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.

Distal radius chondrosarcoma in a 35-year-old female patient: A case report.

Key Clinical Message: Chondrosarcoma, although rare in the distal radius, poses significant challenges. Early diagnosis through incisional biopsy is essential. Surgical resection with margin control and fibular grafting can be effective, but vigilant surveillance is crucial due to its aggressive nature. Metastasis demands consideration of additional interventions or palliative care. Abstract: Chondrosarcomas constitute a rarity in the upper limbs, and their occurrence in the distal radius is even rarer with only one case previously documented. We report a case of distal radius chondrosarcoma in a 35-year-old female patient who presented with pain and swelling in her left wrist. Following an initial examination, an incisional biopsy was performed, confirming the diagnosis of dedifferentiated chondrosarcoma. The patient underwent a marginal resection of the distal radius and first carpal with ipsilateral fibular and locking compression plate fixation. Unfortunately, despite the interventions, the patient experienced recurrent swelling and ultimately required below-elbow amputation, followed by above elbow amputation due to metastasis. Unfortunately, the patient passed away due to recurrence and metastasis.

Dedifferentiated Chondrosarcoma: Diagnostic Controversies and Emerging Therapeutic Targets.

PURPOSE OF REVIEW: The pathogenesis of dedifferentiated chondrosarcoma is controversial, and no genetic abnormality has consistently been identified in the disease. Focusing on the diagnostic challenges encountered in dedifferentiated chondrosarcoma, the following review aims at summarizing the tumor's active neoplastic pathways while highlighting therapeutic modalities that could potentially be explored to enhance patient survivorship. RECENT FINDINGS: Owing to the challenging examination of small needle biopsy sampling as well as the disease's overlapping morphological and immunohistochemical features with other bone and soft-tissue sarcomas, the diagnosis of dedifferentiated chondrosarcoma can be problematic. While combined doxorubicin- and cisplatin-based regimens remain the first-line systemic chemotherapy in the disease, ~50% of tumors carry EXT1/2 or IDH1/2 mutations, advancing EXT or IDH inhibitors as potential alternative therapies, respectively. Despite systemic chemotherapy, dedifferentiated chondrosarcoma remains an aggressive tumor with dismal prognosis and limited survival. A multidisciplinary collaboration across multiple cancer centers is warranted to yield an accurate diagnosis, understand the disease's underlying pathogenesis, develop adequate treatment, and improve patient survivorship.

Establishment and characterization of a novel dedifferentiated chondrosarcoma cell line, SMU-DDCS, harboring an IDH1 mutation.

Dedifferentiated chondrosarcoma (DDCS) is a high-grade subtype with a bi-morphic histological appearance of a conventional chondrosarcoma component and it can abruptly transition to a high-grade non-cartilaginous sarcoma. To better understand the biological features of DDCSs and to help develop new therapies, a novel DDCS cell line, SMU-DDCS, was established. Tissue from an open biopsy of a tumor resected from a 75-year-old patient was subjected to primary culture. The cell line was established and authenticated by assessing DNA microsatellite short tandem repeats. The cells maintained in monolayer cultures exhibited constant growth, spheroid formation, and high invasive capacity. Out of the four mice inoculated with SMU-DDCS cells, tumors developed in three mice after 2 weeks. R132C mutation was found in the IDH1 but not the IDH2 genomic DNA sequence of SMU-DDCS cells. SMU-DDCS cells exhibited low chemosensitivity to doxorubicin, methotrexate, and cisplatin. This SMU-DDCS cell line harboring an IDH1 mutation will be a useful tool for investigating DDCS development and for evaluating novel therapeutic agents against it.

A Retrospective Multi-Institutional Cohort Analysis of Clinical Characteristics and Outcomes in Dedifferentiated Chondrosarcoma.

BACKGROUND: Dedifferentiated chondrosarcoma (DDCS) is a rare subset of chondrosarcoma. It is an aggressive neoplasm characterized by a high rate of recurrent and metastatic disease with overall poor outcomes. Systemic therapy is often used to treat DDCS; however, the optimal regimen and timing are not well defined, with current guidelines recommending following osteosarcoma protocols. METHODS: We conducted a multi-institutional retrospective analysis of clinical characteristics and outcomes of patients with DDCS. Between 1 January 2004 and 1 January 2022, the databases from five academic sarcoma centers were reviewed. Patient and tumor factors, including age, sex, tumor size, site, location, the treatments rendered, and survival outcomes, were collected. RESULTS: Seventy-four patients were identified and included in the analysis. Most patients presented with localized disease. Surgical resection was the mainstay of therapy. Chemotherapy was used predominantly in the metastatic setting. Partial responses were low (n = 4; 9%) and occurred upon treatment with doxorubicin with cisplatin or ifosfamide and single-agent pembrolizumab. For all other regimens, stable disease was the best response. Prolonged stable disease occurred with the use of pazopanib and immune checkpoint inhibitors. CONCLUSIONS: DDCS has poor outcomes and conventional chemotherapy has limited benefit. Future studies should focus on defining the possible role of molecularly targeted therapies and immunotherapy in the treatment of DDCS.

Primary dedifferentiated chondrosarcoma of the lung with a 4-year history of breast cancer: A case report.

BACKGROUND: Primary dedifferentiated chondrosarcoma (DDCS) of the lung is extremely rare and has a poor prognosis, especially in patients with a history of carcinomas and related treatment. Herein, we report a case of primary DDCS of the lung in a patient with a 4-year history of breast cancer and related treatment. CASE SUMMARY: A 49-year-old woman was admitted to our hospital with complaints of headache, dizziness, slurred speech, and dyskinesia in May 2021. Computed tomography (CT) examinations showed multiple nodules in the brain, vertebral body, and both lungs with multiple enlarged lymph nodes in the right hilum and mediastinum, which were considered metastases of breast cancer. No obvious mass was discovered in the right hilum. After several months of related administration, the patient's headache disappeared, and her condition improved. However, new problems of asthma, dyspnea, cough, and restricted activity appeared in late November 2021. Although the CT scan indicated that the lesions in the brain, lung, and vertebral body had shrunk or disappeared, a soft tissue density lesion appeared in her right hilum and blocked the bronchial lumen. To relieve her dyspnea, part of the mass was resected, and a stent was placed via fiberoptic bronchoscopy. Following a complete pathological examination of the tumor, it was confirmed to be a primary DDCS of the lung. The patient then received two rounds of systemic chemotherapy with a regimen of cisplatin + ifosfamide + doxorubicin hydrochloride liposome, palliative radiotherapy for the tumor in her right lung, and four cycles of systemic chemotherapy and targeted therapy with a regimen of temozolomide combined with bevacizumab successively. She was in stable condition after the completion of the systemic chemotherapy and targeted therapy but underwent rapid progression after lung radiotherapy. The CT examinations showed multiple nodules in the brain and in both lungs, and the tumor in the right hilum was increased in size. CONCLUSION: This case revealed a rare primary DDCS of the lung with a medical history of breast cancer, meaning a worse prognosis and making it more difficult to treat.

Comparative analysis of miRNA expression in dedifferentiated and well-differentiated components of dedifferentiated chondrosarcoma.

Dedifferentiated chondrosarcoma (DDCS) is a rare malignant cartilage tumor arising out of a low-grade chondrosarcoma, whereby the well-differentiated and the dedifferentiated components coexist in the same localization. DDCS has a massively increased metastatic potential in comparison to low-grade chondrosarcoma. So far, the underlying mechanisms of DDCS development and the increased malignancy are widely unknown. Targeted DNA sequencing revealed no genetic differences between both tissue components. Besides genetic events, alterations in epigenetic control may play a role in DDCS development. In this preliminary study, we have analyzed the differential miRNA expression in paired samples of both components of four primary DDCS cases and a rare lung metastasis with both components using the nCounter MAX analysis system from NanoString technologies. We identified 21 upregulated and two downregulated miRNAs in the dedifferentiated components of the primary cases. Moreover, three miRNAs were also significantly deregulated in the dedifferentiated component of the lung metastasis, supporting their possible role in DDCS development. Additionally, validated targets of the 23 deregulated miRNAs are involved in signaling pathways, like PI3K/Akt, Wnt/ß-catenin, and TGF-ß, as well as in cellular processes, like cell cycle regulation, apoptosis, and dedifferentiation. Further investigations are necessary to confirm and understand the role of the identified miRNAs in DDCS development.

Prognostic Significance of Percentage and Size of Dedifferentiation in Dedifferentiated Chondrosarcoma.

Dedifferentiated chondrosarcoma is rare, aggressive, and microscopically bimorphic. How pathologic features such as the amounts of dedifferentiation affect prognosis remains unclear. We evaluated the percentages and sizes of dedifferentiation in a consecutive institutional series of dedifferentiated chondrosarcomas from 1999 to 2021. The statistical analysis included cox proportional hazard models and log-rank tests. Of the 67 patients (26 women, 41 men; age, 39 to >89 [median 61] years; 2 with Ollier disease), 58 presented de novo; 9 were identified with conventional chondrosarcomas 0.6-13.2 years (median, 5.5 years) prior. Pathologic fracture and distant metastases were noted in 27 and 7 patients at presentation. The tumors involved the femur (n = 27), pelvis (n = 22), humerus (n = 7), tibia (n = 4), scapula/ribs (n = 4), spine (n = 2), and clivus (n = 1). In the 56 resections, the tumors ranged in size from 3.5 to 46.0 cm (median, 11.5 cm) and contained 1%-99.5% (median, 70%) dedifferentiated components that ranged in size from 0.6 to 24.0 cm (median, 7.3 cm). No correlation was noted between total size and percentage of dedifferentiation. The dedifferentiated components were typically fibrosarcomatous or osteosarcomatous, whereas the associated cartilaginous components were predominantly grade 1-2, rarely enchondromas or grade 3. The entire cohort's median overall survival and progression-free survival were 11.8 and 5.4 months, respectively. In the resected cohort, although the total size was not prognostic, the percentage of dedifferentiation ≥20% and size of dedifferentiation >3.0 cm each predicted worse overall survival (9.9 vs 72.5 months; HR, 3.76; 95% CI, 1.27-11.14; P = .02; 8.7 vs 58.9 months; HR, 3.03; 95% CI, 1.21-7.57; P = .02, respectively) and progression-free survival (5.3 vs 62.1 months; HR, 3.05; 95% CI, 1.13-8.28; P = .03; 5.3 vs 56.6 months; HR, 2.50; 95% CI, 1.06-5.88; P = .04, respectively). In conclusion, both the percentages and sizes of dedifferentiation were better prognostic predictors than total tumor sizes in dedifferentiated chondrosarcomas, highlighting the utility of their pathologic evaluations.

Case report: Treatment of metastatic dedifferentiated chondrosarcoma with pembrolizumab yields sustained complete response.

Dedifferentiated chondrosarcomas (DDCS) are aggressive tumors with poor outcomes. Treatment of localized DDCS is primarily surgical, though most patients present with unresectable or metastatic disease. Systemic treatment options for advanced DDCS are limited, and the benefits of chemotherapy in this patient population remain controversial. Among other systemic therapy options, there is emerging clinical evidence to support the use of immunotherapy in patients with advanced DDCS. However, studies regarding the efficacy of immunotherapy in advanced DDCS are limited. Here, we present the case of a patient with metastatic, programmed death-ligand 1 (PD-L1)-positive DDCS treated with pembrolizumab who showed a sustained complete response for 24 months after initiation of therapy. To our knowledge, this case represents one of few documented cases of metastatic chondrosarcoma with sustained response to immunotherapy. The impressive response seen with PD-L1 inhibition in our patient indicates that immunotherapy is a successful treatment option in a subset of DDCS patients, and further investigation is needed to identify potential responders to immunotherapy.

A Case Report and Brief Literature Review on Dedifferentiated Chondrosarcoma in Proximal Phalanx: A Rare Location.

Dedifferentiated chondrosarcoma (DDCS) is a rare entity, constituting only 1-2% of all primary bone tumors, and has a dismal prognosis. Nearly two-thirds of the primary tumors of DDCSs are found in the appendicular skeleton, mostly involving the femur, humerus, and pelvis. DDCS of the small bones of the hand and foot are exceedingly rare with only four cases documented in the literature so far. In this report, we present a case of a 91-year-old woman with a rapidly growing bone tumor initially thought to be a trigger finger, which, on histologic examination of the amputation, turned out to be DDCS. On a follow-up CT scan, multiple pulmonary metastases were identified. Next-generation sequencing identified isocitrate dehydrogenase 2 (IDH2) (p.R172S, c.516G>T), TERT (c.-146C>T), and TP53 (c.559+1G>A) mutations. Microsatellite instability was equivocal and tumor mutation burden was low. Due to the advanced age of the patient, she was given palliative treatment and was alive at the six-month follow-up.

Appendicular dedifferentiated chondrosarcoma: A management and survival study from the SEER database.

Introduction: Dedifferentiated chondrosarcoma (DDC) is an aggressive osseous neoplasm with a dismal prognosis. Treatment commonly involves limb-salvage surgery or amputation. In patients with appendicular DDC, we sought to describe demographic, clinical and treatment characteristics (1), analyze risk factors for metastasis (2) and overall death (3), and assess survival rates by treatment (4). Materials and methods: Two-hundred-and-five patients from the SEER Database were included in our analysis. Demographic, clinical and treatment variables were analyzed. Multivariate regression was performed to identify risk factors. Survival analysis was performed using the Kaplan-Meier method. Results: Fifty-one (24.9 %) of the patients included presented metastasis at diagnosis. The most common locations were the lungs, other sites, and bone. Surgery to the primary site was more common in patients without metastasis (94.2 %) than those with (78.2 %); limb-salvage procedures were more common than amputations. Tumors >8 cm (T2) and those discontinuous (T3) were more likely to present metastasis at diagnosis (OR = 2.54, p = 0.043 and OR = 7.4, p = 0.008, respectively). Female gender was found to be a protective factor for overall death on crude analysis (OR = 0.33, p = 0.019). Metastases to sites other than the lungs (M1b) had the highest risk of overall death (OR = 49, p = 0.01). Combination of surgery and chemotherapy showed a trend towards higher overall survival in non-metastatic patients (p = 0.1069 and p = 0.1703). Conclusions: Appendicular DDC displays a high metastatic rate and low survival rates. The most common procedure is a limb-salvage surgery. Tumor size increases the risk of presenting metastases at diagnosis and female gender is a protective factor against death.

Chondroitin sulfate proteoglycan 4 expression in chondrosarcoma: A potential target for antibody-based immunotherapy.

Chondrosarcoma is a common primary bone malignancy whose phenotype increases with its histologic grade. They are relatively resistant to chemotherapy and radiation therapy limiting curative options for disseminated disease. Chondroitin sulfate proteoglycan 4 (CSPG4) is a cell surface proteoglycan that is highly expressed across various human cancers, including chondrosarcoma, and has restricted distribution in healthy tissues, making it an attractive target for the antibody-based therapy. CSPG4 specific chimeric antigen receptor (CAR) T cell therapies have been shown to be effective in treating other cancers such as melanoma and triple negative breast cancer. The goal of this study was to assess the prevalence of CSPG4 in human chondrosarcoma and to assess the efficacy of CSPG4 specific CAR T cells in lysing chondrosarcoma cells in vitro. Using immunohistochemistry (IHC), we stained a tissue microarray containing primary conventional and dedifferentiated chondrosarcoma from 76 patients with CSPG4 specific monoclonal antibodies (mAbs). In addition, we incubated 2 chondrosarcoma cell lines with CSPG4-targeting CAR T cells and subsequently evaluated cell survival. Our results showed medium to high expression of CSPG4 in 29 of 41 (71%) conventional chondrosarcoma tumors and in 3 of 20 (15%) dedifferentiated chondrosarcoma tumors. CSPG4 expression showed a positive association with time to metastasis and survival in both subtypes. CSPG4 CAR T treated cell lines showed a lysis of respectively >80% and 70% demonstrating CSPG4-targeted CAR T cells effective in killing CSPG4-positive chondrosarcoma tumors.

Dedifferentiated chondrosarcoma of the ring finger: a case report of an exceptional surgical treatment and review of literature.

The DDCS is a rare, highly malignant tumor characterized by two distinct histopathologic components. The diagnosis is insidious, and the prognosis is poor. The therapy is primarily surgical. It is possible to associate chemotherapy if the nonchondrogenic component is a responder. Unfortunately, very few cases of DDCS of the hand are described in the literature. Therefore, few scientific comparisons are possible regarding diagnosis and therapy. For this reason, we decided to present a sporadic case of DDCS of the fourth finger of the left hand, presented with a seven months history of pain and swelling, which appeared after the treatment of recurrent enchondroma and was treated with amputation and complex reconstruction. To our knowledge, no similar cases have been previously reported in the literature.

Dedifferentiated chondrosarcoma of the middle finger arising from a solitary enchondroma: A case report.

BACKGROUND: Dedifferentiated chondrosarcoma (DDCS) accounts for 10% of all chondrosarcomas and has the poorest outcome, with a 5-year survival rate of 7%-25%. DDCS commonly occurs in the femur and pelvis, whereas DDCS of the finger is extremely rare. Furthermore, the histological findings of preexisting solitary enchondroma samples are important and valuable for diagnosing malignant transformations. CASE SUMMARY: We report our experience with DDCS in the proximal phalanx of the left middle finger of an 87-year-old woman. She had undergone surgery for enchondroma, with curettage and artificial bone grafting, 11 years ago, in the same location. Several years after the primary surgery, the left middle finger gradually started to enlarge, and the growth speed increased in the past year. Plain radiographs showed an expansive osteolytic lesion with calcifications and residual grafting material. Owing to the suspicion of malignancy, we performed ray amputation. Histological findings revealed an abrupt transition between the low-grade chondrosarcoma and dedifferentiated sarcoma components. The dedifferentiated components showed the features of a high-grade undifferentiated pleomorphic sarcoma. The patient was diagnosed with DDCS arising from a preexisting enchondroma. She had no local recurrence or distant metastasis and died of pneumonia 6 years and 10 months after the second surgery. CONCLUSION: The histological findings of a precursor lesion showed a typical enchondroma, suggesting that DDCS can arise from enchondroma.

Dedifferentiated Chondrosarcoma: A Case Series and Review of the Literature.

Background: Dedifferentiated chondrosarcoma (DCS) is a rare and aggressive malignancy with a poor prognosis. The purpose of this investigation was to describe our treatment and outcomes of 16 DCS patients at our institution and provide a review of the current literature. Methods: This study was a retrospective review over a consecutive twenty-year period. Data including treatment details and outcomes were recorded. Results: A total of 16 cases from 2000 to 2018 were identified. The median age (IQR) was 62 years (52; 69) and the majority of DCS arose in the femur (50%, n=8) and pelvis (25%, n=4). Fourteen (88%) cases underwent limb salvage/wide margin resection (n=13) or intralesional surgery (n=1). For all DCS, the median survival (IQR) was 46 months (12; 140), with both a five and ten-year probability of 32.1% (95% CI, 7.3% to 57.0%). At study conclusion, 81.3% (n=13) were deceased and 18.7% (n=3) were alive. Conclusions: Our findings confirm the poor prognosis of DCS patients, with a five-year estimate of 32%. Together with existing literature, our data might help enable future strategic recommendation of these patients.

Clinical features and treatment outcomes of dedifferentiated and grade 3 chondrosarcoma: A multi-institutional study.

Chondrosarcoma is the second most common primary malignant bone tumor. In this multicenter study, we sought to evaluate the disease-specific survival (DSS) and disease-free survival (DFS), and prognostic factors in patients with dedifferentiated chondrosarcoma (DDCS) or grade 3 chondrosarcoma (G3CS) in Japan. We retrospectively investigated the treatment outcomes and prognostic factors in 62 patients with DDCS and 19 patients with G3CS at 15 institutions participating in the Japanese Musculoskeletal Oncology Group. We also clarified significant clinicopathological factors for oncological outcomes. In surgery for primary lesions aimed at cure, a histologically negative margin (R0) was obtained in 93% (14/15) of patients with G3CS and 100% (49/49) of patients with DDCS. The 5-year DSS was 18.5% in patients with DDCS and 41.7% in patients with G3CS (p = 0.13). Local control was obtained in 80% (12/15) and 79.6% (39/49) of patients with G3CS and DDCS in the primary lesion after surgery with a wide surgical margin, respectively. In multivariate analysis, stage and no treatment/palliative treatment for the primary lesion were independent prognostic factors for DSS of DDCS, and age and no treatment/palliative treatment for DSS of G3CS. The 5-year DFS rate was 22.8% in 26 patients with DDCS who did not receive adjuvant chemotherapy, and 21.4% in 14 patients who received adjuvant chemotherapy. The prognosis of DDCS remains poor, although R0 resection was carried out in most cases. Effective and/or intensive chemotherapeutic regimens or agents should be considered or developed for patients with high-grade chondrosarcoma, particularly for those with DDCS.

Peripheral and periosteal chondrosarcoma: MRI-pathological correlation in 58 cases.

OBJECTIVE: To determine whether MRI can distinguish atypical cartilaginous tumour/grade 1 peripheral/periosteal chondrosarcoma (ACT/Gd1 PP-CS) from high-grade peripheral/periosteal chondrosarcoma (HG-PP-CS) or dedifferentiated peripheral/periosteal chondrosarcoma (DD-PP-CS). MATERIALS AND METHODS: Retrospective review of patients diagnosed between January 2007 and December 2020 who had undergone resection of PP-CS. Data collected included age, sex, and skeletal location. Histological tumour grades based on surgical resection were classified as ACT/grade 1 PP-CS, HG-PP-CS, or DD-PP-CS. A variety of MRI features were reviewed independently by 2 musculoskeletal radiologists blinded to final diagnosis and compared between the 3 groups. For statistical analysis, HG-PP-CS and DD-PP-CS were combined. RESULTS: Fifty-eight patients fulfilled the inclusion criteria, 31 (53%) males and 27 (47%) females with a mean age at diagnosis of 46.1 years (range 11-83 years), 14 (24%) of whom had an underlying diagnosis of diaphyseal aclasis. Forty-one (70.7%) cases were peripheral and 17 (29.3%) periosteal, 38 (66%) involving the flat bones, 15 (26%) the major long bones, 3 (5%) the spine, and 2 (3%) the bones of the hands and feet. Final histology revealed 33 (57%) ACT/Gd1-PP-CS, 18 (31%) HG-PP-CS, and 7 (12%) DD-PP-CS. Periosteal tumours were 16 times more likely to be HG/DD-CS compared to peripheral tumours (p < 0.001). Intra-medullary tumour extension was predictive of HG/DD-CS (p = 0.004) for both tumour types, while cap thickness (p = 0.04) and a diffuse cap type (p = 0.03) were differentiating features of low-grade and high-grade peripheral CS. DISCUSSION: A variety of features can help differentiate low-grade from high-grade peripheral/periosteal CS, the most significant being origin from the bone surface.

Dedifferentiated chondrosarcoma: current standards of care.

Dedifferentiated chondrosarcomas are aggressive variants of chondrosarcoma, associated with poor outcomes. Tumor biphasism is the norm. The majority of these tumors are symptomatic at presentation. Radiologically, large soft tissue masses with bony destruction predominate. Treatment protocols of these tumors are not well defined. Surgical resection forms the standard of care for localized disease. (Neo)adjuvant therapies remain controversial as the results from multiple (mainly retrospective) studies remain conflicting. Age at presentation, stage and ability to obtain negative resection margins are important prognostic factors. The overall prognosis is dismal. Newer and novel therapies targeting the complex genetic makeup of these tumors have renewed interest in the adjuvant setting that could hold promise in the near future.

Lay abstract Dedifferentiated chondrosarcomas are rare cancers composed of two components: a high-grade component and a low-grade component, with one abruptly blending into another. These rare tumors affect middle-aged individuals and present with pain and swelling in the affected site. X-rays and other scans often show tumor within the soft tissue with bony destruction. Although the precise treatment protocol is not well defined, surgery remains the standard of care for those where the tumor has not spread elsewhere. Once the disease spreads to other parts of the body, the outcome is very poor. The role of certain drugs targeting the tumor (chemotherapeutic agents) is controversial. This review briefly describes the genetic basis, treatment modalities involved and newer agents being developed for this lethal cancer.

Establishment and Characterization of a Novel Dedifferentiated Chondrosarcoma Cell Line DDCS2.

BACKGROUND: The dedifferentiated variant of chondrosarcoma is highly aggressive and carries an especially grim prognosis. While chemotherapeutics has failed to benefit patients with dedifferentiated chondrosarcoma significantly, preclinical chemosensitivity studies have been limited by a scarcity of available cell lines. There is, therefore, an urgent need to expand the pool of available cell lines. METHODS: We report the establishment of a novel dedifferentiated chondrosarcoma cell line DDCS2, which we isolated from the primary tumor specimen of a 60-year-old male patient. We characterized its short tandem repeat (STR) DNA profile, growth potential, antigenic markers, chemosensitivity, and oncogenic spheroid and colony-forming capacity. RESULTS: DDCS2 showed a spindle to polygonal shape and an approximate 60-hour doubling time. STR DNA profiling revealed a unique genomic identity not matching any existing cancer cell lines within the ATCC, JCRB, or DSMZ databases. There was no detectable contamination with another cell type. Western blot and immunofluorescence assays were consistent with a mesenchymal origin, and our MTT assay revealed relative resistance to conventional chemotherapeutics, which is typical of a dedifferentiated chondrosarcoma. Under ex vivo three-dimensional (3D) culture conditions, the DDCS2 cells produced spheroid patterns similar to the well-established CS-1 and SW1353 chondrosarcoma cell lines. CONCLUSION: Our findings confirm DDCS2 is a novel model for dedifferentiated chondrosarcoma and therefore adds to the limited pool of current cell lines urgently needed to investigate the chemoresistance within this deadly cancer.

Differential expression of angiogenesis markers HSP70, HSP90, VEGF and pERK1/2 in both components of dedifferentiated chondrosarcomas.

Dedifferentiated chondrosarcomas (DDCS) are highly malignant bimorphic mesenchymal tumors with poor outcome and limited treatment options. Genes and proteins involved in angiogenesis play an important role in the development of invasion and metastasis. Immunohistochemical stains targeting HSP70, pERK1/2 and VEGFA were applied to a TMA containing 29 DDCS cases representing both tumor components. Higher expression of HSP70 and pERK1/2 was noted in the dedifferentiated component. RNA sequencing performed in 8 paired cases of DDCS comparing well differentiated and dedifferentiated components, showed higher expression of several HSP70 family members and HSP90 in the dedifferentiated component. Furthermore, high mobility group AT-hook 2 (HMAG2) and SET nuclear proto-oncogene demonstrated higher expression in the dedifferentiated component. Thus, the well differentiated and dedifferentiated components of DDCS are different, histologically and transcriptomically. The dedifferentiated component of DDCS shows higher expression of markers that are associated with malignant behavior. Some of these may represent future treatment targets.