

Key Clinical Message: Desmoplastic fibroma presents similar to other soft tissue tumors to such an extent that even a gold standard investigation can miss. Abstract: This is to report a mass in a 47-year-old male arising from the chest wall, which was first thought to be a hemangioma but was later diagnosed as a case of desmoplastic fibroblastoma with the help of a biopsy.

A Rare Case of a Malignant Epithelioid Neoplasm With an Underlying Novel EWSR1::ZBT44 Fusion, Identified on Next-Generation Sequencing (NGS).

The clinicopathological spectrum of undifferentiated round cell sarcomas of bone and soft tissues is expanding after the 5th edition of the WHO classification. A 23-year-old male patient presented with a lump in his left thigh of 3 months' duration. Radiological examination revealed a well-defined, solid-cystic lobulated, soft tissue lesion in the proximal medial region of his left thigh, measuring 7.7 cm in the largest dimension. The referring diagnosis was an epithelioid sarcoma. Histopathological review of the tumor sections revealed a cellular tumor composed of malignant epithelioid to focally "rhabdoid-like" cells in a variable hyalinized and myxoid stroma with geographic areas of necrosis. In addition, there were areas reminiscent of hemangiopericytomatous vasculature. By immunohistochemistry, the tumor cells were diffusely positive for CD34, focally and distinctly for pan keratin (AE1/AE3). INI1/SMARCB1 and SMARCA4 (BRG1) were diffusely positive (normal). Next-generation sequencing with a wide sarcoma panel revealed EWSR1exon8::ZBT44exon4 fusion. The present example constitutes the first malignant epithelioid tumor with a hemangiopericytomatous growth pattern, exhibiting this rare fusion. The differential diagnoses of this tumor and their corresponding immunohistochemical profile are discussed. This example highlights the value of NGS in unraveling rare fusions and in differentiating these tumors from their several mimics.

The effect of gadolinium-based intravenous contrast in the initial characterization of musculoskeletal soft tissue tumors.

OBJECTIVE: To determine if gadolinium-based contrast agents increase the sensitivity, specificity or reader confidence of malignant potential in musculoskeletal soft tissue tumors. METHODS: Pre- and post-contrast MRI studies from 87 patients were read by three independent radiologists of different experience. Readers noted malignant potential and confidence in their diagnosis based on pre-contrast and post-contrast MRI studies. Statistical models assessed for agreement between MRI reader diagnosis and pathologic results as well as analyzing effects of contrast on reader confidence. Inter- and intra-observer variabilities of malignant potential were also calculated. RESULTS: 87 patients (48 benign and 39 malignant; mean [± SD] age 51 ± 17.9 and 57.1 ± 17.1, respectively) were evaluated. For all readers, pre-contrast and post-contrast sensitivities were 68.1 % and 70.6 % while pre-contrast and post-contrast specificities were 84.6 % and 83.8 %, respectively without significant change (p=0.88). There was not a significant association with the use of contrast and prediction of malignant potential with or without the resident reader (p=0.65 and p=0.82). Use of contrast was significantly associated with higher levels of reader confidence (p=0.02) for all readers. Inter- and intra-observer variabilities were in good agreement (W = 0.77 and 0.70). CONCLUSION: The addition of a post-contrast sequence increased reader confidence in their diagnosis without a corresponding significant increase in accurate prediction of malignant potential.

Utility of artificial intelligence in a binary classification of soft tissue tumors.

Soft tissue tumors (STTs) pose diagnostic and therapeutic challenges due to their rarity, complexity, and morphological overlap. Accurate differentiation between benign and malignant STTs is important to set treatment directions, however, this task can be difficult. The integration of machine learning and artificial intelligence (AI) models can potentially be helpful in classifying these tumors. The aim of this study was to investigate AI and machine learning tools in the classification of STT into benign and malignant categories. This study consisted of three components: (1) Evaluation of whole-slide images (WSIs) to classify STT into benign and malignant entities. Five specialized soft tissue pathologists from different medical centers independently reviewed 100 WSIs, representing 100 different cases, with limited clinical information and no additional workup. The results showed an overall concordance rate of 70.4% compared to the reference diagnosis. (2) Identification of cell-specific parameters that can distinguish benign and malignant STT. Using an image analysis software (QuPath) and a cohort of 95 cases, several cell-specific parameters were found to be statistically significant, most notably cell count, nucleus/cell area ratio, nucleus hematoxylin density mean, and cell max caliper. (3) Evaluation of machine learning library (Scikit-learn) in differentiating benign and malignant STTs. A total of 195 STT cases (156 cases in the training group and 39 cases in the validation group) achieved approximately 70% sensitivity and specificity, and an AUC of 0.68. Our limited study suggests that the use of WSI and AI in soft tissue pathology has the potential to enhance diagnostic accuracy and identify parameters that can differentiate between benign and malignant STTs. We envision the integration of AI as a supportive tool to augment the pathologists' diagnostic capabilities.

Radiomics approach to distinguish between benign and malignant soft tissue tumors on magnetic resonance imaging.

Objective: To build a radiomics signature based on MRI images and evaluate its capability for preoperatively identifying the benign and malignant Soft tissue neoplasms (STTs). Materials and methods: 193 patients (99 malignant STTs and 94 benign STTs) were at random segmented into a training cohort (69 malignant STTs and 65 benign STTs) and a validation cohort (30 malignant STTs and 29 benign STTs) with a portion of 7:3. Radiomics features were extracted from T2 with fat saturation and T1 with fat saturation and gadolinium contrast images. Radiomics signature was developed by the least absolute shrinkage and selection operator (LASSO) logistic regression model. The receiver that operated characteristics curve (ROC) analysis was used to assess radiomics signature's prediction performance. Inner validation was performed on an autonomous cohort that contained 40 patients. Results: A radiomics was developed by a total of 16 radiomics features (5 original shape features and 11 were wavelet features) achieved favorable predictive efficacy. Malignant STTs showed higher radiomics score than benign STTs in both training cohort and validation cohort. A good prediction performance was shown by the radiomics signature in both training cohorts and validation cohorts. The training cohorts and validation cohorts had an area under curves (AUCs) of 0.885 and 0.841, respectively. Conclusions: A radiomics signature based on MRI images can be a trustworthy imaging biomarker for identification of the benign and malignant STTs, which could help guide treatment strategies.

Angioleiomyoma: An Update with a 142-Case Series.

Angioleiomyomas are uncommon, noncancerous, smooth muscle tumors that primarily arise from blood vessels. Previous studies have yielded limited data due to the lack of interdisciplinary approaches or restricted patient pools. This study aims to provide a comprehensive analysis of angioleiomyomas, including the demographic, clinical, radiological, and histopathological features, with a large number of patients. Conducted as a retrospective investigation at a single center from January 2005 to June 2023, this study involved 142 patients. Relevant information was extracted from electronic medical records, covering clinical, radiological, histological, and demographic details. Angioleiomyomas mostly occurred at age 59 (1-87), predominately affect females (53%) and commonly arise in subcutaneous tissue (85%) and the lower limbs (76%). MRI findings revealed characteristic signals, with a high prevalence of the solid histologic type (65%), often displaying a reticular sign. Smooth muscle Actin was universally present (n = 95/95), while Desmin and Caldesmon showed positive expression in 83% (n = 71/85) and 98% (n = 92/94) of cases, respectively. This study presents an updated and comprehensive analysis of angioleiomyomas. Typically appearing as well-defined nodules in the extremities, these tumors can be effectively diagnosed using MRI, though histopathological analysis is generally essential for confirmation. Treatment primarily involves straightforward excision, with notable low complication and recurrence rates.

Recent advances in molecular profiling of bone and soft tissue tumors.

The molecular characterization of soft tissue and bone tumors is a rapidly evolving field that has changed the perspective of how these tumors are diagnosed today. Morphology and clinico-radiological context still represent the cornerstone of diagnostic considerations but are increasingly complemented by molecular data that aid in objectifying and confirming the classification. The spectrum of analyses comprises mutation or gene fusion specific immunohistochemical antibodies, fluorescence in situ hybridization, DNA and RNA sequencing as well as CpG methylation profiling. This article provides an overview of which tools are presently available to characterize bone and soft tissue neoplasms molecularly, what limitations should be considered, and what conclusions can be drawn from the individual findings.

GLI1-Altered Soft Tissue Tumor in the Tongue-A Case Report and Literature Review.

Background: Soft tissue tumors with fusions or amplifications of the GLI1 gene have distinctive molecular characteristics and have recently been considered a unique pathological entity, thus named "GLI1-altered soft tissue tumors." It is a rare mesenchymal neoplasm that involves soft tissues at any site. Case presentation: We report an example of this condition in a 13-year-old Chinese male patient who presented with a mass in the tongue. The tumor was multilobulated; the tumor cells were arranged in nests and sheets, had a rich, delicate fibrovascular network, and were separated by a hyalinized fibrous stroma. The tumor cells were epithelioid to ovoid, with variable eosinophilic to pale vacuolated cytoplasm and round to oval nuclei. Immunostaining revealed that the tumor cells were positive for CDK4 and CD56. Fluorescence in situ hybridization (FISH) for GLI1 translocation was positive, with a high level of amplification of the translocated segment. Literature review: We present a comprehensive literature review of this condition, focusing on its clinical presentation, histological features, immunohistochemical profile, molecular characteristics, and prognosis.