MicroRNAs as Prognostic Biomarkers and Therapeutic Targets in Chondrosarcoma.

Chondrosarcoma, the second most common primary malignant bone tumor, originates from cartilaginous tissue and accounts for almost 20% of all primary bone tumors. The management of chondrosarcoma remains challenging due to its diverse clinical course and prognosis, which can range from benign to highly aggressive with a huge risk of metastasis. Emerging research has demonstrated the importance of microRNA (miRNA) dysregulation in the pathogenesis of chondrosarcoma. MiRNAs are small, noncoding RNA molecules that play an essential role in gene expression regulation by targeting specific messenger RNAs (mRNAs) for degradation or translational repression. This article provides an extensive review of current miRNA research in chondrosarcoma, focusing on diagnostic strategies, cell cycle regulation, drug resistance, biomarkers of progression, and stem cell phenotype. We will examine recent studies identifying differentially expressed miRNAs in chondrosarcoma compared to normal cartilage tissue, exploring their potential as diagnostic and prognostic biomarkers. Furthermore, we will discuss the role of miRNAs in regulating cell cycle progression and their potential as therapeutic targets to overcome drug resistance. We will also investigate the prospective utility of miRNAs as biomarkers of progression and their role in modulating the stem cell phenotype of chondrosarcoma cells. This article offers a comprehensive analysis of current miRNA research in chondrosarcoma, focusing on its potential as diagnostic and prognostic biomarkers, therapeutic targets, and regulators of disease progression. By integrating the latest discoveries in this field, we aim to contribute to the development of novel approaches to the prevention, diagnosis, and treatment of chondrosarcoma, ultimately enhancing patient outcomes.

FGF23 Expression Is a Promising Immunohistochemical Diagnostic Marker for Undifferentiated Pleomorphic Sarcoma of Bone (UPSb).

Background: Undifferentiated pleomorphic sarcoma of bone (UPSb) is a rare primary bone sarcoma that lacks a specific line of differentiation. Distinguishing between UPSb and other malignant bone sarcomas, including dedifferentiated chondrosarcoma and osteosarcoma, is challenging due to their overlapping features. We have previously identified that UPSb tumours have elevated mRNA levels of Fibroblast Growth Factor 23 (FGF23) transcripts compared to other sarcomas including osteosarcoma. In the present study, we evaluated the specificity and practicality of FGF23 immunoreactivity as a specific diagnostic tool to differentiate UPSb tumours from osteosarcomas and dedifferentiated chondrosarcomas. Methods: A total of 10 UPSb, 10 osteosarcoma, and 10 dedifferentiated chondrosarcoma cases (all high-grade), were retrieved and immunohistochemistry for FGF23 was performed. Results: FGF23 protein was expressed at high levels in 80-90% of undifferentiated pleomorphic sarcoma of the bone cases, whereas it was expressed at significantly lower levels in dedifferentiated chondrosarcoma and osteosarcoma cases. A semiquantitative analysis, considering the intensity of immunoreactivity, confirmed significantly elevated FGF23 expression levels in UPSb tissues compared to those observed in osteosarcoma and dedifferentiated chondrosarcoma tissues. Conclusions: The results we present here suggest that FGF23 immunohistochemistry may be a useful tool to aid in differentiating UPSb from morphologically similar malignant bone sarcomas, especially in situations where sampling is restricted and there is limited clinical information available.

Secondary peripheral chondrosarcoma in multiple osteochondromas: a retrospective single-institution case series.

BACKGROUND: Multiple osteochondromas is genetic disorder characterized by the formation of multiple benign cartilage-capped bone tumors, named osteochondromas, during skeletal development. The most feared complication is the secondary peripheral chondrosarcoma, a malignant cartilaginous neoplasm that arises from the chondroid cap of pre-existent osteochondromas. We conducted a retrospective cohort study on patients diagnosed and followed up from 1960 to 2019 to describe the clinical and pathological features of individuals affected by peripheral chondrosarcoma in multiple osteochondromas, to evaluate follow up information and individual outcome and to compare the results with literature. Data, including age, gender, site, histological grade, cartilage cap thickness, surgical treatments, surgical margins, genotype mutational status as well as treatment details were captured from the hospital electronic health records and from Registry of Multiple Osteochondromas. In addition, a complete histological review of all hematoxylin and eosin (H&E)-stained sections has been performed by expert pathologists. RESULTS: One hundred five of the screened cases were included in the present study. The age at diagnosis of SPC ranges from 13 to 63, with median age at diagnosis of 34 years. The site most frequently affected by malignant degeneration was the pelvis (46 patients, 44%) with higher incidence in male patients (32 males vs.14 females). The second one was lower limbs (including femur, fibula, or tibia), identified in 35 patients. Histological information - available for 103 patients - showed: 59 patients with grade 1; 40 patients had a grade 2 and 4 patients had a grade 3. The most common surgical treatment was the complete resection, followed by debulking, amputation and partial resection. Most of cases did not have recurrence of the disease. Outcome in disease-free survival highlights that a worse course of the disease was associated with histological grade 2 or 3, and partial resection surgery. In most of analyzed cases (94%) a pathogenic variant was identified. CONCLUSIONS: In conclusion, the present study gives an overview of the secondary peripheral chondrosarcomas, confirming that this disease represents an impacting complication for multiple osteochondromas patients and suggests that malignant transformation can occur also in younger patient, in a not irrelevant number of cases.

Rare Dedifferentiated Periosteal Chondrosarcoma with 11-Year Metastatic Relapse: A Case Report.

A 50-year-old man presented for evaluation of a periscapular mass. Biopsy suggested a low-grade chondrosarcoma; however, the resected specimen revealed a grade 2 chondrosarcoma with a low-grade dedifferentiated mesenchymal component. The mass multiply recurred as chondrosarcoma without a dedifferentiated component before the patient developed lung metastases of chondrosarcoma without a dedifferentiated component 11 years after the initial diagnosis and died of disease. This is one of the first reported cases of a dedifferentiated chondrosarcoma with low-grade dedifferentiated component. While overall prognosis may be better than in typical dedifferentiated chondrosarcoma, this tumor demonstrated numerous local recurrences as well as metastasis.

Tracheal Chondrosarcoma-A Novel Presentation of Lynch Syndrome.

This case report describes a man in his 60s with no cancer history who presented with 2 weeks of dysphagia, dysphonia, and a left neck mass.

Delay in Diagnosis and Treatment of Primary Bone Tumors.

BACKGROUND: Delay in the diagnosis and treatment of bone tumors continues to be a common problem. Prolonged diagnosis can significantly reduce the chances of successful treatment of the disease. Accordingly, the aim of this study was to assess the delay in the diagnosis of primary bone tumors, identify the most common symptoms and analyze the course of the diagnostic and therapeutic path. MATERIAL AND METHODS: Thirty-two (K=18; M=14) patients treated surgically for primary bone tumors were included in the retrospective study. Patient records were analyzed. Delay in diagnosis was defined as the time from the onset of symptoms to the initial diagnosis and referral to an orthopedic oncology center. RESULTS: The median delay in diagnosis was 7 (3-12) months. For tumors located in the pelvis, the delay was 10 months, compared to 5 months for the upper limb and 7 months for the lower limb (p=0.2312). The delay was 6 months In patients with osteosarcoma, and 8 months in chondrosarcoma patients (p=0.1786). At the first office visit, an x-ray was ordered in 19 cases (59.4%), of whom 9 patients (47.4%) were referred on to the oncology center. The most common symptoms were pain in the affected area (90.6%), limited mobility (28.1%) and pathological fracture (25%). After admission to an orthopedic department, a biopsy was performed after 5.5 (3-8.2) days. The histology results were ready after another 14 (8-18) days, and surgical treatment was performed after 95 (76-100) days. CONCLUSIONS: 1. Although patients show typical symptoms of bone tumors, only a small proportion are referred directly to an oncology center. After a primary bone tumor is suspected, further diagnostic and therapeutic activities proceed efficiently, in accordance with the current guidelines.

A machine learning-based model for clinical prediction of distal metastasis in chondrosarcoma: a multicenter, retrospective study.

Background: The occurrence of distant metastases (DM) limits the overall survival (OS) of patients with chondrosarcoma (CS). Early diagnosis and treatment of CS remains a great challenge in clinical practice. The aim of this study was to investigate metastatic factors and develop a risk stratification model for clinicians' decision-making. Methods: Six machine learning (ML) algorithms, including logistic regression (LR), plain Bayesian classifier (NBC), decision tree (DT), random forest (RF), gradient boosting machine (GBM) and extreme gradient boosting (XGBoost). A 10-fold cross-validation was performed for each model separately, multicenter data was used as external validation, and the best (highest AUC) model was selected to build the network calculator. Results: A total of 1,385 patients met the inclusion criteria, including 82 (5.9%) patients with metastatic CS. Multivariate logistic regression analysis showed that the risk of DM was significantly higher in patients with higher pathologic grades, T-stage, N-stage, and non-left primary lesions, as well as those who did not receive surgery and chemotherapy. The AUC of the six ML algorithms for predicting DM ranged from 0.911-0.985, with the extreme gradient enhancement algorithm (XGBoost) having the highest AUC. Therefore, we used the XGB model and uploaded the results to an online risk calculator for estimating DM risk. Conclusions: In this study, combined with adequate SEER case database and external validation with data from multicenter institutions in different geographic regions, we confirmed that CS, T, N, laterality, and grading of surgery and chemotherapy were independent risk factors for DM. Based on the easily available clinical risk factors, machine learning algorithms built the XGB model that predicts the best outcome for DM. An online risk calculator helps simplify the patient assessment process and provides decision guidance for precision medicine and long-term cancer surveillance, which contributes to the interpretability of the model.

IDH-negative chondrosarcoma with metachronous dedifferentiation only in the metastatic site-A diagnostic pitfall.

Dedifferentiated chondrosarcoma is a subtype of chondrosarcoma with a biphasic histological appearance of a chondrosarcoma component transitioning to a high-grade, noncartilaginous sarcoma. It is particularly difficult to confirm the diagnosis when a sarcoma lacking cartilaginous component occurs at a distant location from the primary lesion. The patient was a 72-year-old woman with multiple lesions in the pelvis, lungs, and liver, 18 months after resection of grade 2 central chondrosarcoma of the sternum. Imaging showed no cartilage component in any location. Although a needle biopsy from the pelvic region confirmed the diagnosis as high-grade sarcoma without a cartilage component, it was difficult to distinguish between a new primary sarcoma and metachronous metastatic lesions from patient's known prior dedifferentiated chondrosarcoma. We therefore performed a comparative molecular analysis by whole-exome sequencing of the biopsy sample and the resected sternal central chondrosarcoma. Both lesions had no IDH1/2 mutations but shared 19 somatic mutations and wide-range chromosomal losses, indicating similar origin. This case illustrates the challenge is coupling a diagnosis of metastatic dedifferentiated chondrosarcoma when no chondroid component is evident. Our study also highlights the benefit of genomic analysis in this differential diagnosis, especially in the context of dedifferentiated chondrosarcoma lacking IDH1/2 mutations.

Extraskeletal mesenchymal chondrosarcoma arising from soft tissues: A rare case report.

BACKGROUND: Chondrosarcomas are an exceedingly rare form of cancer, impacting only a few individuals per million. Among chondrosarcomas, a small fraction belongs to the mesenchymal sub-type. Furthermore, only one-third of mesenchymal chondrosarcomas manifest in extraskeletal locations. CASE: A 38-year-old woman was referred by a midwife after experiencing pain in the right upper quadrant of her right breast for 2 months. The mass had been palpable for 1 week before the initial assessment. According to radiological evaluations, the tumor is outside breast tissue and not connected to the bones. Hence, a biopsy of the mass is done. The biphasic morphology of the tumor during pathological evaluation, in addition to immunohistochemistry testing, confirms the diagnosis of extraskeletal mesenchymal chondrosarcoma (EMCS). Finally, the mass was surgically removed, and 6 months of chemotherapy were administered to the patient. CONCLUSION: Given the tumor's rarity and the lack of established guidelines, diagnosing EMCS can be challenging and prone to errors. As such, meticulous sampling, along with precise pathological and imaging investigations, is imperative to accurately establish the diagnosis of these tumors.

The clinical significance of CD44v6 in malignant and benign primary bone tumors.

BACKGROUND: The objective of this study was to assess the expression profile of CD44v6, a potential cancer stem cell marker, and its diagnostic and predictive significance in three distinct types of primary bone tumors. METHODS: In this study, we utilized real-time qRT-PCR and immunohistochemistry to examine the gene and protein levels of CD44v6 in a total of 138 fresh bone tissues. This included 69 tumor tissues comprising osteosarcoma (N = 23), chondrosarcoma (N = 23), and GCT (N = 23), as well as 69 corresponding non-cancerous tumor margins. Furthermore, we investigated the circulating level of CD44v6 by isolating peripheral blood mononuclear cells from 92 blood samples. Among these, 69 samples were obtained from patients diagnosed with primary bone tumors, while the remaining 23 samples were from healthy donors. The primary objectives of our investigation were to assess the correlation between CD44v6 expression levels and clinic-pathological features of the patients, as well as to evaluate the diagnostic and predictive values of CD44v6 in this context. RESULTS: In patients with osteosarcoma and chondrosarcoma tumors, both the gene and protein expression of CD44v6 were found to be significantly higher compared to the GCT group. Furthermore, the circulating level of CD44v6 was notably elevated in patients diagnosed with osteosarcoma and chondrosarcoma in comparison to the GCT group and patients with malignant tumor characteristics. Additionally, we observed a strong correlation between the gene and protein levels of CD44v6 and important tumor indicators such as tumor grade, metastasis, recurrence, and size at the tumor site. CD44v6 shows potential in differentiating patients with bone tumors from both control groups and tumor groups with severe and invasive characteristics from those with non-severe features. Importantly, the expression level of CD44v6 also demonstrated predictive value for determining tumor grade and the likelihood of recurrence. CONCLUSION: CD44v6 is likely to play a role in the development of primary bone tumors and has the potential to serve as a diagnostic biomarker for bone cancer. However, to obtain more accurate and conclusive findings, further mechanistic investigations involving larger population samples are necessary.

Extraskeletal myxoid chondrosarcoma: a case report.

Extraskeletal myxoid chondrosarcoma is a rare mesenchymal neoplasm of uncertain differentiation, characterized morphologically by abundant myxoid stroma, a multinodular growth pattern, and uniform cells arranged in strands, clusters, and reticular networks. It usually occurs in adults in the fifth decade, most often in the deep soft tissues of the proximal extremities. The molecular hallmark of this tumor, present in over 90% of cases, is the fusion of NR4A3 with EWSR1 at 22q12.2 or TAF15 at 17q12. Many other tumors with uniform tumor cells embedded in a myxoid matrix can mimic Extraskeletal myxoid chondrosarcoma, and the distinction can be difficult, often requiring immunohistochemistry and/or molecular testing. We herein report the case of an Extraskeletal myxoid chondrosarcoma that occurred in a 74-year-old woman who consulted for a slowly enlarging thigh mass, while highlighting the key morphologic, immunohistochemical, and molecular features of this rare type of soft tissue sarcoma, as well as a summary table gathering diagnostic features of relevance to the differential diagnosis.

[Diagnosis and treatment of rare malignant temporal bone tumors].

Objective:To analyze the diagnosis, treatment and prognosis of patients with rare malignant tumors of the temporal bone. Methods:Four cases of rare temporal bone malignant tumors in our hospital between March 2014 and December 2020 were reviewed, including two cases of chondrosarcoma, one case of fibrosarcoma and one case of endolymphatic cystic papillary adenocarcinoma. There were three males and one female, ages between 28 and 56 years at the time of surgery. Common symptoms included hearing loss, facioplegia, tinnitus, and headache. All patients underwent imaging examinations to evaluate the extent of the lesions. Tumors were removed by subtotal temporal bone resection or infratemporal fossa approach, and postoperative adjuvant radiotherapy was applied if necessary. Results:One of the two chondrosarcoma patients was cured by complete resection of the tumor for 75 months, the other one recurred after the first excision of the tumor and underwent infratemporal fossa approach resection of skull base mass again with no recurrence found yet for 112 months. One patient with fibrosarcoma survived for 28 months after surgery with a positive margin and post-operative radiotherapy. One patient with endolymphatic cystic papillary adenocarcinoma recurred 12 months after subtotal lithotomy, and underwent subtotal temporal bone resection again, combined with radiotherapy. No recurrence was found for 63 months. Conclusion:The incidence of rare temporal bone malignant tumors is extremely low, the location is hidden, and the symptoms are atypical. Attention should be paid for early detection and early treatment. Surgical resection is the main treatment, and radiotherapy can be supplemented in the advanced stage or with a positive margin.

Chondrosarcoma of Ureter in an Elderly Patient: A Case Report.

Chondrosarcoma is a rare type of cancer that can affect the upper urinary tract. Because of its rarity, the clinical presentation of chondrosarcoma can be similar to other urinary tract conditions, such as renal colic, hematuria, and urothelial carcinoma. The primary treatment for chondrosarcoma is the surgical removal of the tumor, and radiation or chemotherapy may be used for advanced cases. However, because of the limited number of patients with this condition, there are no established guidelines for chemotherapy, and the outcomes are unclear. In this case, we present a 71-year-old female patient who was diagnosed with ureteral chondrosarcoma. She presented with abdominal pain and hydronephrosis, and a tumor was found beneath a small stone. The patient underwent nephroureterectomy and received oral fluorouracil chemotherapy due to the advanced stage of the disease. Fortunately, the patient survived, and at the 7 months post-operative follow-up there was no evidence of recurrence. In conclusion, the chondrosarcoma of the upper urinary tract is a rare condition that can be difficult to diagnose due to its similarity to other urinary tract conditions. Treatment typically involves the surgical removal of the tumor, with radiation or chemotherapy reserved for advanced cases. However, because of the limited number of patients, there are no established guidelines for chemotherapy, and the outcomes of treatment are unclear.

Extraskeletal Myxoid Chondrosarcomas: The Uncommon Clinicopathologic Manifestations and Significance of TAF15::NR4A3 Fusion.

Extraskeletal myxoid chondrosarcoma (EMC) is an ultrarare sarcoma typically exhibiting myxoid/reticular histology and NR4A3 translocation. However, morphologic variants and the relevance of non-EWSR1::NR4A3 fusions remain underexplored. Three challenging pan-Trk-expressing cases, featuring cellular to solid histology, were subjected to RNA exome sequencing (RES), unveiling different NR4A3-associated fusions. Alongside RES-analyzed cases, fluorescence in situ hybridization was performed to confirm 58 EMCs, with 48 available for pan-Trk immunostaining and KIT sequencing. Except for 1 (2%) NR4A3-rearranged EMC without identifiable partners, 46 (79%), 9 (16%), and 2 (3%) cases harbored EWSR1::NR4A3, TAF15::NR4A3, and TCF12::NR4A3 fusions, respectively. Five EWSR1::NR4A3-positive EMCs occurred in the subcutis (3) and bone (2). Besides 43 classical cases, there were 8 cellular, 4 rhabdoid/anaplastic, 2 solid, and 1 mixed tumor-like variants. Tumor cells were oval/spindle to pleomorphic and formed loose myxoid/reticular to compact sheet-like or fascicular patterns, imparting broad diagnostic considerations. RES showed upregulation of NTRK2/3, KIT, and INSM1. Moderate-to-strong immunoreactivities of pan-Trk, CD117, and INSM1 were present in 35.4%, 52.6%, and 54.6% of EMCs, respectively. KIT p. E554K mutation was detected in 2/48 cases. TAF15::NR4A3 was significantly associated with size >10 cm (78%, P = .025). Size >10 cm, moderate-to-severe nuclear pleomorphism, metastasis at presentation, TAF15::NR4A3 fusion, and the administration of chemotherapy portended shorter univariate disease-specific survival, whereas only size >10 cm (P = .004) and metastasis at presentation (P = .032) remained prognostically independent. Conclusively, EMC may manifest superficial or osseous lesions harboring EWSR1::NR4A3, underrecognized solid or anaplastic histology, and pan-Trk expression, posing tremendous challenges. Most TAF15::NR4A3-positive cases were >10 cm in size, ie, a crucial independent prognosticator, whereas pathogenic KIT mutation rarely occurred.

High-Grade Chondrosarcoma of the Proximal Phalanx: an Unusual Case of a Rare Entity.

Chondrosarcoma of the hand is a rare disease, but is one of the more common malignancies of the hand. Biopsies and imaging are a fundamental step in determining correct diagnosis, grading and selection for best treatment. We describe the case of a 77-year-old male complaining of a painless swelling in the proximal phalanx of the third ray of left hand. A biopsy was performed and the histology revealed a G2 chondrosarcoma. The patient underwent III ray amputation with metacarpal bone disarticulation and sacrifice of the radial digit nerve of the fourth ray. Definitive histology revealed grade 3 CS. Eighteen months after surgery, the patient is apparently disease-free with a good functional and aesthetic outcome although with persistent paresthesia of the fourth ray. Although there is no agreement in the literature for the treatment of low-grade chondrosarcomas, wide resection or amputation can be considered the mainstay treatment for high-grade tumors. Key words: chondrosarcoma, proximal phalanx, ray amputation, surgical treatment, tumor hand.

Association Between Insurance Status and Chondrosarcoma Stage at Diagnosis in the United States: Implications for Detection and Outcomes.

INTRODUCTION: Chondrosarcoma is a common primary bone tumor, and survival is highly influenced by stage at diagnosis. Early detection is paramount to improve outcomes. The aim of this study is to analyze the association between insurance status and stage of chondrosarcoma at the time of diagnosis. METHODS: A comparative cross-sectional study was conducted using the Surveillance, Epidemiology and End Results database. Patients with a diagnosis of chondrosarcoma between 2007 and 2016 were included. Exposure variable was insurance status and the outcome chondrosarcoma staging at the time of diagnosis. Control variables included tumor grade, age, sex, race, ethnicity, marital status, place of residence, and primary site. Both unadjusted and adjusted (multiple logistic regression) odds ratios (ORs) and 95% confidence intervals (CIs) were computed to estimate the association between insurance status and stage. RESULTS: An effective sample of 2,187 patients was included for analysis. In total, 1824 (83%) patients had health insurance (nonspecified), 277 (13%) had Medicaid, and the remaining 86 (4%) had no insurance. Regarding stage at diagnosis, 1,213 (55%) had localized disease, whereas 974 (45%) had a later stage at presentation. Before adjustment, the odds of being diagnosed at an advanced (regional/distant) stage were 55% higher in patients without insurance (unadjusted OR 1.55; 95% CI 1.003 to 2.39). After adjusting for potential confounders, the odds increased (adjusted OR 1.94; 95% CI 1.12 to 3.32). Variables with a significant association with a later stage at diagnosis included older age ( P < 0.001), male sex ( P < 0.001), pelvic location ( P < 0.001), and high grade ( P < 0.001). CONCLUSION: Being uninsured in the United States increased the odds of a late-stage diagnosis of chondrosarcoma by 94% when compared with insured patients. Lack of medical insurance presumably leads to diminished access to necessary diagnostic testing, which results in a more advanced stage at diagnosis and ultimately a worse prognosis. Efforts are required to remediate healthcare access disparities. LEVEL OF EVIDENCE: Level III.

Keratin-positive fibrotic extraskeletal myxoid chondrosarcoma: a close mimic of myoepithelial tumour.

AIMS: Extraskeletal myxoid chondrosarcoma (EMC) is a rare form of adult sarcoma with distinct histology and NR4A3 gene fusion. Immunohistochemically, EMCs are variably positive for S100 protein and neuroendocrine markers. Unlike histologically similar soft-tissue myoepithelial tumours, keratin expression is rare. Prompted by two recent EMC cases with diffuse keratin expression, we investigated the expression of epithelial markers in a molecularly confirmed cohort of EMC and identified two additional similar cases. METHODS AND RESULTS: Four keratin-positive EMCs occurred in one man and three women aged 46-59 years. All tumours displayed nonclassic histology with prominent stromal fibrosis, and keratin AE1/AE3 was expressed either diffusely (N = 2) or focally (N = 2). In one tumour, keratin expression was limited to the sclerotic area. All tumours coexpressed epithelial membrane antigen and two additionally expressed S100 protein or glial fibrillary acidic protein. All tumours harboured NR4A3 fusions, including TAF15::NR4A3 (N = 1) and EWSR1::NR4A3 (N = 3). Two cases were initially considered as most consistent with myoepithelial tumours based on widespread stromal fibrosis and keratin expression. DNA methylation analysis classified two tumours tested as EMCs. CONCLUSIONS: We identified a small subset of EMCs characterised by keratin expression and prominent stromal fibrosis. This histological pattern must be recognised in the differential diagnosis of myoepithelial tumours because misclassification may lead to the erroneous prediction of tumour behaviour and may alter patient management. NR4A3 genetic analysis should be considered even in the face of keratin expression and prominent stromal fibrosis.

Biology and Management of High-Grade Chondrosarcoma: An Update on Targets and Treatment Options.

This review provides an overview of histopathology, clinical presentation, molecular pathways, and potential new systemic treatments of high-grade chondrosarcomas (CS), including grade 2−3 conventional, dedifferentiated, and mesenchymal CS. The diagnosis of CS combines radiological and histological data in conjunction with patient clinical presentations. Conventional CS is the most frequent subtype of CS (85%) and represents about 25% of primary bone tumors in adults; they can be categorized according to their bone location into central, peripheral, and periosteal chondrosarcomas. Central and peripheral CS differ at the molecular level with either IDH1/2 mutations or EXT1/2 mutations, respectively. CDKN2A/B deletions are also frequent in conventional CS, as well as COL2A1 mutations. Dedifferentiated CS develops when low-grade conventional CS transforms into a high-grade sarcoma and most frequently exhibits features of osteosarcoma, fibrosarcoma, or undifferentiated pleomorphic sarcoma. Their molecular characteristics are similar to conventional CS. Mesenchymal CS is a totally different pathological entity exhibiting recurrent translocations. Their clinical presentation and management are different too. The standard treatment of CSs is wide en-bloc resection. CS are relatively radiotherapy resistant; therefore, doses >60 Gy are needed in an attempt to achieve local control in unresectable tumors. Chemotherapy is possibly effective in mesenchymal chondrosarcoma and is of uncertain value in dedifferentiated chondrosarcoma. Due to resistance to standard anticancer agents, the prognosis is poor in patients with metastatic or unresectable chondrosarcomas. Recently, the refined characterization of the molecular profile, as well as the development of new treatments, allow new therapeutic options for these rare tumors. The efficiency of IDH1 inhibitors in other malignancies suggests that these inhibitors will be part of IDH1/2 mutated conventional CS management soon. Other treatment approaches, such as PIK3-AKT-mTOR inhibitors, cell cycle inhibitors, and epigenetic or immune modulators based on improving our understanding of CS molecular biology, are emerging.

Conventional Chondrosarcoma with Clear Cell Features in the Rib: Report of Two Cases and Review of the Literature.

A subset of clear cell chondrosarcomas may contain focal areas of low-grade conventional chondrosarcoma; however, it is rare to find foci resembling clear cell chondrosarcoma admixed with areas otherwise typical conventional chondrosarcoma. We report two patients with conventional chondrosarcoma with clear cell features occurring in the rib, one in the setting of multiple hereditary exostoses (MHE) and the other without MHE. Both patients were found to have a destructive rib mass with a soft tissue component and underwent en bloc resection. Histologic examination revealed predominantly grade 2 conventional chondrosarcomas; however, multiple foci containing large cells with pale eosinophilic to clear cytoplasm, distinct cell borders, centrally located nuclei, and conspicuous nucleoli, resembling clear cell chondrosarcoma were identified throughout the specimen. The significance of clear cell features in an otherwise typical conventional chondrosarcoma, to our knowledge, is unknown and deserves recognition. Finally, these tumors highlight the need for careful histologic examination and proper classification as unexpected findings may impact management.

Extraskeletal myxoid chondrosarcoma: A study of 17 cases focusing on the diagnostic utility of INSM1 expression and presenting rare morphological variants associated with non-EWSR1::NR4A3 fusions.

Extraskeletal myxoid chondrosarcoma (EMC) is a rare sarcoma of uncertain lineage. Insulinoma-associated protein 1 (INSM1) has recently been described as a highly specific and sensitive immunohistochemical marker for EMC. The goal of this study was to evaluate the diagnostic significance of INSM1 immunohistochemistry in EMC. Furthermore, correlations between molecular and morphological findings were performed. Sixteen of 17 EMC cases were stained with the INSM1 antibody. Tumors with at least 5% INSM1-positive cells and any staining intensity were considered positive. Molecular testing was successfully performed in 12/17 cases. The immunohistochemical analysis detected 13 INSM1-positive (81%) and 3 INSM1-negative tumors (19%). The extent of the staining was classified as 1+ in 7 cases (44%), 2+ in 2 cases (13%), 3+ in 2 cases (13%) and 4+ in 2 cases (13%). Intensity of immunostaining was weak in 5 cases (31%), moderate in 2 cases (13%) and strong in 6 cases (38%). Molecular assays revealed 8 EWSR1::NR4A3 positive tumors (67%), 2 TAF15::NR4A3 positive tumors (17%), 1 TCF12::NR4A3 positive tumor (8%) and 1 NR4A3 positive tumor (8%) in which no other gene alteration was identified. Two of them, namely TCF12 positive and one TAF15 positive tumors, were highly cellular and partially associated with pseudopapillary architecture. Our study found that moderate/strong expression of INSM1 in more than 25% of tumor cells was present in only 31% of cases. Thus, the diagnostic utility of INSM1 is rather low. Two morphologically unique cases of non-EWSR1 rearranged EMC with an extremely rare pseudopapillary growth pattern are also reported.