Search Results (499)

Sarcoma awareness among healthcare practitioners in our institution was limited, prompting an evaluation of their ability to recognize early presentations and initiate appropriate work-up for soft tissue and bone sarcomas. A structured survey assessed familiarity with key clinical features, recommended investigations, and perceived contributors to diagnostic delay. Overall awareness was modest, but higher among healthcare practitioners with prior sarcoma exposure, oncology-focused training, longer experience, or heavier patient loads; female practitioners and oncology nurses also scored higher. Confidence in identifying red-flag symptoms was strongly linked to familiarity with guideline-based practice. Despite these strengths, notable gaps persisted across specialties and training levels, indicating that exposure alone is insufficient. Targeted education, improved recognition of early warning signs, and clearer referral pathways are needed to reduce diagnostic delays and support timely management of suspected sarcomas. Full article

Background and Clinical Significance: Malignant transformation of giant cell tumor of bone (GCTB) is a rare but clinically significant event, most commonly associated with radiotherapy, denosumab therapy, or recurrent disease. Secondary malignant transformation occurring in the absence of recognized risk factors is exceptionally uncommon. We report a rare case of high-grade sarcomatous transformation of proximal humeral GCTB after a prolonged latency period without prior radiotherapy, denosumab exposure, or documented recurrence; Case Presentation: A 27-year-old female initially presented with right shoulder pain and was diagnosed with proximal humeral GCTB. She underwent intralesional curettage and bone grafting, with histopathological confirmation of benign GCTB. Nine years later, she developed progressive shoulder pain, functional limitation, and systemic symptoms. Imaging demonstrated an aggressive lytic lesion with cortical destruction and soft-tissue extension involving the proximal humerus. Repeat curettage and histopathological evaluation revealed high-grade spindle cell sarcoma consistent with malignant transformation of GCTB. The patient received neoadjuvant chemotherapy followed by wide resection and endoprosthetic reconstruction of the proximal humerus, with additional adjuvant chemotherapy postoperatively. At two-year follow-up, she remained disease-free with excellent functional recovery and satisfactory quality of life; Conclusions: This case highlights the potential for delayed malignant transformation of GCTB even in the absence of established predisposing factors. Clinicians should maintain long-term vigilance in patients treated for GCTB, particularly when new pain, functional decline, or aggressive radiologic features develop years after initial treatment. Early recognition and multidisciplinary management are essential to optimize oncologic and functional outcomes. Full article

Objectives: Thoracic sarcomas are a heterogeneous group of rare mesenchymal tumors. This study aimed to identify prognostic factors for overall survival (OS) and progression-free survival (PFS) in patients undergoing resection of primary thoracic soft tissue and bone sarcomas. Methods: We retrospectively reviewed patients with primary intrathoracic or chest wall sarcomas who underwent surgical resection between 2005 and 2020. Eighty-four patients were included: 60 with soft tissue sarcoma and 24 with bone sarcoma. Univariate and multivariate Cox regression analyses were performed to identify prognostic factors for PFS and OS. Results: The most common histological subtypes were chondrosarcoma (19%) and undifferentiated pleomorphic sarcoma (17.8%). Overall, 54.8% of patients were female, and the mean age was 55.7 years (SD 17.9). Neoadjuvant and adjuvant therapies were primarily administered in intermediate- (G2) and high-grade (G3) tumors. Median OS was 28.4 months. On multivariate analysis, high tumor grade (G3 vs. G1–2) independently predicted worse PFS (HR 3.21, 95% CI 1.34–7.68; p = 0.01) and OS (HR 4.40, 95% CI 1.56–12.41; p = 0.01). Larger tumor size (HR 1.09, 95% CI 1.03–1.15; p = 0.001) and incomplete resection (HR 12.21, 95% CI 2.56–58.34; p = 0.002) were independently associated with worse OS, while lung metastases at diagnosis independently predicted worse PFS (HR 4.89, 95% CI 1.21–19.69; p = 0.03). Conclusions: Histological grade is the strongest independent predictor of survival in resected thoracic sarcoma. Surgery alone appears adequate for low-grade sarcomas, whereas multimodal treatment strategies seem particularly relevant for patients with higher-grade sarcomas. Full article

Background: Primary malignant bone tumors of the pelvis account for 10–15% of all primary bone sarcomas, most commonly chondrosarcoma, osteosarcoma, and Ewing’s sarcoma. Although advances have shifted treatment toward internal hemipelvectomy, pelvic resections remain challenging due to the complex anatomy. The need for pelvic reconstruction is controversial, balancing potential stability against higher complication rates. This review evaluates the role of pelvic ring reconstruction, focusing on techniques, outcomes, and complications. Methods: A systematic literature review was performed in June 2025 using PubMed, MEDLINE and Cochrane Library as the primary databases, with the following search string: (hemipelvectomy) AND (orthopedic), acknowledging that this search strategy may be limited in scope. Studies published within the last five years were considered. After performing a full-text assessment of 80 studies, 14 studies were included in this review. Data regarding patients, methods, and outcomes were extracted and summarized. Results: Among the 14 included studies, seven investigated patient-specific three-dimensional (3D) printed pelvic reconstructions, four reported biological reconstruction techniques, two studies focused on non-reconstructive management and one study evaluated alternative stabilization using segmental spinal instrumentation. 3D printed and other reconstructive techniques were associated with improvements in the Musculoskeletal Tumor Society score, reduced pain, and demonstrated osseointegration with few mechanical failures. Although individual case series demonstrated good ambulation and stable fixation, complication rates, particularly wound and infection-related events, remained frequent. Type III reconstructions and personalized implants showed the highest functional gains but occasionally revealed asymptomatic fretting wear. In contrast, the only Level I evidence indicated significantly higher complication and infection rates in reconstructed patients and better functional outcomes in those managed without reconstruction when spinopelvic stability was preserved. Non-reconstructive strategies, including spinal instrumentation, supported early ambulation with low mechanical failure, while pediatric patients treated without reconstruction experienced a high complication rate but acceptable long-term oncologic outcomes. Conclusions: Current evidence suggests that routine pelvic ring reconstruction after internal hemipelvectomy may not be justified based on the currently available evidence. Patient-specific 3D-printed implants appear to provide consistent improvements in function, pain reduction, and mechanical stability, but are associated with a relevant risk of wound-related and infectious complications. In patients with preserved spinopelvic stability, non-reconstructive strategies may achieve comparable functional outcomes with lower morbidity. Therefore, pelvic reconstruction should be performed selectively, and further prospective multicenter studies are needed to better define appropriate patient selection and optimize reconstructive strategies. Full article

Background/Objectives: Bone and soft tissue sarcomas frequently affect children, adolescents, and young adults, yet data on chemotherapy-related ovarian reserve decline in this population remain limited. We aimed to characterize anti-Müllerian hormone (AMH) dynamics during treatment and identify factors associated with post-neoadjuvant chemotherapy (post-NACT) ovarian reserve. Methods: We conducted a retrospective, single-center, longitudinal cohort study of 85 female patients with bone and soft tissue sarcoma who underwent serial serum AMH testing during treatment. In the paired cohort with complete baseline and post-NACT AMH measurements (n = 75), post-NACT AMH was defined as the value obtained at the surgery/post-neoadjuvant time point after completion of NACT. Log-transformed multivariable linear modeling and left-censored Tobit regression sensitivity analysis were performed. Results: Median AMH declined from 3.46 ng/mL at baseline to 0.39 ng/mL after the first NACT cycle and to 0.15 ng/mL after the second cycle, corresponding to reductions of 88.7% and 95.7%, respectively. In the paired cohort, median AMH declined from 3.81 ng/mL to 0.19 ng/mL post NACT, with a median absolute decline of 2.75 ng/mL and a median percent decline of 94.4%. In the log-transformed multivariable linear model, log(baseline AMH) was the sole independent predictor of log(post-NACT AMH) (β = 0.735, 95% CI 0.357–1.114, p < 0.001). In Tobit sensitivity analysis, 4 post-NACT AMH values were treated as left-censored at 0.05 ng/mL, and the pattern remained consistent. Conclusions: Ovarian reserve depletion in female sarcoma patients occurred predominantly within the first one to two cycles of NACT. These findings support early, individualized fertility preservation counseling in this population. Full article

Rhabdomyosarcoma (RMS) confined to the bone marrow represents an exceptionally rare and aggressive presentation that can mimic primary hematological malignancies, often leading to diagnostic delays and therapeutic challenges. We report the case of a 34-year-old woman who presented with clinical and laboratory findings highly suggestive of a hematological disorder, including cytopenias and diffuse bone marrow involvement. Initial evaluation raised suspicion for leukemia; however, comprehensive diagnostic work-up, including immunohistochemistry and molecular studies, ultimately confirmed the diagnosis of PAX3/FOXO1 gene-rearranged alveolar RMS isolated in the bone marrow, with no identifiable primary soft tissue mass. The patient was treated with an intensive multi-agent chemotherapy regimen, resulting in a marked hematological recovery and a significant radiological improvement after a limited number of cycles. We further reviewed the limited literature on bone-marrow-confined RMS, highlighting the proposed pathophysiological mechanisms, diagnostic pitfalls, and reported treatment strategies. Given the absence of standardized management guidelines for this rare entity, therapeutic approaches are often extrapolated from conventional RMS protocols or regimens used for high-grade sarcomas. Our experience supports the potential efficacy of intensive chemotherapy in achieving meaningful clinical responses. This case report emphasizes the challenges in the diagnosis of RMS confined to the bone marrow due to its atypical presentation. It also highlights the poor prognosis and aggressiveness of this entity compared to conventional RMS. Full article

Fibrous dysplasia is one of the most common skeletal lesions. The wide spectrum of clinical manifestations ranges from asymptomatic conditions (typical of monostotic forms) to severe skeletal diseases with deformity and fractures for polyostotic fibrous dysplasia. The classical radiological features include: an osteolytic geographic pattern, ground-glass bone matrix, cortical thinning/cortical scalloping, bone deformities and enlargement, concavity of margins (evaluated with MRI), and cystic areas (MRI). All the bones can be affected, and the proximal femur is the most common one (about 30% of cases). Nonetheless, the disease can also affect cranio-facial bones, leading to compression of neural structures, as well as deformation and enlargement of facial bones, leading to the so-called “leontiasis ossea” or “facies leonine”. The polyostotic forms of fibrous dysplasia can be associated with multiple soft-tissue myomas (Mazabraud syndrome) or several endocrine diseases (McCune–Albright syndrome). In every diagnostic step of the disease, as well as in different fibrous dysplasia forms, imaging plays a key role. Indeed, radiology is fundamental to assess the suspicion of fibrous dysplasia in classical monostotic forms, representing the sole diagnostic tool needed in many cases. Imaging is also fundamental to staging and following up on more severe polyostotic forms, as well as for detecting complications. In this comprehensive updated review article, we examine every aspect of the disease, with a main focus on imaging presentation. The indications for biopsy are discussed as well. Most importantly, the article details the potential risk of malignant transformation (osteosarcoma, fibrosarcoma, chondrosarcoma, and other rarer sarcomas, all accounting for <1% of cases) underlying the radiological patterns of these conditions. The occurrence of aneurysmal bone cyst-like changes on fibrous dysplasia is also analyzed in the article. This review article aims to be a comprehensive guide for radiologists and clinicians involved in the care of patients affected by various forms of fibrous dysplasia, and a starting point for future research. Many classical and atypical cases are collected as an iconographic comprehensive representation. Full article

Background and Objectives: Sarcomas are rare malignancies of mesenchymal origin comprising less than 1% of all adult solid tumors, exhibiting marked histological heterogeneity and variable clinical behavior. Data from Eastern European tertiary oncology centers remain scarce. This study characterized the clinicopathological features, treatment modalities, and survival outcomes of patients with sarcomas of the extremities and trunk treated at the “Prof. Dr. Alexandru Trestioreanu” Institute of Oncology from Bucharest over a ten-year period. Materials and Methods: We conducted a retrospective analysis of 164 patients diagnosed with sarcomas of the extremities and trunk between 2010 and 2020 at “Prof. Dr. Alexandru Trestioreanu” Institute of Oncology. Variables included age, sex, tumor localization, histological subtype, immunohistochemical profile, treatment modalities, recurrence, metastatic spread, and overall survival (OS). Kaplan–Meier curves estimated survival; log-rank tests were applied for subgroup comparisons. Results: The cohort comprised 82 males and 82 females (50.0% each), with a mean age of 48.8 ± 18.3 years. The lower limb was the most frequent site (n = 96, 58.5%), particularly the thigh/femur (34.1%). The most common subtypes were undifferentiated pleomorphic sarcoma (14.6%), osteosarcoma (12.2%), and fibrosarcoma (11.0%). Surgery was performed in 75.6%, chemotherapy in 80.5%, and radiotherapy in 59.8%. Local recurrence occurred in 35.4% and distant metastases in 41.5%. The median OS was 96.0 months (vital status known for 160/164 patients; 90 deceased, 70 alive; OS duration available in 126 patients). Metastatic disease was associated with shorter observed survival in descriptive Kaplan–Meier analysis (log-rank p < 0.001); this comparison is exploratory given the time-dependent nature of the variable. Survival ranged from 11.5 months (leiomyosarcoma) to 162.5 months (dermatofibrosarcoma protuberans) by histotype. Conclusions: This study provides clinically relevant epidemiological and survival data from Romania. The findings illustrate real-world heterogeneity of sarcoma presentations and outcomes at an Eastern European tertiary center and highlight the need for improved diagnostic standardization, prospective data collection, and integration within specialized sarcoma networks. Full article

Ewing sarcoma (ES) is a bone malignancy primarily, well known by its t(11;22)(q24;q12) chromosomal translocation. Despite high initial treatment success, ES frequently recurs, likely due to micrometastatic disease present at diagnosis but undetected during primary treatment. This study aims to characterize transcriptomic differences between primary and metastatic ES to identify genes and pathways associated with the metastatic phenotype. Using the Search Tag Analyze Resource for National Center for Biotechnology Information’s Gene Expression Omnibus, seven independent gene expression series were identified, yielding 37 metastatic and 82 primary ES tumor samples. Differentially expressed genes were defined using a significance threshold of p < 0.05 and absolute experimental log ratio > 0.1 and were analyzed using Ingenuity Pathway Analysis. This integrative transcriptomic analysis identified 753 significant molecules. Metastatic ES was characterized by upregulation of lung-associated surfactant proteins and secretoglobin family members, along with downregulation of genes involved in extracellular matrix organization. Additional genes of interest included SLC6A14, CXCL14, and TBX3, which have been implicated in tumor progression in other malignancies. These findings provide a computationally derived molecular profile associated with metastatic ES and highlight candidate genes and pathways that warrant further validation. This integrative approach offers a framework for future studies focused on understanding metastatic biology in rare pediatric cancers. Full article

Background: Megaprosthetic reconstruction is the standard of care for limb salvage after tumor resection around the knee, but the full burden of unplanned revision surgery is rarely reported as a structured composite outcome. We evaluated 241 consecutive patients over 21 years at a tertiary orthopedic oncology center. Methods: This retrospective cohort included 241 patients (160 distal femur, 78 proximal tibia, three combined) treated between 2003 and 2024. Revision-free survival (RFS, composite of any unplanned revision or amputation) and amputation-free survival were estimated by Kaplan–Meier analysis; independent predictors were identified by Cox regression. A pre-specified major-event composite (amputation, implant removal, or recurrence resection) was used for sensitivity analysis. Results: Mean age was 34.9 ± 19.5 years; mean follow-up was 120.2 months. Negative resection margin (R0) was achieved in 85.5% (206/241). Unplanned revision was required in 25 patients (10.4%); overall limb salvage was 92.9%. Five-year RFS was 73.8% (distal femur) vs. 65.0% (proximal tibia; p = 0.084), and 5-year limb salvage was 88.9% vs. 84.3% (p = 0.081). Surgical margin was strongly associated with outcome: 5-year RFS 75.4% (R0) vs. 48.7% (R1/R2; p < 0.001); 5-year limb salvage 90.6% vs. 71.5% (p = 0.003). On exploratory multivariate Cox analysis, proximal tibia site and positive margin were associated with worse revision-free survival; within the proximal tibia subgroup, absence of gastrocnemius flap coverage was also associated with worse outcome (interpreted with caution given the small flap subgroup, n = 11, and limited event count). Conclusions: In this single-center series, megaprosthetic reconstruction around the knee achieved acceptable revision-free survival and limb salvage. Surgical margin status was the strongest independent predictor of both endpoints, reinforcing the well-established importance of oncologic margin quality and site-specific soft tissue strategies. Full article

Background/Objectives: Primary spinal sarcomas, encompassing both bone and soft tissue histotypes, demand individualized reconstruction due to heterogeneous tumor biology, anatomic complexity, and host environments compromised by radiation, systemic therapy, or prior surgery. This narrative review reframes post-resection spinal reconstruction through a precision-medicine lens. Methods: A structured literature review was performed using PubMed and Scopus, targeting articles published between 2000 and 2026. Searches encompassed spinal sarcoma reconstruction, radiation and fusion, biologic reconstruction, and emerging technologies. Results: Tumor grade, radiation exposure, and systemic therapy timing emerge as multiplicative determinants of reconstructive environment quality, with drug-class-specific perioperative effects warranting stratified management. Vascularized bone grafts achieve reliable fusion in compromised hosts where avascular constructs fail. A precision-oriented reconstructive ladder is proposed as a conceptual, hypothesis-generating framework to guide strategy selection. Hybrid PSI-VBG constructs may further expand reconstructive possibilities. The evidence base remains largely composed of small, retrospective series. Conclusions: Individualized strategies anchored in tumor biology and host environment are the cornerstone of durable spinal sarcoma reconstructions. The proposed framework requires prospective, multi-institutional validation. Standardized outcome definitions, prospective registries, and histotype-stratified analyses are needed to advance the field. Full article

Background/Objectives: Large language models (LLMs) are increasingly applied to medical image interpretation; however, their diagnostic accuracy and reliability in musculoskeletal radiology remain uncertain. This study evaluates the diagnostic performance and confidence calibration of LLMs in detecting and classifying bone tumors on radiographs. Methods: This retrospective observational study analyzed a dataset of 257 radiographs with confirmed diagnoses obtained from Radiopaedia, including normal studies and a spectrum of benign and malignant bone tumors. Cases were selected to ensure representation across multiple tumor types. Three LLMs (ChatGPT 5.3, X-ray Interpreter GPT-4.1, and X-ray Interpreter Gemini) evaluated each image using a standardized prompt assessing abnormality detection, tumor detection, classification, and confidence. Outcomes included diagnostic accuracy, false positive abnormality rates, false negative rates, tumor hallucination rates, and confidence calibration. Results: Abnormality detection was high across models, with Gemini demonstrating the highest sensitivity (up to 100%). Tumor detection was strongest in lesions with characteristic features, including osteosarcoma and osteochondroma. False negative rates varied substantially, with GPT-4.1 demonstrating the highest rate (29.9%), followed by ChatGPT (24.8%) and Gemini (6.6%). Primary diagnostic accuracy was highest for osteosarcoma in GPT-4.1 (80%), while ChatGPT 5.3 performed best in benign lesions, including osteochondroma (84.6%) and non-ossifying fibroma (76.9%). Tumor subtype classification remained limited across all models and was poorest for Ewing sarcoma (0% in ChatGPT and GPT-4.1; 10.3% in Gemini). False positive abnormality rates were highest in GPT-4.1 (40.7%), followed by Gemini (25.9%) and ChatGPT (13.5%). Tumor hallucination occurred only in Gemini (12.3%). All models demonstrated confidence miscalibration, with higher confidence observed in incorrect predictions and in tumor-negative cases. Conclusions: LLMs demonstrate strong performance in detecting radiographic abnormalities but remain limited in tumor subtype classification, particularly for diagnostically challenging lesions such as Ewing sarcoma. Elevated false positive and false negative rates, along with systematic overconfidence—especially in GPT-4.1—highlight important limitations for clinical use. These findings support the role of LLMs as adjunctive tools rather than independent diagnostic systems. Full article

Objective: To characterize the frequency, timing, patterns of first distant metastasis, and post-metastatic survival in uterine sarcoma using population-based registry data. Methods: This study included all patients diagnosed with uterine sarcoma between 2000 and October 2025 in the regional cancer registry of Saxony-Anhalt, Germany. Patients with carcinosarcoma were excluded. Metastatic disease was classified as primary (present at diagnosis or ≤3 months) or metachronous (>3 months). Metastatic patterns were analyzed based on the first metastatic presentation only. Overall survival (OS), recurrence-free survival (RFS), and post-metastatic OS were estimated using Kaplan–Meier methods. RFS was defined as the interval from confirmed tumor-free status after primary therapy to first recurrence or death, and was restricted to patients who achieved tumor-free status (n = 114). Multivariable Cox regression analyses for OS and RFS were performed with administrative censoring at 5 years. Results: A total of 155 patients with uterine sarcoma were included. During follow-up, 54 patients (34.8%) were diagnosed with metastatic disease, of whom 30 (55.6%) presented with primary metastatic disease. Lung was the most frequent site of first metastasis, followed by bone, peritoneum, and liver; 43.4% of metastatic patients had multiple synchronous metastatic sites at first presentation. Median time to first metastasis was short, with several metastatic sites showing median values of zero months, reflecting the high proportion of primary metastatic disease. Median post-metastatic OS was 12 months. Advanced FIGO (Fédération Internationale de Gynécologie et d’Obstétrique) stage and failure to achieve tumor-free status after primary therapy were independently associated with worse OS, whereas histologic subtype was not. Conclusions: In this population-based cohort, metastatic disease occurred in more than one-third of patients with uterine sarcoma and was frequently present at diagnosis. Lung metastases predominated as the first site of distant spread, and post-metastatic survival was poor. These findings underscore the importance of comprehensive staging at diagnosis and highlight the aggressive metastatic behavior of uterine sarcoma in real-world practice. Full article

Introduction: Soft tissue sarcomas (STS) exhibit profound molecular heterogeneity. While recurrent gene fusions hold significant diagnostic and therapeutic value—guiding treatment selection and identifying novel molecular targets—our understanding of their broader clinical implications remains limited. Materials and Methods: We performed next-generation sequencing (NGS; FusionPlex Sarcoma v2, Archer™) and bioinformatic analysis (STAR v.2.7, Arriba) on formalin-fixed paraffin-embedded (FFPE) core needle biopsy specimens. The cohort consisted of patients enrolled in a phase II clinical trial (NCT03651375) who received preoperative chemoradiotherapy according to the UNRESARC protocol. Results: The analysed cohort comprised nine adult patients (median age 66 years; range 44–73) diagnosed with undifferentiated pleomorphic sarcoma (UPS; n = 3), malignant peripheral nerve sheath tumour (MPNST; n = 3), myxofibrosarcoma (MFS; n = 2), and leiomyosarcoma (LMS; n = 1), predominantly high-grade (G3; 5/9) and extremity-localised (6/9). Gene fusions were detected in one-third of patients (3/9), exclusively in G3 tumours. Specifically, we identified an SGSH-PRKCA fusion in MFS (thigh), a LINC01133-OGA fusion in MPNST (thorax), and a concurrent JAZF1-MYH7B (chr7:27995037 intronic-chr20:33563203 exon/splice-site, out-of-frame but preserving myosin domains) with a PRKCA-associated intergenic rearrangement (chr1, retaining C1/kinase domains) in UPS (upper back). Notably, the SGSH-PRKCA and JAZF1-MYH7B pairs have not been previously described in the literature for these STS subtypes. Fusion-positive (F1) cases showed stable radiological disease (RECIST 1.1 SD) and EORTC C/D pathological responses with 5–20% residual viable tumour, whereas fusion-negative (F0) cases showed a wider range of radiological and pathological outcomes, including partial response, progression, and stable disease. Conclusions: Our analysis suggests that broad genomic profiling may provide complementary molecular information in diagnostically challenging cases managed at specialised sarcoma centres, particularly when morphology and immunohistochemistry are insufficient. In the present series, however, the detected rearrangements did not alter systemic treatment, and the data do not support claims of prognostic, predictive, or therapeutic actionability. Full article

Background/Objectives: Head and neck sarcomas account for 11% of all soft tissue and 9% of all bone sarcomas in the UK. Diagnostic delays are common, with non-specific symptoms and histological misdiagnosis reported in up to 42% of cases. This study aims to evaluate the association between presenting symptoms, symptom duration, and tumour size to inform a tailored HNS diagnostic strategy for early referral to a tertiary centre. Methods: We analysed a retrospective cohort of 425 adult and paediatric patients referred to the London Sarcoma Service between 2002 and 2025. Results: Our cohort analysis identified a median tumour size of 44.00 mm and symptom duration of 3 months. Although symptom duration did not predict tumour size (β = 0.63, p = 0.76), non-specific symptoms (swelling, pain, nasal/oral changes) were significantly associated with larger tumours (OR 1.96–3.66), alongside systemic symptoms (β = 22.90 mm, p = 0.044). Each 1 mm increase in tumour size was also associated with a 2.60% increased chance of a higher-grade sarcoma (OR = 1.03 per mm, p < 0.001). Conclusions: To our knowledge, this is the largest cohort study to characterise diagnostic patterns in HNS. Our findings reveal three critical insights: 1. Current size-based referral thresholds are inadequate. 2. Non-specific symptoms, such as nasal or oral symptoms, are frequently overlooked. 3. The anatomical complexity of the HN region demands early tailored diagnostic strategies. We propose a hypothesis-generating ‘1–2–1’ framework to support earlier clinical suspicion, which requires prospective validation. Full article