[New aspects in fine needle biopsies of the lymph nodes]. / Neue Aspekte zur Feinnadelpunktion von Lymphknoten.

BACKGROUND: The cytology of lymph nodes is a cost-effective method with a short turnaround time and low risk to patients that delivers valuable information on the cause of the lymphadenopathies. OBJECTIVES: To discuss the value of lymph node cytology in the diagnosis of lymph node swellings. METHODS: Analysis of the causes of the controversially discussed aspects of lymph node cytology. Presentation of the diagnostic groups of lymph node cytology according to the Sydney system. RESULTS: The technical aspects of lymph node sampling during fine needle biopsy, as well as the subsequent preparation of the correctly fixed direct smears and the triage of the sample for the auxiliary studies, may pose a significant challenge for some puncturers. The whole spectrum of modern pathologic auxiliary studies can be applied to correctly triaged cytologic samples. The diagnoses of fine needle biopsies of the lymph nodes can be divided into five groups according to the recently proposed Sydney reporting system: insufficient/non-diagnostic, benign, atypical, suspicious, and malignant. Further details concerning the diagnosis as well as recommendations on how to proceed are additionally included in cytologic reports. CONCLUSIONS: The improvement of lymph node sampling as well as the technical aspects of the sample handling, including the application of auxiliary studies, considerably increase the diagnostic value of fine needle biopsy of the lymph nodes. Wide implementation of the usage of the diagnostic groups for reporting fine needle biopsies of the lymph nodes can standardize reporting and improve communication with other clinical specialists.

Intimal sarcomas and undifferentiated cardiac sarcomas carry mutually exclusive MDM2, MDM4, and CDK6 amplifications and share a common DNA methylation signature.

Undifferentiated mesenchymal tumors arising from the inner lining (intima) of large arteries are classified as intimal sarcomas (ISA) with MDM2 amplification as their molecular hallmark. Interestingly, undifferentiated pleomorphic sarcomas (UPS) of the heart have recently been suggested to represent the cardiac analog of ISA due to morphological overlap and high prevalence of MDM2 amplifications in both neoplasms. However, little is known about ISAs and cardiac UPS without MDM2 amplifications and molecular data supporting their common classification is sparse. Here, we report a series of 35 cases comprising 25 ISAs of the pulmonary artery, one ISA of the renal artery and 9 UPS of the left atrium. Tumors were analyzed utilizing the Illumina Infinium MethylationEPIC BeadChip array, enabling copy number profile generation and unsupervised DNA methylation analysis. DNA methylation patterns were investigated using t-distributed stochastic neighbor embedding (t-SNE) analysis. Histologically, all ISAs and UPS of the left atrium resembled extra-cardiac UPS. All cases exhibited highly complex karyotypes with overlapping patterns between ISA and UPS. 29/35 cases showed mutually exclusive amplifications in the cell-cycle associated oncogenes MDM2 (25/35), MDM4 (2/35), and CDK6 (2/35). We further observed recurrent co-amplifications in PDGFRA (21/35), CDK4 (15/35), TERT (11/35), HDAC9 (9/35), and CCND1 (4/35). Sporadic co-amplifications occurred in MYC, MYCN, and MET (each 1/35). The tumor suppressor CDKN2A/B was frequently deleted (10/35). Interestingly, DNA methylation profiling (t-SNE) revealed an overlap of ISA and cardiac UPS. This "ISA" methylation signature was distinct from potential histologic and molecular mimics. In conclusion, our data reveal MDM4 and CDK6 amplifications in ISAs and UPS of the left atrium, lacking MDM2 amplification. We further report novel co-amplifications of various oncogenes, which may have therapeutic implications. Finally, the genetic and epigenetic concordance of ISAs and UPS of the left atrium further supports a shared pathogenesis and common classification.

18F-NaF-PET/CT in patients with primary hyperparathyroidism and brown tumors.

INTRODUCTION: Brown tumors (BT) are non-neoplastic bone lesions infrequently occurring in patients with long-standing severe hyperparathyroidism (HPT). BT may be identified and characterized using 18-F-sodium fluoride-positron-emission-tomography/computed tomography (18F-NaF-PET/CT). We present a retrospective series of eight primary hyperparathyroidism (pHPT) patients with BT imaged with 18F-NaF-PET/CT. MATERIALS AND METHODS: Imaging assessment included location, diameter, maximum standardized uptake value (SUVmax), metabolically active lesion volume (PETvol) of BT, total metabolically active bone volume (TMBvol) per patient and several computed tomography (CT) features of BT. Where appropriate, we analyzed the association between characteristic features of BT in 18F-NaF-PET/CT, histopathology, clinical symptomatology and laboratory parameters. RESULTS: In our cohort of 8 patients (median age, 49 years, range, 26-73), 72 BT were found. The mean PETvol of BT was 89.48 cm3 ± 122.81 cm3 and the mean SUVmax was 17.5 ± 7.8. The total PETvol of BT per patient correlated positively with serum calcium (r = 0.810, p = 0.015), and negatively with glomerular filtration rate (GFR) (r = - 0.762, p = 0.028). TMBvol correlated significantly with serum PTH (r = 0.810, p = 0.015), alkaline phosphatase (r = 0.762, p = 0.028), and duration of postoperative hospitalization (r = 0.826, p = 0.011, 24.3 days ± 19.8 days). CONCLUSION: 18F-NaF-PET/CT is a valuable non-invasive whole-body imaging technique for the assessment of patients with pHPT and BT. TMBvol is associated with PTH and alkaline phosphatase, and the requirement for intense postoperative calcium substitution, which determines the duration of hospitalization.

Experimental mummification-In the tracks of the ancient Egyptians.

Understanding natural and artificial postmortem alterations in different tissues of the human body is essential for bioarchaeology, paleogenetics, physical anthropology, forensic medicine, and many related disciplines. With this study, we tried to gain a better understanding of tissue alterations associated with the artificial mummification techniques of ancient Egypt, in particular for mummified visceral organs. We used several entire porcine organs and organ sections (liver, lung, stomach, ileum, and colon), which provided a close approximation to human organs. First, we dehydrated the specimens in artificial natron, before applying natural ointments, according to the ancient literary sources and recent publications. We periodically monitored the temperature, pH value, and weight of the specimens, in addition to radiodensity and volumetric measurements by clinical computed tomography and sampling for histological, bacteriological, and molecular analyses. After seven weeks, mummification was seen completed in all specimens. We observed a considerable loss of weight and volume, as well as similar courses in the decay of tissue architecture but varying levels of DNA degradation. Bacteriologically we did not detect any of the initially identified taxa in the samples by the end of the mummification process, nor any fungi. This feasibility study established an experimental protocol for future experiments modeling ancient Egyptian mummification of visceral organs using human specimens. Understanding desiccation and mummification processes in non-pathological tissues of specific visceral organs may help to identify and interpret disease-specific alterations in mummified tissues in ancient Egyptian canopic jars and organ packages contained in whole mummies.

Management of cytologic material, preanalytic procedures and biobanking in lymph node cytopathology.

The range of pathologies that lymph node (LN) fine needle cytology (FNC) may encounter is extremely wide and ancillary techniques, in addition to traditional smears, are generally required to reach reliable cytologic diagnoses. Storing part of the cytologic material may be useful or necessary for molecular testing. The main difficulties concern the generally small size of the sample and the different methods of acquisition of LN-FNC. Therefore, the preanalytic phase is extremely important for LN-FNC. This article outlines the management of LN-FNC material, vials, technical devices (e.g.: additional smears, cytospin slides, LBC slides, cards, resins, etc.) and main ancillary techniques to assess their optimal application, taking into account the different diagnostic needs and cell storage.

Prognostic value of tumor suppressors in osteosarcoma before and after neoadjuvant chemotherapy.

BACKGROUND: Primary bone cancers are among the deadliest cancer types in adolescents, with osteosarcomas being the most prevalent form. Osteosarcomas are commonly treated with multi-drug neoadjuvant chemotherapy and therapy success as well as patient survival is affected by the presence of tumor suppressors. In order to assess the prognostic value of tumor-suppressive biomarkers, primary osteosarcoma tissues were analyzed prior to and after neoadjuvant chemotherapy. METHODS: We constructed a tissue microarray from high grade osteosarcoma samples, consisting of 48 chemotherapy naïve biopsies (BXs) and 47 tumor resections (RXs) after neoadjuvant chemotherapy. We performed immunohistochemical stainings of P53, P16, maspin, PTEN, BMI1 and Ki67, characterized the subcellular localization and related staining outcome with chemotherapy response and overall survival. Binary logistic regression analysis was used to analyze chemotherapy response and Kaplan-Meier-analysis as well as the Cox proportional hazards model was applied for analysis of patient survival. RESULTS: No significant associations between biomarker expression in BXs and patient survival or chemotherapy response were detected. In univariate analysis, positive immunohistochemistry of P53 (P = 0.008) and P16 (P16; P = 0.033) in RXs was significantly associated with poor survival prognosis. In addition, presence of P16 in RXs was associated with poor survival in multivariate regression analysis (P = 0.003; HR = 0.067) while absence of P16 was associated with good chemotherapy response (P = 0.004; OR = 74.076). Presence of PTEN on tumor RXs was significantly associated with an improved survival prognosis (P = 0.022). CONCLUSIONS: Positive immunohistochemistry (IHC) of P16 and P53 in RXs was indicative for poor overall patient survival whereas positive IHC of PTEN was prognostic for good overall patient survival. In addition, we found that P16 might be a marker of osteosarcoma chemotherapy resistance. Therefore, our study supports the use of tumor RXs to assess the prognostic value of biomarkers.

A rare posterior mediastinal mass: chordoma.

A 72-year-old female presented with 2 years of pro-gradient pain in the upper thoracic spine radiating to the left arm and leg. MRI revealed a 2.7 × 2.0 × 12 cm paravertebral mass at T2/T3, extending into the foraminal and epidural nerves with extensive dural sac contact in the left hemithorax. The removed tumour was surprisingly soft for a schwannoma or chordoma. However, after the surgery, histopathology revealed the presence of brachyury protein (T-box transcription factor T), which is characteristic of a chordoma. While chordomas are extremely rare, it is important that they are kept in mind for the differential diagnosis of a posterior mediastinal mass. Successful treatment can only be achieved through a complete en bloc resection. This can often be complex due to their location along the spine. This case report aims to highlight the features and treatment of this rare disease.

Improving Sarcoma Outcomes: Target Trial Emulation to Compare the Impact of Unplanned and Planned Resections on the Outcome.

This study follows the Target Trial Emulation (TTE) framework to assess the impact of unplanned resections (UEs) and planned resections (PEs) of sarcomas on local recurrence-free survival (LRFS), metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS). Sarcomas, malignant tumors with mesenchymal differentiation, present a significant clinical challenge due to their rarity, complexity, and the frequent occurrence of UEs, which complicates effective management. Our analysis utilized real-world-time data from the Swiss Sarcoma Network, encompassing 429 patients, to compare the impact of UEs and PEs, adjusting for known prognostic factors through a multivariable Cox regression model and propensity score weighting. Our findings reveal a significantly higher risk of local recurrence for UEs and a short-term follow-up period that showed no marked differences in MFS, CSS, and OS between the UE and PE groups, underlining the importance of optimal initial surgical management. Furthermore, tumor grade was validated as a critical prognostic factor, influencing outcomes irrespective of surgical strategy. This study illuminates the need for improved referral systems to specialized sarcoma networks to prevent UEs and advocates for the integration of TTE in sarcoma research to enhance clinical guidelines and decision-making in sarcoma care. Future research should focus on the prospective validations of these findings and the exploration of integrated care models to reduce the incidence of UEs and improve patient outcomes.

Impact of Institutional Practices and Surgical Complexity on Sarcoma Surgery Costs: Driving Efficiency in Value-Based Healthcare.

BACKGROUND: Sarcomas present a unique challenge within healthcare systems due to their rarity and complex treatment requirements. This study explores the economic impact of sarcoma surgeries across three Swiss tertiary healthcare institutions, utilizing a consistent surgical approach by a single surgeon to eliminate variability in surgical expertise as a confounding factor. METHODS: By analyzing data from 356 surgeries recorded in a real-world-time data warehouse, this study assesses surgical and hospital costs relative to institutional characteristics and surgical complexity. RESULTS: Our findings reveal significant cost variations driven more by institutional resource management and pricing strategies than by surgical techniques. Surgical and total hospitalization costs were analyzed in relation to tumor dignity and complexity scores, showing that higher complexity and malignancy significantly increase costs. Interestingly, it was found that surgical costs accounted for only one-third of the total hospitalization costs, highlighting the substantial impact of non-surgical factors on the overall cost of care. CONCLUSIONS: The study underscores the need for standardized cost assessment practices and highlights the potential of predictive models in enhancing resource allocation and surgical planning. By advocating for value-based healthcare models and standardized treatment guidelines, this research contributes to more equitable and sustainable healthcare delivery for sarcoma patients. These insights affirm the necessity of including a full spectrum of care costs in value-based models to truly optimize healthcare delivery. These insights prompt a reevaluation of current policies and encourage further research across diverse geographical settings to refine cost management strategies in sarcoma treatment.

The Next Frontier in Sarcoma Care: Digital Health, AI, and the Quest for Precision Medicine.

The landscape of sarcoma care is on the cusp of a transformative era, spurred by the convergence of digital health and artificial intelligence (AI). This perspectives article explores the multifaceted opportunities and challenges in leveraging these technologies for value-based, precision sarcoma care. We delineate the current state-of-the-art methodologies and technologies in sarcoma care and outline their practical implications for healthcare providers, administrators, and policymakers. The article also addresses the limitations of AI and digital health platforms, emphasizing the need for high-quality data and ethical considerations. We delineate the promise held by the synergy of digital health platforms and AI algorithms in enhancing data-driven decision-making, outcome analytics, and personalized treatment planning. The concept of a sarcoma digital twin serves as an illustrative paradigm for this integration, offering a comprehensive, patient-centric view of the healthcare journey. The paper concludes with proposals for future research aimed at advancing the field, including the need for randomized controlled trials or target trial emulations and studies focusing on ethical and economic aspects. While the road to this transformative care is laden with ethical, regulatory, and practical challenges, we believe that the potential benefits far outweigh the obstacles. We conclude with a call to action for multidisciplinary collaboration and systemic adoption of these technologies, underscoring the urgency to act now for the future betterment of sarcoma care and healthcare at large.

Benchmarking Time-to-Treatment Initiation in Sarcoma Care Using Real-World-Time Data.

Benchmarking is a fundamental tool for enhancing quality within a patient-centered healthcare framework. This study presents an analysis of time-to-treatment initiation (TTI) for sarcoma patients, utilizing a database encompassing 266 cases from the Swiss Sarcoma Network. Our findings indicate a median TTI of 30 days across the cohort, with bone sarcomas and deep soft tissue sarcomas demonstrating a shorter median TTI of 28 days, followed by superficial soft tissue sarcomas at 42 days. The data reveal that the use of real-world-time data (RWTD) may account for a longer TTI observed, as it offers more comprehensive capture of patient journeys, unlike conventional datasets. Notably, variability in TTI was observed between different treatment institutions, which underscores the need for standardized processes across centers. We advocate for a selective referral system to specialized centers to prevent capacity overload and ensure timely treatment initiation. Our analysis also identified significant delays in TTI for unplanned 'whoops'-resections, highlighting the importance of early specialist referral in optimizing treatment timelines. This study emphasizes the potential benefits of a streamlined, data-informed approach to sarcoma care. However, further research is required to establish the direct impact of integrated care models on TTI and patient outcomes in the context of sarcoma treatment.

Enhancing Healthcare for Sarcoma Patients: Lessons from a Diagnostic Pathway Efficiency Analysis.

Sarcomas, rare and with lower survival rates than common tumors, offer insights into healthcare efficiency via the analysis of the total interval of the diagnostic pathway, combining the patient interval (time between the first symptom and visit with a physician) and diagnostic interval (time between first physician visit and histological diagnosis). Switzerland's healthcare system, Europe's costliest, lacks research on treating rare conditions, like mesenchymal tumors. This study examines the total interval of the diagnostic pathway for optimization strategies. Analyzing a dataset of 1028 patients presented from 2018 to 2021 to the Swiss Sarcoma Board (MDT/SB-SSN), this retrospective analysis delves into bone sarcoma (BS), soft-tissue sarcoma (STS), and their benign counterparts. Demographic and treatment data were extracted from medical records. The patient interval accounted for the largest proportion of the total interval and secondary care interval for the largest proportion of the diagnostic interval. Age, grade, and localization could be elicited as influencing factors of the length of different components of the total interval. An increasing age and tumor size, as well as the axial localization, could be elicited as factors increasing the probability of sarcoma. The patient and secondary care interval (SCI) offer the greatest potential for optimization, with SCI being the bottleneck of the diagnostic interval. New organizational structures for care work-ups are needed, such as integrated practice units (IPU) as integral part of value-based healthcare (VBHC).

Unlocking the Power of Benchmarking: Real-World-Time Data Analysis for Enhanced Sarcoma Patient Outcomes.

Benchmarking is crucial for healthcare providers to enhance quality and efficiency, notably for complex conditions like sarcomas. Multidisciplinary teams/sarcoma boards (MDT/SBs) are vital in sarcoma management, but differences in their processes can affect patient outcomes and treatment costs, despite adherence to international guidelines. To address this issue, this study aimed to compare two MDT/SBs and establish an interoperable digital platform, Sarconnector®, for real-time-world data assessment and automated analysis. The study included 983 patients, 46.0% of whom female, with a median age of 58 years, and 4.5% of patients presented with metastasis at diagnosis. Differences were observed in the number of first-time presentations, follow-up presentations, primary sarcomas, biopsies and chemotherapy indications between the two MDT/SB. The results highlight the importance of benchmarking and utilizing a harmonized data approach, such as the RWT approach provided by the Sarconnector®, to standardize and evaluate quality and cost metrics. By identifying areas of improvement and making data-driven decisions on the meta-level, healthcare providers can optimize resources and improve patient outcomes. In conclusion, benchmarking with the RWT harmonized data approach provided by the Sarconnector® can help healthcare providers improve the overall effectiveness of the healthcare system and achieve better outcomes for their patients in terms of both outcomes and costs.

Digital Examination of LYmph node CYtopathology Using the Sydney system (DELYCYUS): An international, multi-institutional study.

BACKGROUND: After a series of standardized reporting systems in cytopathology, the Sydney system was recently introduced to address the need for reproducibility and standardization in lymph node cytopathology. Since then, the risk of malignancy for the categories of the Sydney system has been explored by several studies, but no studies have yet examined the interobserver reproducibility of the Sydney system. METHODS: The authors assessed interobserver reproducibility of the Sydney system on 85 lymph node fine-needle aspiration cytology cases reviewed by 15 cytopathologists from 12 institutions in eight different countries, resulting in 1275 diagnoses. In total, 186 slides stained with Diff-Quik, Papanicolaou, and immunocytochemistry were scanned. A subset of the cases included clinical data and results from ultrasound examinations, flow cytometry immunophenotyping, and fluorescence in situ hybridization analysis. The study participants assessed the cases digitally using whole-slide images. RESULTS: Overall, the authors observed an almost perfect agreement of cytopathologists with the ground truth (median weighted Cohen κ = 0.887; interquartile range, κ = 0.210) and moderate overall interobserver concordance (Fleiss κ = 0.476). There was substantial agreement for the inadequate and malignant categories (κ = 0.794 and κ = 0.729, respectively), moderate agreement for the benign category (κ = 0.490), and very slight agreement for the suspicious (κ = 0.104) and atypical (κ = 0.075) categories. CONCLUSIONS: The Sydney system for reporting lymph node cytopathology shows adequate interobserver concordance. Digital microscopy is an adequate means to assess lymph node cytopathology specimens.

Time and Accuracy to Establish the Diagnosis of Soft Tissue Tumors: A Comparative Analysis from the Swiss Sarcoma Network.

Soft tissue tumors are rare tumors, and their histological examination remains a challenge. The establishment of the correct initial histopathologic diagnosis is critical. However, due to the rarity of soft tissue and bone tumors and the inherent difficulty of their classification and diagnostics, discrepancies may occur in up to one third of cases. For these reasons, several studies recommend the involvement of experienced pathologists frequently performing sarcoma diagnostics. Until now, there is only scarce information about how long it takes to establish a correct sarcoma diagnosis. We thus analyzed all consecutive patients presented to the Swiss Sarcoma Network Tumor Board (SSN-MDT/SB) with a primary diagnosis of a soft tissue tumor over a 2-year period (01/2019 to 12/2020) based on a tumor biopsy. We then compared the final histopathological diagnosis of two comparable institutions with similar case load, but different workflows: (i) institution A, with an initial diagnosis performed by a local pathologist, and reviewed by a reference pathologist, and (ii) institution B, with the final diagnosis performed directly by a reference pathologist. In addition, we analyzed the time from biopsy to establishment of the diagnosis. A total of 347 cases were analyzed, 196 from institution A, and 149 from institution B. In 77.6% of the cases, the diagnosis from the local pathologist was concordant with the expert review. Minor discrepancies were found in 10.2% of the cases without any consecutive changes in treatment strategy. In the remaining 12.2% of the cases, there were major discrepancies which influenced the treatment strategy directly. Establishing the final report took significantly longer in institution A (4.7 working days) than in institution B (3.3 working days; p < 0.01). Our results confirm the importance of a pathological second review by a reference pathologist. We recommend direct analysis by experts, as diagnoses can be made more accurately and quickly. Within the SSN, establishing the sarcoma diagnosis is overall accurate and quick but still can be improved.

Novel RGAG1-BCOR gene fusion revealed in a somatic soft tissue sarcoma with a long follow-up.

BCOR-rearranged sarcomas are rare and belong to the Ewing-like sarcomas (ELS). Their morphology and histopathological features make the diagnosis challenging. We present a case, initially diagnosed as an unusual extraskeletal myxoid chondrosarcoma (EMC). A 54-year-old male patient developed an asymptomatic swelling of the lower leg. Imaging showed a 9.5-cm large intramuscular soft tissue mass. Due to its morphological and immunohistochemical profile on biopsy, it was initially diagnosed as an EMC. The patient was treated by complete resection and adjuvant radiotherapy and remained free of tumor at 7 years follow-up. Using next-generation sequencing (NGS), we retrospectively identified RGAG1-BCOR gene fusion (confirmed by RT-PCR), which has not been described in somatic soft tissue tumors so far. This finding broadens the spectrum of partner genes in the BCOR-rearranged sarcomas in a tumor with a well-documented, long clinical follow-up.

Podoplanin-positive cells are a hallmark of encapsulating peritoneal sclerosis.

BACKGROUND: Encapsulating peritoneal sclerosis (EPS) and simple peritoneal sclerosis are important complications of long-term peritoneal dialysis (PD). Podoplanin is expressed by mesothelial cells and lymphatic vessels, which are involved in inflammatory reactions in the peritoneal cavity. METHODS: We studied 69 peritoneal biopsies from patients on PD (n = 16), patients with EPS (n = 18) and control biopsies taken at the time of hernia repair (n = 15) or appendectomy (n = 20). Immunohistochemistry was performed to localize podoplanin. Additionally, markers of endothelial cells, mesothelial cells, myofibroblasts (smooth muscle actin), proliferating cells, and double labelling for smooth muscle actin/podoplanin were used on selected biopsies. RESULTS: Podoplanin was present on the endothelium of lymphatic vessels in the submesothelial fibrous tissue and on mesothelial cells. In patients on PD and in biopsies with appendicitis, the mesothelial cells demonstrated a cuboidal appearance and circumferential podoplanin staining, with gaps between the cells. The number of lymphatic vessels was variable, but prominent at sites of fibrosis. In patients with EPS, a diffuse infiltration of podoplanin-positive cells with a fibroblastic appearance was present in 15 out of 18 biopsies. This pattern was focally present in 3 out of 16 on PD and none in the 35 controls. The podoplanin-positive cells did not express the endothelial marker or the mesothelial marker (calretinin). CONCLUSIONS: EPS is characterized by a population of podoplanin and smooth muscle actin double-positive cells. Podoplanin might be a suitable morphological marker supporting the diagnosis and might be involved in the pathogenesis of EPS.