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.

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: 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.

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.

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.

[Chondrosarcoma in Mafucci's syndrome -- an interdisciplinary approach to a rare disease]. / Chondrosarcoma Mafucci-szindrómában - egy ritka kórkép interdiszciplináris megközelítése.

Mafucci's syndrome is a rare genetic but non-hereditary disorder, characterized by multiple enchondromas (enchondromatosis), hemangiomas and, rarely, lymphangiomas. The risk for malignant transformation of enchondromas is very high, and chondrosarcomas can develop which mainly metastatize to the lungs. A case report of a 61-years-old male, whose enchondromatosis developed at his age of 10 years, is described. The initial diagnosis had been Ollier's disease at that time, and it was modified to Mafucci's syndrome only in 1995 when hemangiomatosis developed on the right hand. He had a unilateral disorder affecting his right upper and lower extremities. In 2010, a chondrosarcoma developed on his right leg and amputation was performed. In 2012, a thoracic CT scan revealed pulmonary metastases on both sides. This case report underlines the importance of the multidisciplinary approach and cooperation between various specialties in diagnosing and early detecting this type of cancer. Orv. Hetil., 2012, 153, 1035-1038.

A case of McCune-Albright syndrome associated with pituitary GH adenoma: therapeutic process and autopsy.

BACKGROUND: McCune-Albright syndrome (MAS) is a clinical syndrome with low incidence, and its concurrence with pituitary GH adenoma is rare. Little of the history, treatment and outcome has been studied. METHOD: Follow-up of a 37-year-old male patient of MAS associated with pituitary GH adenoma was performed continuously recording the disease development and the treatment process until death, after which an autopsy was performed. RESULTS: Radiation therapy (RT) efficaciously controlled GH hypersecretion, however, it may have been the cause of the malignant transformation of the dysplastic bone tissue, which eventually caused brain hernia and death; autopsy demonstrated that the cranium had significant thickening (as much as 10 cm), the pathological diagnosis was fibrous dysplasia of bone associated with chondrosarcoma; and undifferentiated chondrosarcoma with malignant fibrous histocytoma subtype in the sellar region; nodular goiter with the thyroid gland, one nodus was pathologically demonstrated as papillary carcinoma. CONCLUSION: GH adenoma, present in a patient with MAS, might be cured by RT; but the risk of malignant transformation of the dysplastic bone tissue in the field of irradiation make it controversial. Lessons from the case reported here told us that we should take great caution when recommending RT for patients like this.

[Synovial chondromatosis]. / Sinovijalna hondromatoza.

Synovial chondromatosis is an uncommon benign disorder of the synovial membrane ofjoints, tendon sheaths, or bursae characterized by the formation of multiple cartilaginous nodules or osseus loose bodies. It is usually a monoarticular disease, and 33 different localizations have been described until now. The aim of this review article is to present the newest knowledge on the etiology, diagnosis, differential diagnosis, and management of synovial chondromatosis. Malignant transformation to chondrosarcoma is an unusual but possible complication. It is closely connected with recurrence rate and usually occurs many years after surgical treatment. More specific details related to surgical treatment of most often affected joints, i.e. shoulder, elbow, hip, knee, and ankle are reported as well at the end of this review article.

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.

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.

Temporal changes in characteristics of injection-site sarcomas in cats: 392 cases (1990-2006).

OBJECTIVE: To evaluate changes in characteristics of feline injection-site sarcomas (ISSs) from 1990 through 2006. DESIGN: Retrospective case series. ANIMALS: 392 cats with a histologic diagnosis of soft tissue sarcoma, osteosarcoma, or chondrosarcoma at potential injection sites. PROCEDURES: Classification and anatomic location of tumors and signalment of affected cats were compared between ISSs diagnosed before and after publication of the Vaccine Associated Feline Sarcoma Task Force vaccination recommendations in 1996. RESULTS: From before to after publication of the vaccination recommendations, proportions of ISSs significantly decreased in the interscapular (53.4% to 39.5%) and right and left thoracic (10.2% to 3.6% and 9.1% to 1.3%, respectively) regions. On the other hand, proportions of ISSs significantly increased in the right thoracic limb (1.1% to 9.5%) and the combined regions of the right pelvic limb with right lateral aspect of the abdomen (12.5% to 25.0%) and the left pelvic limb with left lateral aspect of the abdomen (11.4% to 13.8%). Patterns of tumor classification and signalment did not change. CONCLUSIONS AND CLINICAL RELEVANCE: Despite publication of the vaccination recommendations, a high proportion of tumors still developed in the interscapular region. There was also an increase in lateral abdominal ISSs, which are more difficult to treat and are likely attributable to aberrant placement of injections intended for the pelvic limbs. Veterinarians are complying with vaccination recommendations to some extent, but they need to focus on administering vaccines as distally as possible on a limb to allow for complete surgical margins if amputation of a limb is required.

[Clinicopathologic study of Ollier's disease and its chondrosarcomatous transformation].

OBJECTIVE: To explore the clinicopathologic features of Ollier's disease, its chondrosarcomatous transformation and related differential diagnoses. METHODS: A total of 19 cases of Ollier's disease and 8 control cases of pure multiple enchondroma were investigated by imaging studies including X-ray, CT or MRI, and hematoxylin and eosin stain. RESULTS: Among 19 cases of Ollier's disease, 12 were men and 7 were women with a mean age of 20 years (range, 5-66 years). Ollier's disease involving short tubular bones of extremity were lytic defects with bony expansion, thinning or disappearance of the overlying cortex surrounded by periosteal fibrous tissues. When occurring in the long bones, the disease showed radiolucent columns of dysplastic cartilage that extended from the metaphysis to diaphyseal and created bowing deformation and limb asymmetry. Microscopically, the cartilage present in the small bones of the hands and feet tended to be more hypercellular with more abundant enlarged or binucleated nuclei. The lesion in long bones appeared multicentric, surrounding with a thin rim of bone and calcification. Six cases of Ollier's disease had developed secondary low-grade chondrosarcoma. CONCLUSIONS: Low-grade chondrosarcomatous transformation can occur in dysplastic cartilage of Ollier's disease. The diagnosis of such sarcomatous transformation should be determined by invasion, but not atypicality of the cartilagenous cells. There are certain differences between the secondary chondrosarcoma of Ollier's disease and conventional chondrosarcoma on clinical, radiographical and pathological grounds.

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.

Recurrent chondrosarcoma of the right skull base in a patient with Maffucci syndrome.

Maffucci syndrome is a rare, sporadic disease characterized by the development of multiple enchondromas and subcutaneous hemangiomas. Patients with Maffucci syndrome have a 23-37% risk of malignancy, with chondrosarcomas being the most common. Although the development of a chondrosarcoma in a patient with Maffucci syndrome may be expected, intracranial chondrosarcomas are rare. We present a patient with Maffucci syndrome who was diagnosed with an intracranial chondrosarcoma after presenting with hearing loss and vomiting. After three craniotomies and two recurrences of chondrosarcoma of the right skull base, the patient demonstrated a positive outcome to treatment with external radiation therapy.

Synovial chondromatosis of the foot and ankle.

BACKGROUND: Synovial chondromatosis (SC) is a benign condition where the synovial lining of joints, bursae, or tendon sheaths undergoes metaplasia and ultimately forms cartilaginous loose bodies. Synovial chondromatosis of the foot and ankle is exceedingly rare, and outcomes following surgical excision are largely unknown. MATERIALS AND METHODS: An Institutional Review Board-approved retrospective review of our institution's surgical database from 1970 to 2006 revealed 8 patients with SC of the foot and/or ankle confirmed by pathology. RESULTS: Eight patients (4 female and 4 male) presented with pain, locking, or stiffness. Average age at presentation was 37 (range, 19 to 60) years. Average followup was 9.5 (range, 1 to 31) years. Six patients had involvement of the ankle, and two, the midfoot. Four patients underwent ankle synovectomy with loose body removal, and were pain-free at last followup. One patient underwent excision and midfoot arthrodesis for severe midfoot destruction. Three patients ultimately underwent below knee amputation, one for multiple recurrences and two for malignant transformation to low-grade chondrosarcoma. CONCLUSION: To our knowledge, this is the largest reported series of patients with SC of the foot and ankle. In half the patients, synovectomy with excision of loose bodies resulted in pain free return to normal function, without recurrence, at last followup. However, recurrence occurred in 3 (37.5%) of 8 patients with subsequent malignant transformation to low-grade chondrosarcoma occurring in 2 patients.