Proton and carbon ion beam treatment with active raster scanning method in 147 patients with skull base chordoma at the Heidelberg Ion Beam Therapy Center-a single-center experience.

BACKGROUND: This study aimed to compare the results of irradiation with protons versus irradiation with carbon ions in a raster scan technique in patients with skull base chordomas and to identify risk factors that may compromise treatment results. METHODS: A total of 147 patients (85 men, 62 women) were irradiated with carbon ions (111 patients) or protons (36 patients) with a median dose of 66 Gy (RBE (Relative biological effectiveness); carbon ions) in 4 weeks or 74 Gy (RBE; protons) in 7 weeks at the Heidelberg Ion Beam Therapy Center (HIT) in Heidelberg, Germany. The median follow-up time was 49.3 months. All patients had gross residual disease at the beginning of RT. Compression of the brainstem was present in 38%, contact without compression in 18%, and no contact but less than 3 mm distance in 16%. Local control and overall survival were evaluated using the Kaplan-Meier Method based on scheduled treatment (protons vs. carbon ions) and compared via the log rank test. Subgroup analyses were performed to identify possible prognostic factors. RESULTS: During the follow-up, 41 patients (27.9%) developed a local recurrence. The median follow-up time was 49.3 months (95% CI: 40.8-53.8; reverse Kaplan-Meier median follow-up time 56.3 months, 95% CI: 51.9-60.7). No significant differences between protons and carbon ions were observed regarding LC, OS, or overall toxicity. The 1­year, 3­year, and 5­year LC rates were 97%, 80%, and 61% (protons) and 96%, 80%, and 65% (carbon ions), respectively. The corresponding OS rates were 100%, 92%, and 92% (protons) and 99%, 91%, and 83% (carbon ions). No significant prognostic factors for LC or OS could be determined regarding the whole cohort; however, a significantly improved LC could be observed if the tumor was > 3 mm distant from the brainstem in patients presenting in a primary situation. CONCLUSION: Outcomes of proton and carbon ion treatment of skull base chordomas seem similar regarding tumor control, survival, and toxicity. Close proximity to the brainstem might be a negative prognostic factor, at least in patients presenting in a primary situation.

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.

The Extracompartmental Tumoral Invasion of Extraskeletal Myxoid Chondrosarcoma Induces Distant Metastasis.

BACKGROUND: Extraskeletal myxoid chondrosarcoma (EMC) is a rare malignant soft-tissue tumor and often shows extracompartmental tumoral invasion. The aim of our study was to investigate the clinical features, especially extracompartmental tumoral invasion (ETI) of EMC. PATIENTS AND METHODS: A total of 35 operative patients diagnosed with EMC were enrolled in this study from January 1980 to March 2018 in the Cancer Institute Hospital of The Japanese Foundation for Cancer Research. The operative procedure was principally wide excision. Univariate analysis assessed how clinicopathological factors (e.g. age, gender, tumor site, tumor size, histopathological grade, surgical margin, metastasis before operation, barrier invasion, local recurrence, metastasis after operation) influenced patient prognosis. We assessed how clinicopathological factors influenced ETI of EMC. RESULTS: Among 35 patients, 10 patients showed ETI. The average follow-up was 5.57 (range=0.2-20 years). The 5- and 10-year overall survival was 91.3% and 71.2%, respectively. The 5- and 10-year overall survival of patients with M0 disease was 96.1% and 73.2%, respectively, while both were 75.0% for those with M1 disease, respectively. The patients with distant metastasis at first visit tended to have a poor prognosis (p=0.07). It is notable that all of the 10 patients with ETI had distant metastasis after surgery. CONCLUSION: Patients with distant metastasis at first visit tended to have a poor prognosis. ETI of EMC induced distant metastasis after surgery. Patients with ETI of EMC should, therefore, be carefully monitored over a prolonged period.

Surgical Management of Multifocal Chondrosarcoma in Ollier Disease.

Ollier disease is a rare congenital disease in which multiple enchondromas occur. The tumors can transform to malignant chondrosarcomas of various histologic grades. The patient we described has been treated in our orthopedic department six times, always being referred on account of new lesions. The tumors were excised with margins of healthy tissue. Each tumor was subjected to a histological examination to determine its type and grade. Chondroid tumors should be diagnosed carefully, because the treatment depends on their histologic features. If surgery is performed, removal of the tumor with a margin of healthy tissue is crucial for the patient's well-being and good prognosis.

A molecular study of synovial chondromatosis.

Synovial chondromatosis (SC) is a rare benign cartilaginous neoplasm in which recurrent fibronectin 1 (FN1) and activin receptor 2A (ACVR2A) gene rearrangements have been recently reported. Triggered by a case of malignant transformation in SC (synovial chondrosarcoma) showing a novel KMT2A-BCOR gene fusion by targeted RNA sequencing, we sought to evaluate the molecular abnormalities in a cohort of 27 SC cases using a combined methodology of fluorescence in situ hybridization (FISH) and/or targeted RNA sequencing. Results showed that FN1 and /or ACVR2A gene rearrangements were noted in 18 cases (67%), with an FN1-ACVR2A fusion being confirmed in 15 (56%) cases. Two cases showed only FN1 gene rearrangement, without other abnormalities. A novel FN1-NFATc2 gene fusion was noted in one case by RNA sequencing. The remaining nine cases showed no abnormalities in FN1 and ACVR2A genes. No additional cases showed BCOR gene alterations. In conclusion, this study confirms that FN1-ACVR2A fusion is the leading pathogenetic event in SC, at even higher frequency than previously reported. FISH methodology emerges as an appropriate tool in the identification of FN1 and ACVR2A gene abnormalities, which can be used in challenging cases. Further studies are needed to determine the recurrent potential of BCOR abnormalities in this disease.

Chondrosarcoma as inaugural manifestation of monostotic Paget's disease of Bone.

Sarcomatous degeneration is one of the serious and rare complications of Paget's disease of bone. Osteosarcoma is the most common secondary tumour, while other variants such as chondrosarcoma are extremely uncommon. We describe a unique case of Paget's chondrosarcoma of the pelvis in an elderly female patient, with no previous established diagnosis of osteitis deformans. We emphasize clinical and radiologic aspects that should raise suspicion of malignant transformation, revealing good correlation with the final histopathological diagnosis.

Skull Base Chondrosarcoma Caused by Ollier Disease: A Case Report and Literature Review.

BACKGROUND: Ollier disease (OD) is a rare, nonhereditary bone disease that is characterized by the presence of multiple enchondromatosis (3 or more) with a typical asymmetric distribution which is mainly confined to the appendicular skeleton. OD's most serious complication is the transformation of an enchondroma into chondrosarcoma. The most common sites for chondrosarcoma are in the pelvic and shoulder bones, the superior metaphyseal and diaphyseal regions of the extremities. However, the cranium is an extremely rare site for chondrosarcoma because of OD. CASE DESCRIPTION: We report the case of a 27-year-old woman who was admitted to our hospital with paroxysmal headaches over 1 month and left ptosis for 2 weeks. Magnetic resonance imaging (MRI) scan revealed a mass was located at the left side of the parasellar area. The mass was surgically removed, and histopathologic examination confirmed chondrosarcoma grade I. During follow-up, more imaging examinations and pathologic examination confirmed the final diagnosis was OD. CONCLUSIONS: Intracranial chondrosarcoma caused by OD is extremely rare but should be considered in the differential diagnosis when primary chondrosarcoma is diagnosed. Preoperative diagnosis is challenging, and definitive diagnosis requires immunohistochemical examination and systematic examination of the body. Surgical resection is the most effective therapy for rapid relief of symptoms. For patients with OD with normal intracranial MRI, long-term follow-up is necessary.

Tumor Formation of Adult Stem Cell Transplants in Rodent Arthritic Joints.

PURPOSE: While imaging matrix-associated stem cell transplants aimed for cartilage repair in a rodent arthritis model, we noticed that some transplants formed locally destructive tumors. The purpose of this study was to determine the cause for this tumor formation in order to avoid this complication for future transplants. PROCEDURES: Adipose-derived stem cells (ADSC) isolated from subcutaneous adipose tissue were implanted into 24 osteochondral defects of the distal femur in ten athymic rats and two immunocompetent control rats. All transplants underwent serial magnetic resonance imaging (MRI) up to 6 weeks post-transplantation to monitor joint defect repair. Nine transplants showed an increasing size over time that caused local bone destruction (group 1), while 11 transplants in athymic rats (group 2) and 4 transplants in immunocompetent rats did not. We compared the ADSC implant size and growth rate on MR images, macroscopic features, histopathologic features, surface markers, and karyotypes of these presumed neoplastic transplants with non-neoplastic ADSC transplants. RESULTS: Implants in group 1 showed a significantly increased two-dimensional area at week 2 (p = 0.0092), 4 (p = 0.003), and 6 (p = 0.0205) compared to week 0, as determined by MRI. Histopathological correlations confirmed neoplastic features in group 1 with significantly increased size, cellularity, mitoses, and cytological atypia compared to group 2. Six transplants in group 1 were identified as malignant chondrosarcomas and three transplants as fibromyxoid sarcomas. Transplants in group 2 and immunocompetent controls exhibited normal cartilage features. Both groups showed a normal ADSC phenotype; however, neoplastic ADSC demonstrated a mixed population of diploid and tetraploid cells without genetic imbalance. CONCLUSIONS: ADSC transplants can form tumors in vivo. Preventive actions to avoid in vivo tumor formations may include karyotyping of culture-expanded ADSC before transplantation. In addition, serial imaging of ADSC transplants in vivo may enable early detection of abnormally proliferating cell transplants.

Chondrosarcoma: A Rare Misfortune in Aging Human Cartilage? The Role of Stem and Progenitor Cells in Proliferation, Malignant Degeneration and Therapeutic Resistance.

Unlike other malignant bone tumors including osteosarcomas and Ewing sarcomas with a peak incidence in adolescents and young adults, conventional and dedifferentiated chondrosarcomas mainly affect people in the 4th to 7th decade of life. To date, the cell type of chondrosarcoma origin is not clearly defined. However, it seems that mesenchymal stem and progenitor cells (MSPC) in the bone marrow facing a pro-proliferative as well as predominantly chondrogenic differentiation milieu, as is implicated in early stage osteoarthritis (OA) at that age, are the source of chondrosarcoma genesis. But how can MSPC become malignant? Indeed, only one person in 1,000,000 will develop a chondrosarcoma, whereas the incidence of OA is a thousandfold higher. This means a rare coincidence of factors allowing escape from senescence and apoptosis together with induction of angiogenesis and migration is needed to generate a chondrosarcoma. At early stages, chondrosarcomas are still assumed to be an intermediate type of tumor which rarely metastasizes. Unfortunately, advanced stages show a pronounced resistance both against chemo- and radiation-therapy and frequently metastasize. In this review, we elucidate signaling pathways involved in the genesis and therapeutic resistance of chondrosarcomas with a focus on MSPC compared to signaling in articular cartilage (AC).

Chondrosarcoma of the cervical spine.

This case report describes the diagnosis, surgical treatment, and management of a patient with low-grade chondrosarcoma of the cervical spine that initially presented as myositis ossificans. Chondrosarcoma is rare in the cervical spine and in this patient, may have been the result of an injury from a motor vehicle crash. The management of this patient has been unusual in that a complete excision was not performed because the patient refused standard treatment.

Endoscopic Endonasal Approach in Skull Base Chondrosarcoma Associated with Maffucci Syndrome: Case Series and Literature Review.

BACKGROUND: Maffucci syndrome is a nonhereditary disorder in which patients develop multiple enchondromas and cutaneous, visceral, or soft tissue hemangiomas. The potential malignant progression of enchondroma into a secondary chondrosarcoma is a well-known fact. Nevertheless, chondrosarcoma located at the skull base in patients with Maffuci syndrome is a very rare condition, with only 18 cases reported in the literature. CASE DESCRIPTION: We report 2 other cases successfully treated through an expanded endoscopic endonasal approach and discuss the condition based on the literature review. CONCLUSIONS: Skull base chondrosarcoma associated with Maffucci syndrome is a rare condition. The disease cannot be cured, therefore surgical treatment should be performed in symptomatic patients aiming for maximal tumor resection with function preservation. The endoscopic endonasal approach is a safe and reliable alternative for the management of these tumors.

Maffucci Syndrome. An Interesting Case and a Review of the Literature.

Maffucci syndrome, a rare sporadic form of enchondromatosis, is characterized by hemangiomas and multiple enchondromas, benign cartilaginous tumors that arise near growth plates. Previous studies demonstrate that individuals diagnosed with Maffucci syndrome have approximately 100% lifetime risk of malignant transformation. Identification of Maffucci syndrome by surgical excision and pathological diagnosis can be life-saving due to its high malignant potential relative to other subtypes of enchondromatosis such as Ollier's disease. We report a case of a 58-year-old man with enchondromatosis who experienced malignant transformation of the enchondroma in his distal femur into a chondrosarcoma. He underwent a right distal femoral replacement without complications. Two years later, new masses were identified in his left hand and excised following progressive growth, pain, and functional limitation. Pathology confirmed these to be hemangiomas, and he was diagnosed with Maffucci syndrome. At last follow-up, patient reported additional nodular tumor growths occurring unilaterally on the left side. For patients with Maffucci syndrome, continual follow-up and careful surveillance of these masses is crucial as these lesions can cause fractures, deformities, pain, and undergo malignant transformation. Our report reviews the literature and outlines the treatment and management plans for patients with this rare and potentially dangerous disorder.

Odyssey of an elbow synovial chondromatosis.

Synovial chondromatosis of the elbow is an uncommon condition. However, a chondrosarcoma arising from the former is remarkably rare. The authors report a case of an elbow chondrosarcoma secondary to synovial chondromatosis in a 38-year-old woman. Before the development of chondrosarcoma, the patient underwent 3 operations and 3 sessions of radiosynovectomy because of continuous recurrence of synovial chondromatosis on the left elbow. After the last radiosynovectomy, magnetic resonance imaging and biopsy showed a grade II chondrosarcoma secondary to synovial chondromatosis. The patient underwent further surgery and custom-made arthroplasty because of aseptic loosening of the prosthesis. Four months after the last intervention, 3 subcutaneous nodes appeared on the patient's elbow and were histologically found to be a recurrence of chondrosarcoma (grade III). Amputation by disarticulation of the shoulder was performed in addition to biopsy of another subcutaneous node on the abdomen. The biopsy showed metastasis of chondrosarcoma. At final follow-up, the patient had lung metastasis 7 years after the initial diagnosis. A reason for the manifestation of primary synovial chondromatosis and its progression to chondrosarcoma has not been found. Synovial chondromatosis progressing to chondrosarcoma in the elbow was reported in only 1 case, with no clear initial diagnosis. The role of radiosynovectomy in the development of chondrosarcoma is unknown, and no reports have described the treatment of elbow synovial chondromatosis. Although synovial chondromatosis is benign, its metaplastic nature is a marker of possible malignancy, especially with signs of recurrence and aggression. The role of radiosynovectomy in malignant changes should be examined in future studies.

Chondrosarcoma of the nasal cavity in a patient with Maffucci syndrome: case report and review of the literature.

INTRODUCTION: Maffucci syndrome is a rare, congenital, non-hereditary mesodermal dysplasia, manifested by multiple enchondromas and hemangiomas. Malignant transformation of these lesions is seen in up to 40% of the cases. CASE REPORT: We present a case of a patient with Maffucci syndrome and an associated chondrosarcoma of the nose. Treatment consisted of surgical resection. Because of the low grade of the tumor, additional treatment, such as radiotherapy, was not necessary. CONCLUSION: Maffucci syndrome is an exceedingly rare mesodermal dysplasia. Its manifestation in the head and neck region is even less common. Malignant transformation of the associated enchondromas is common, and should be considered whenever a change of the clinical course occurs. Random, periodically performed X-ray examinations give little additional information on malignant transformation and are considered useless.

Radiation-induced dedifferentiated chondrosarcoma with orbital invasion.

PURPOSE: To report 2 interventional cases of dedifferentiated chondrosarcoma with orbital involvement after radiotherapy performed in childhood and to review the literature on chondrosarcoma in the orbit following radiation treatment. METHODS: Retrospective analysis of medical records of 2 patients with chondrosarcoma of the orbits with review of the literature. RESULTS: The first patient developed chondrosarcoma of the orbital and maxillary sinus 36 years after external beam radiation therapy to the OS to treat retinoblastoma. The second patient developed a large orbital chondrosarcoma 35 years after external beam radiation therapy in the treatment of craniofacial fibrous dysplasia. CONCLUSIONS: These cases highlight the risk of secondary chondrosarcoma in patients following radiotherapy and the importance of lifetime monitoring.

High-grade intracranial chondrosarcoma presenting with haemorrhage.

Chondrosarcomas are rare sarcomas that produce malignant cartilage, infrequently arising as a primary intracranial tumour. We present a patient with intracranial chondrosarcoma with intratumoural haemorrhage arising in an unusual location and with unusual imaging findings. A 46-year-old man presented with headache, nausea, and vomiting over the previous 24 hours. Physical and neurological examinations were normal. Cranial CT scans and MRI revealed a large right pre-frontal (subdural) and interhemispheric heterogeneous density associated with a frontal, partially calcified mass and midline shift. An awake craniotomy was performed. With the intra-operative quick section favouring subdural hematoma, the lesion was subtotally resected. Follow-up imaging confirmed residual mass. Pathology examination revealed a high-grade malignant neoplasm with chondroid differentiation, diagnosed as conventional Grade III chondrosarcoma. The patient was referred to oncology for follow-up and radiation therapy. Intracranial chondrosarcoma was first reported in 1899, and since then continues to be an extremely rare malignancy of the brain. These tumours commonly present as extra-axial masses, originating from the skull base, and produce symptoms due to progressive enlargement and compression of local structures. Unusual presentations of these tumours, such as vascularity, intratumoural haemorrhage, and intra-axial location, may complicate pre-surgical decision making by altering the provisional diagnosis prior to intervention. This patient emphasises the importance of careful analysis and incorporation of imaging findings into surgical decision making. Specific imaging characteristics that, in such unusual situations, are suggestive of chondrosarcoma should motivate an aggressive surgical approach to optimise adjuvant interventions.

Chondrosarcoma arising within a radiation-induced osteochondroma several years following childhood total body irradiation: case report.

Malignant degeneration arising in radiation-induced osteochondromas is extremely rare. We report a case of a 34-year-old man with a chondrosarcoma arising from an osteochondroma of the left posterior eighth rib that developed following total body irradiation received as part of the conditioning regimen prior to bone marrow transplantation at age 8. To our knowledge, this is only the fourth reported case of a chondrosarcoma arising within a radiation-induced osteochondroma and the first case occurring following childhood total body irradiation.

Cytogenetic analysis of a low-grade secondary peripheral chondrosarcoma arising in synovial chondromatosis.

Secondary chondrosarcoma is a malignant chondroid tumor arising in a benign precursor. Synovial chondromatosis is a benign chondroid lesion that rarely transforms to chondrosarcoma. We present the case of a 54-year-old male with the diagnosis of low-grade secondary peripheral chondrosarcoma developed in the context of synovial chondromatosis. Cytogenetics revealed a novel aberration t(1;14)(q23.1~24;q24.1~3). Multicolor banding (mBAND) analysis described the chromosomal regions involved in this translocation with a higher detail. Diagnosis of such borderline lesions is very difficult and cytogenetics is helpful in characterizing these tumors.