Symptomatic Neuroma Development following En Bloc Resection of Skeletal and Soft-Tissue Tumors: A Retrospective Analysis of 331 Cases.

BACKGROUND: Although symptomatic neuroma formation has been described in other patient populations, these data have not been studied in patients undergoing resection of musculoskeletal tumors. This study aimed to characterize the incidence and risk factors of symptomatic neuroma formation following en bloc resection in this population. METHODS: The authors retrospectively reviewed adults undergoing en bloc resections for musculoskeletal tumors at a high-volume sarcoma center from 2014 to 2019. The authors included en bloc resections for an oncologic indication and excluded non-en bloc resections, primary amputations, and patients with insufficient follow-up. Data are provided as descriptive statistics, and multivariable regression modeling was performed. RESULTS: The authors included 231 patients undergoing 331 en bloc resections (female, 46%; mean age, 52 years). Nerve transection was documented in 87 resections (26%). There were 81 symptomatic neuromas (25%) meeting criteria of Tinel sign or pain on examination and neuropathy in the distribution of suspected nerve injury. Factors associated with symptomatic neuroma formation included age 18 to 39 [adjusted OR (aOR), 3.6; 95% CI, 1.5 to 8.4; P < 0.01] and 40 to 64 (aOR, 2.2; 95% CI, 1.1 to 4.6; P = 0.04), multiple resections (aOR, 3.2; 95% CI, 1.7 to 5.9; P < 0.001), preoperative neuromodulator requirement (aOR, 2.7; 95% CI, 1.2 to 6.0; P = 0.01), and resection of fascia or muscle (aOR, 0.5; 95% CI, 0.3 to 1.0; P = 0.045). CONCLUSION: The authors' results highlight the importance of adequate preoperative optimization of pain control and intraoperative prophylaxis for neuroma prevention following en bloc resection of tumors, particularly for younger patients with a recurrent tumor burden. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Effects of selective cyclooxygenase-2 inhibitor robenacoxib on primary cells derived from feline injection-site sarcoma.

Feline injection-site sarcomas (FISSs) are highly invasive malignant mesenchymal neoplasms that arise from injection sites in cats. Although the tumorigenesis of FISSs is still uncertain, there is a consensus that FISS is associated with chronic inflammation caused by irritation of injection-related trauma and foreign chemical substances. Chronic inflammation can provide a proper microenvironment for tumour development, which has been known as one of the risk factors of tumorigenesis in many tumours. To investigate the tumorigenesis of FISS and screen for its potential therapeutic targets, cyclooxygenase-2 (COX-2), an inflammation-enhancing enzyme, was selected as a target for this study. In vitro experiments using FISS- and normal tissue-derived primary cells and robenacoxib, a highly selective COX-2 inhibitor, were performed. The results demonstrated that expression of COX-2 could be detected in formalin-fixed and paraffin-embedded FISS tissues and FISS-derived primary cells. Cell viability, migration and colony formation of FISS-derived primary cells were inhibited, and cell apoptosis was enhanced by robenacoxib in a dose-dependent manner. However, susceptibility to robenacoxib varied in different lines of FISS primary cells and was not completely correlated with COX-2 expression. Our results suggest that COX-2 inhibitors could be potential adjuvant therapeutics against FISSs.

Radiation-induced sarcomas following childhood cancer - A Canadian Sarcoma Research and Clinical Collaboration Study (CanSaRCC).

BACKGROUND: Radiation-induced sarcoma (RIS) is a late toxicity of radiation therapy (RT) usually associated with poor prognosis. Due to ongoing improvements in childhood cancer treatment and patient outcomes, RIS may become more prevalent notwithstanding evolving indications for RT. Due to limited reported studies, we sought to review our experience with RIS in survivors of pediatric cancer. METHODOLOGY: Data were collected on RIS patients following treatment for childhood cancer (initial diagnosis <18 years) identified in the CanSaRCC database. Additionally, details on the protocol guidance at time of treatment were compared with current guidelines for the same disease. RESULTS: Among 12 RIS identified, median age at initial diagnosis was 3.5 years (range 0.16-14) and the latency from RT to RIS diagnosis was 24.5 (range 5.4-46.2) years. Initial diagnoses included neuroblastoma, rhabdomyosarcoma, Ewing sarcoma, Wilms tumor, retinoblastoma and Hodgkin's Lymphoma. RIS histologies included osteosarcoma and soft tissue sarcomas. In comparison to protocols followed at time of diagnosis to current ones (2022), 7/12 (58%) patients would have required RT. RIS treatment included chemotherapy, radiation and surgery in 3/11 (27%), 10/11 (90%), and 7/11 (63%) patients, respectively. With a median follow-up time of 4.7 years from diagnosis of RIS, 8 (66%) patients were alive and 4 (33%) had died of progressive RIS. CONCLUSION: RIS is a serious late effect of radiotherapy in childhood cancer; however, radiation remains an integral component of primary tumor management and requires participation from a specialized multi-disciplinary team, aiming to mitigate RIS and other potential late effects.

Clinical and Pathologic Characterization of 94 Radiation-Associated Sarcomas: Our Institutional Experience.

Radiation-associated sarcomas are an uncommon complication of therapeutic radiation. However, their prevalence has increased with the more widespread use of this treatment modality. The clinical, pathologic and genetic characteristics of radiation-associated sarcomas are not fully understood. In this study we describe the features of 94 radiation-associated sarcomas reviewed at our institution between 1993 and 2018, evaluate their overall survival (OS) and progression-free survival (PFS) outcomes, and compare them with their sporadic counterparts reviewed within the same time period. Histologic subtypes of all radiation-associated sarcomas included 31 (33%) undifferentiated sarcomas, 20 (21%) osteosarcomas, 17 (18%) angiosarcomas, 10 (11%) malignant peripheral nerve sheath tumor (MPNST), 9 (10%) leiomyosarcomas, 4 (4%) myxofibrosarcomas, and 3 (3%) rhabdomyosarcomas. Six patients had a documented cancer predisposition syndrome. The most common preceding neoplasms included adenocarcinoma (47%) and squamous cell carcinoma (19%), with a mean latency of 13 years. Multivariable Cox survival analysis demonstrated that advanced stage at diagnosis based on pT category (AJCC eighth edition) and fragmented resection were associated with worse survival outcomes. In addition, there was a statistically significant difference in PFS between radiation-associated undifferentiated sarcomas and MPNST when compared to their sporadic counterparts using the Kaplan-Meier method and Log-rank analysis. Overall, our study shows that radiation-associated sarcomas comprise a wide clinico-pathologic spectrum of disease, with a tendency for aggressive clinical behavior. This study further delineates the understanding of these uncommon diseases. Future studies are necessary to better understand the genetic and epigenetic changes that drive the differences in behavior between these tumors and their sporadic counterparts, and to offer better treatment options.

Investigating the role of signal transducer and activator of transcription 3 in feline injection site sarcoma.

BACKGROUND: Feline injection-site sarcomas (FISSs) are malignant mesenchymal tumors of different histotypes. The pathogenesis of FISS has been correlated with chronic inflammation, resulting in neoplastic transformation. Activation of the Janus kinase-signal transducer and activator of transcription 3 (STAT3) have been demonstrated to play a critical role in tumor development by regulating signaling pathways involved in cell proliferation, survival, metastasis, and angiogenesis in human medicine. To characterize the role of STAT3 in FISS, we first detected STAT3 and phosphorylated STAT3 in formalin-fixed and paraffin-embedded (FFPE) FISS tissues using immunohistochemical staining. RESULTS: STAT3 was detected in 88.9% (40/45) of FISS cases, and phosphorylated STAT3 was detected in 53.3% (24/45) of cases. However, the expression levels of both forms of STAT3 were not correlated with tumor grade. To study the role of STAT3 in tumor survival, two primary cells derived from FISSs of two cats exhibiting consistent immunophenotypes with their parental FFPE tissues were established. A dose-dependent inhibitory effect on cell proliferation was observed in both primary FISS cells treated with the STAT3 inhibitor, 5-hydroxy-9,10-dioxo-9,10-dihydroanthracene-1-sulfonamide. CONCLUSIONS: The STAT 3 may play an important role in the tumorigenesis of FISS and be a potential molecular therapeutic target for FISS.

Pembrolizumab in soft-tissue sarcomas with tertiary lymphoid structures: a phase 2 PEMBROSARC trial cohort.

Immune checkpoint inhibitors (ICIs) show limited clinical activity in patients with advanced soft-tissue sarcomas (STSs). Retrospective analysis suggests that intratumoral tertiary lymphoid structures (TLSs) are associated with improved outcome in these patients. PEMBROSARC is a multicohort phase 2 study of pembrolizumab combined with low-dose cyclophosphamide in patients with advanced STS (NCT02406781). The primary endpoint was the 6-month non-progression rate (NPR). Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety. The 6-month NPR and ORRs for cohorts in this trial enrolling all comers were previously reported; here, we report the results of a cohort enrolling patients selected based on the presence of TLSs (n = 30). The 6-month NPR was 40% (95% confidence interval (CI), 22.7-59.4), so the primary endpoint was met. The ORR was 30% (95% CI, 14.7-49.4). In comparison, the 6-month NPR and ORR were 4.9% (95% CI, 0.6-16.5) and 2.4% (95% CI, 0.1-12.9), respectively, in the all-comer cohorts. The most frequent toxicities were grade 1 or 2 fatigue, nausea, dysthyroidism, diarrhea and anemia. Exploratory analyses revealed that the abundance of intratumoral plasma cells (PCs) was significantly associated with improved outcome. These results suggest that TLS presence in advanced STS is a potential predictive biomarker to improve patients' selection for pembrolizumab treatment.

Risk factors for the development of local recurrence in extremity soft-tissue sarcoma.

INTRODUCTION: Local recurrence (LR) is one of the main pitfalls in surgery for extremities soft tissue sarcoma (eSTS). Achieving clear histopathological margins is the most important factor to reduce the risk of LR, but the ability to do so depends on not only surgical technique but also the interplay between tumor biology, anatomical location and surgical approach. The balance between postoperative morbidity and oncological benefits in reducing the risk of LR needs to be considered. AREAS COVERED: This review will cover which etiological factors for the development of eSTS lead to an increased risk of LR and discuss histological subtypes that have a high risk of LR and which surgical and neoadjuvant therapeutic strategies can minimize the risk of LR. EXPERT OPINION: The traditional view that surgical radicality always results in low rates of LR, while marginality alone always leads to high rates of relapse, is outdated. In the modern era of surgical oncology, limb salvage and high-level function after resectional surgery are the key surgical goals. The best results are achieved by combining effective neoadjuvant treatments with planned bespoke oncological operations that consider the biological and anatomical factors of each individual sarcoma.

Paraneoplastic Secretion of Multiple Phosphatonins From a Deep Fibrous Histiocytoma Causing Oncogenic Osteomalacia.

CONTEXT: Literature suggests that oncogenic osteomalacia is usually caused by a benign mesenchymal tumor secreting fibroblast growth factor subtype-23 (FGF-23), but the involvement of other phosphatonins has only been scarcely reported. We have previously published a seemingly typical case of oncogenic osteomalacia. Following curative neoplasm resection, we now report unique molecular characteristics and biology of this tumor. CASE DESCRIPTION: A 25-year-old man had been diagnosed with severe oncogenic osteomalacia that gradually crippled him over 6 years. 68Ga-DOTA-TATE positron emission tomography/computed tomography scan localized the culprit tumor to his left sole, which on resection revealed a deep fibrous histiocytoma displaying a proliferation of spindle cells with storiform pattern associated with multinucleated giant cells resembling osteoclasts. Circulating FGF-23, which was elevated more than 2-fold, declined to undetectable levels 24 h after surgery. Microarray analysis revealed increased tumor gene expression of the phosphatonins FGF-23, matrix extracellular phosphoglycoprotein (MEPE) and secreted frizzled-related protein subtype 4, with elevated levels of all 3 proteins confirmed through immunoblot analysis. Differential expression of genes involved in bone formation and bone mineralization were further identified. The patient made an astonishing recovery from being wheelchair bound to fully self-ambulant 2 months postoperatively. CONCLUSION: This report describes oncogenic osteomalacia due to a deep fibrous histiocytoma, which coincidentally has been found to induce profound muscle weakness via the overexpression of 3 phosphatonins, which resolved fully upon radical resection of the tumor. Additionally, genes involved in bone formation and bone remodeling contribute to the molecular signature of oncogenic osteomalacia.

Recurrent calcifying aponeurotic fibroma of the hand: managing a rare hand tumour in an evolving healthcare landscape.

Calcifying aponeurotic fibroma (CAF) is a rare benign tumour originating from the aponeuroses of tendons and their bony insertions. A 15-year-old student presented to his general practitioner with a 1-year history of a progressively enlarging painless finger swelling. The lesion was excised by the local paediatric orthopaedic service and recurred over the course of the following 4 months. Histology confirmed a diagnosis of CAF. He was referred to our specialist hand surgery service and the lesion was excised along with the ulnar lateral band and the overlying skin. At 9 months, there was no clinical evidence of recurrence. We are the first group to report the potential benefit of including of the overlying skin in the histological specimen to reduce the residual disease burden. Our case illustrates the technical challenges and considerations of removing a large, recurrent CAF of the hand and highlights the importance of centralised specialist care.

The Risk of Tumor Contamination Associated With Thoracic Instrumentation in Patients With Osteosarcoma: 2 Case Reports and a Literature Review.

Orthopedic surgeons are well aware of tumor contamination at the site of initial biopsy in osteosarcoma. However, tumor contamination in patients with osteosarcoma associated with thoracic instrumentation is not well described. The authors summarize 2 reported cases in addition to the 2 cases at their institution of this phenomenon. Knowledge of tumor contamination and preventative measures against tumor contamination is sparse in the literature, especially pertaining to patients with osteosarcoma undergoing thoracic instrumentation. In this report, the authors hope to increase awareness of these cases and suggest preventative measures to mitigate against tumor contamination in patients with osteosarcoma. The authors report that the median time between thoracic instrumentation and the visible detection of tumor migration to local sites was 5 months. They conclude that tumor contamination associated with thoracic instrumentation is characterized by patients with multiple sites of relapse and aggressive, fatal disease.

Combination therapy with Olaratumab/doxorubicin in advanced or metastatic soft tissue sarcoma -a single-Centre experience.

BACKGROUND: The antibody targeting platelet-derived growth factor receptor alpha (PDGFRA), olaratumab, was approved in 2016 for metastatic soft tissue sarcoma (STS) in combination with doxorubicin based on promising results of a phase Ib/II trial by the Food and Drug Administration (FDA). However, recently the phase III ANNOUNCE trial could not confirm the additional value of olaratumab in this context. METHODS: Here, in a retrospective analysis we share our single-centre experience with olaratumab/doxorubicin in STS by including n = 32 patients treated with olaratumab/doxorubicin between 2016 and 2019. RESULTS: Median progression-free survival (PFS) in the overall cohort was 3.1 months (range 0.6-16.2). A response [complete remission (CR), partial remission (PR) or stable disease (SD)] was seen in n = 11 (34%) cases, whereas n = 21 (66%) patients showed progressive disease (PD). In n = 9 patients surgery was performed subsequently in an individual therapeutic approach. Out of n = 5 patients receiving additional regional hyperthermia, n = 3 achieved PR or SD. CONCLUSIONS: This single-centre experience does also not support the promising phase Ib/II results for olaratumab/doxorubicin in STS. However, our findings do not preclude that olaratumab combination therapy could be valuable in a neoadjuvant setting. This warrants further exploration also taking into account the heterogeneous nature of STS.

What is new about the molecular genetics in matrix-producing soft tissue tumors? -The contributions to pathogenetic understanding and diagnostic classification.

Soft tissue tumors encompass a wide variety of mesenchymal neoplasms exhibiting diverse clinical, pathologic, and molecular features. Among these, osteoid and/or chondroid matrix deposition in some soft tissue tumors represents a noticeable characteristic. Unlike matrices present in bone tumors where they likely reveal the respective cells of origin (i.e., osteoblastic or chondroblastic precursors), those existing in soft tissue tumors more often denote a metaplastic phenomenon and reflect the diversity of differentiation these tumors can display. While many soft tissue tumor types can occasionally harbor metaplastic bone or cartilage as an incidental component or heterologous differentiation, in some other tumor types, the production of these matrices is a frequent and distinctive, if not diagnostic, feature. This review focuses on the latter tumor types where emerging immunohistochemical and molecular evidence has significantly improved our understanding of their respective pathogenesis and histopathological spectra. These tumor types include ossifying fibromyxoid tumor, phosphaturic mesenchymal tumor, synovial chondromatosis, soft tissue chondroma, calcifying aponeurotic fibroma, giant cell tumor of soft tissue, myositis ossificans and related diseases, mesenchymal chondrosarcoma, and extraskeletal osteosarcoma.

What's new in fibroblastic tumors?

Over the last 10 years, a number of advances have been made in our understanding of fibroblastic and myofibroblastic tumors. The rapidly evolving field of molecular diagnostics has resulted in the recognition of new entities and better understanding of tumor pathogenesis, while careful clinicopathologic correlative analyses have led to improvements in modeling tumor behavior. This review will discuss new and emerging entities in fibroblastic neoplasia and provide updates on the pathogenesis, diagnosis, and prognostication of these diverse and challenging tumors.

Arteriovenous graft in kidney transplant patients: Lookout for the rare but fearsome angiosarcoma.

INTRODUCTION: Angiosarcomas are rare tumors, comprising less than 1% of all sarcomas. However, they portend a poor prognosis, as they tend to metastasize early, being of uttermost importance a prompt diagnosis and treatment. CASE DESCRIPTION: We present the case of a 55-year-old female with history of kidney transplantation, immunosuppressed with tacrolimus, prednisolone, and mofetil mycophenolate. Fifteen years after the transplant, she developed an ulcerated lesion on the site of a nonfunctioning arteriovenous graft, which was excised. Histology was compatible with a high grade angiosarcoma that invaded the margins, and immunosuppression was switched to everolimus. Staging imaging exams revealed lymph node, muscle, and lung metastases. Shortly after, nodular lesions appeared compatible with local recurrence of the disease, and the patient showed severe deterioration of her clinical condition, being proposed for palliative chemotherapy. However, the disease showed an explosive progression and the patient died before starting the treatment. CONCLUSION: This case emphasizes the importance of including inspection of the vascular access (functioning or not) in regular post-transplant consultation and value any alterations in the attempt of a timely diagnosis. Although rare, angiosarcoma is an important entity that should be considered in the differential diagnosis of soft tissue masses arising from a vascular access, especially in immunocompromised patients. Aggressive treatment should be offered whenever possible.

Fluorescence-guided resection in bone and soft tissue infiltrating meningiomas.

BACKGROUND: Bone infiltration of the tumour is common in meningioma surgery. This may also affect patients without indicative signs of bone infiltration on preoperative imaging. Unrecognized bone invasion may lead to higher recurrence rates. 5-ALA fluorescence-guided resection (5-ALA-fg) could be a promising tool to help recognize possible bone invasion and/or tumour remnants. However, there is still little data about 5-ALA-fg resection in bone and soft tissue infiltrating meningiomas. METHODS: We performed a retrospective study of 11 patients who were operated with the aid of 5-ALA due to bone and soft tissue infiltrating meningiomas at the University Hospital of St. Poelten between 2013 and 2019. RESULTS: Strong and homogeneous fluorescence of the meningioma was observed in 9 cases (81.8%) and vague and heterogeneous fluorescence in 2 cases (18.2%). Hyperostosis on computerized tomography was evident in 3 of 6 cases (50%) and bone infiltration was visible in preoperative magnetic resonance imaging in 7 of 11 patients (63.6%). All eleven patients showed positive fluorescence of the bone infiltrating part. In all 7 cases where tissue could be collected, histopathological testing verified tumour infiltration (100%). There was also fluorescence of the periosteum in 3 cases and histopathological testing verified tumour infiltration in 100%. CONCLUSION: There is growing evidence that 5-ALA-fg resection can help to identify bone infiltration in meningioma surgery. Therefore, it may help to improve extent of resection. However, further studies are necessary to investigate the rate of false-negative fluorescence and its effect on progression free survival. If 5-ALA-fg resection of meningioma is performed, the attending surgeon should also consider investigating the adjacent periosteum under blue light for detection of possible fluorescence.

Squamous Cell Carcinoma Arising from a Morel-Lavallée Lesion: A Case Report.

CASE: A 72-year-old man presented 20 years after a Morel-Lavallée (ML) lesion with pain and drainage. Biopsies of the lesion and lymph nodes were positive for squamous cell carcinoma (SCC). There was no cutaneous involvement or distant metastasis. After chemotherapy and radiation, he underwent resection of the lesion and lymph nodes with flap closure. Two months postoperatively, he unfortunately developed malignant pleural effusions, hypercalcemia, and kidney injury and was eventually transferred to hospice care and died. CONCLUSION: This is the first report of SCC arising from a ML lesion. Chronic ML lesions should be treated aggressively and monitored for transformation into malignancy, even without cutaneous involvement.

Radiation-Induced Sarcoma After Heterotopic Ossification Prophylaxis: A Case Report.

CASE: Heterotopic ossification (HO) is a pathological formation of bone in nonosseous tissue and is a common complication of orthopaedic procedures. Radiotherapy is often used to prevent HO despite the small risk of secondary malignancy. Here, we report a case of a patient who developed a periprosthetic, radiation-induced sarcoma after delivery of a single fraction of 7 Gy for HO prophylaxis. This sarcoma was found to lie entirely within the treatment field and occurred within 5 years of radiation. CONCLUSION: Appropriate counseling regarding radiation-induced sarcoma formation should be provided to patients considering radiotherapy for this HO prophylaxis.

Incidental Detection of a Radiation-Induced Soft-Tissue Sarcoma on 68Ga-PSMA PET/CT in a Patient Previously Treated for Prostate Cancer.

Radiation-induced sarcoma is a rare complication of radiation therapy. We describe the incidental detection of a radiation-induced undifferentiated soft-tissue sarcoma with increased uptake on Ga-labeled prostate-specific membrane antigen (PSMA) PET/CT in a prostate cancer patient previously treated with surgery and external-beam radiotherapy. Results were confirmed by histological analysis. Ga-PSMA is known to bind not only to PSMA-expressing prostate cancer cells but also to the neovasculature of various other solid tumors. A careful Ga-PSMA PET/CT review of previously irradiated areas is warranted so as not to miss radiation-induced sarcoma in prostate cancer patients.

Phosphaturic mesenchymal tumor and related wound problem.

INTRODUCTION: Phosphaturic mesenchymal tumor mixed connective tissue type (PMT/MCT) is the most common type (up to 90%) of phosphaturic mesenchymal tumor (PMT), a rare clinicopathologic entity. Besides overproduction of fibroblast growth factor 23 (FGF23), there is a big variation of immunohistochemical characteristic across types of PMT, which makes it difficult to obtain an early diagnosis of PMT/MCT. As a benign tumor, PMT/MCT usually happens in subcutaneous tissues and leads to nonhealing of wound. A complete excision of PMT/MCT facilitates wound healing. CONCLUSIONS: Review of the existing evidence indicates that early diagnosis of PMT/MCT is critically important when treating PMT/MCT wound. Hence standardization of early diagnosis for PMT/MCT is mandated.