Fusion transcriptome profiling defines the monoclonal origin of multifocal epithelioid haemangioma of bone.

AIMS: Epithelioid haemangioma (EH) of bone remains a highly controversial entity. Indeed, the WHO classifies EHs of soft tissues as benign tumours, whereas bone EHs are considered intermediate-locally aggressive tumours due to common multifocal presentation and local destructive growth. To gain insights into the clinical behaviour and biology of EH of bone we retrospectively analysed 42 patients treated in a single institution from 1978 to 2021. METHODS AND RESULTS: Multifocal presentation was detected in 17 of 42 patients (40%) primarily as synchronous lesions. Patients were treated with curettage (57%), resection (29%) or biopsy, followed by radiotherapy or embolisation (14%). Follow-up (minimum 24 months) was available for 38 patients, with only five local recurrences (13%) and no death of disease. To clarify whether the synchronous bone lesions in multifocal EH represent multicentric disease or clonal dissemination, four cases were profiled by RNA-sequencing. Separate lesions from the same patient, which showed a similar transcriptional profile, expressed the same fusion transcript (involving FOS or FOSB) with identical gene breakpoints. CONCLUSIONS: These results indicate that, in EH of bone, multifocal lesions are clonally related and therefore represent the spread of a same neoplastic clone rather than simultaneous independent tumours. This finding is in apparent contradiction with the benign clinical course of the disease, and suggests that tumour dissemination in bone EH probably reflects a phenomenon of passive spreading, with tumour cells colonising distal sites while maintaining their benign biological nature.

Synovial chondrosarcoma: a single-institution experience with molecular investigations and review of the literature.

AIMS: To evaluate the available diagnostic histological criteria for synovial chondrosarcoma and to screen for the presence of IDH1/IDH2 mutations in a series of cases of this malignant cartilaginous neoplasm. METHODS AND RESULTS: Ten cases of synovial chondrosarcoma diagnosed at our institute were reviewed. At presentation, all tumours occurred in adults (median age, 62 years). The most common location was the knee joint (five cases), and the size at diagnosis ranged from 30 mm to 170 mm. Eight patients had secondary synovial chondrosarcomas associated with pre-existing/recurrent or concomitant synovial chondromatosis. Five patients had local recurrences and three had lung metastases. All patients with intralesional excisions developed local recurrences, whereas those who underwent wide resections did not. At last follow-up (mean, 91 months), available for nine patients, seven patients were alive and disease-free, one patient had died of disease, and one was alive with paravertebral metastases. Frequent histological features observed included loss of clustering of chondrocytes (nine cases), the presence of variable amounts of myxoid matrix (eight cases), peripheral hypercellularity (eight cases), tumour necrosis (six cases), and spindling of chondrocytes (four cases). Of the seven cases for which it was possible to evaluate bone permeation, six showed infiltration of bone marrow. All seven cases screened for mutations of exon 4 of IDH1 and IDH2 were found to be wild-type. CONCLUSIONS: Histological criteria in correlation with clinical and radiological features allow the recognition of synovial chondrosarcoma. IDH1/IDH2 mutations were not present in synovial chondrosarcoma. Adequate surgical margins are important for disease control.

Osteoblastoma-like osteosarcoma: high-grade or low-grade osteosarcoma?

AIMS: Osteoblastoma-like osteosarcoma is a rare variant of osteosarcoma (1% of all osteosarcomas), histologically similar to osteoblastoma. In the current World Health Organisation (WHO) classification, osteoblastoma-like osteosarcoma is classified within the group of conventional (high-grade) osteosarcomas. However, several published cases have been actually regarded as low-grade malignant tumours. As strict morphological criteria to distinguish between low- and high-grade lesions are not available, we reviewed our series of osteoblastoma-like osteosarcomas in the attempt to identify clinical and morphological features predictive of aggressiveness. METHODS AND RESULTS: We retrieved 15 cases of osteoblastoma-like osteosarcoma from the files of the Istituto Ortopedico Rizzoli. Patients received various treatments. Five patients developed metastasis and five patients developed local recurrences (all after incomplete surgery). Eleven patients were alive without disease, while four patients died of their disease. Statistical analysis revealed a statistically significant (P = 0.048) lower disease-free survival in patients with areas of conventional (high-grade) osteosarcoma. CONCLUSIONS: With the important limitation of a small cohort of patients, the presence of areas of conventional (high-grade) osteosarcoma is the only parameter to predict the aggressiveness of osteoblastoma-like osteosarcoma.

Parosteal extra-axial chordoma of the second metacarpal bone: a case report with literature review.

Extra-axial chordoma is a chordoma that occurs in non-axial locations. It is a very rare tumor, with 20 cases reported to date; 14 in bone and six in soft tissue. Of the 14 skeletal extra-axial chordomas, ten were intramedullary and four were intracortical. We report the first case of parosteal extra-axial chordoma arising in the second metacarpal bone, expressing brachyury on immunohistochemical analysis, and describe the pathologic and radiologic findings. We suggest that extra-axial chordoma can occur in parosteal bone lesions or the hand, without features of bone distribution or bone-specific sites.

Biopsy is not necessary for the diagnosis of soft tissue hemangiomas.

OBJECTIVE: To describe the clinical and ultrasonography (US) findings of soft tissue hemangiomas, and to compare with the results of histologic diagnosis after US-guided biopsy. METHOD AND MATERIALS: We retrospectively studied the files of 97 patients (48 female, 49 male; mean age, 34 years; range 4-84 years) with soft tissue hemangiomas diagnosed from 2004 to 2011. Mean follow-up was 9 years (range 7-13 years). Clinical presentation included intermittent mild pain associated with a soft tissue swelling/palpable mass in all patients, chronic pain and increased local heat in 29 patients, local swelling and decreased range of motion of the adjacent joint in 45 patients, and all the above symptoms in 23 patients. B-mode and color Doppler US evaluation included the site, location, size, shape, margins, presence of calcifications, echo structure and echogenicity. All patients had US-guided biopsy for histologic analysis. RESULTS: US-guided biopsy and histology confirmed the diagnosis of soft tissue hemangioma in 92 of the 97 lesions (94.8%). Histologic examination of the remaining five lesions showed nodular fasciitis (two lesions), endometriosis (one lesion), hemangioendothelioma (two lesions); US of these lesions showed variable size, irregular margins, and deep-seated location. Histologically documented soft tissue hemangiomas were most commonly superficial (74 lesions) and arteriovenous (45 lesions). Shape was most commonly oval (fusiform), margins were most commonly not well defined (irregular, hazing but circumscribed), phleboliths were more common in deep-seated lesions, echo structure was heterogeneous, and echogenicity was most commonly hyperechogen and involuting. CONCLUSION: Clinical presentation and typical B-mode and color Doppler US findings are adequate for the diagnosis of soft tissue hemangiomas without the need for biopsy and histologic analysis. If any clinical or US doubt, an US-guided biopsy should be performed.

Fibrocartilaginous mesenchymoma of bone: a single-institution experience with molecular investigations and a review of the literature.

AIMS: Fibrocartilaginous mesenchymoma is a rare intraosseous lesion, with a total of 26 cases described in the literature. This study describes the clinical, radiological and histological features of eight new cases of fibrocartilaginous mesenchymoma collected at a single institution between 1982 and 2016. The presence of GNAS and IDH1/2 mutations and MDM2 amplification was explored to evaluate possible links between fibrocartilaginous mesenchymoma, fibrous dysplasia, de-differentiated chondrosarcoma and low-grade osteosarcoma. METHODS AND RESULTS: Eight new cases of fibrocartilaginous mesenchymoma of bone identified in our archives, dating from 1982 to 2016, were reviewed. The diagnosis was not performed on the initial biopsy in any of these cases, due mainly to the absence of obvious cartilaginous differentiation. On imaging, the tumour contained cartilaginous calcifications and showed a very strong uptake of contrast medium after injection. Histologically, the tumour was characterized by spindle cell proliferation mimicking a low-grade spindle cell sarcoma, associated with epiphyseal growth-plate-like nodules of cartilage and bone production. Molecularly, no GNAS and IDH1/2 mutations or MDM2 amplification were found in the cases analysed. Only one case recurred 1 year following intralesional resection. None died of disease. CONCLUSIONS: This very rare bone tumour has a typical radiological and histological pattern and a favourable survival outcome after treatment. Local recurrences can be prevented with complete surgery. Fibrocartilaginous mesenchymoma does not seem to be related genetically to fibrous dysplasia, low-grade osteosarcoma and de-differentiated chondrosarcoma.

Development of high-grade osteosarcoma in a patient with recurrent giant cell tumor of the ischium while receiving treatment with denosumab.

Malignant transformation of giant cell tumor of bone (GCTB) without radiotherapy exposure is exceptionally rare, occurring in less than 1% of GCTBs. The safety and efficacy of denosumab in patients with GCTB was recently reported. We herein report a case of a benign recurrent GCTB with an H3F3A mutation that underwent secondary malignant transformation during treatment with denosumab. A 29-year-old woman underwent curettage of a GCTB of the left ischium in 2005. Ten years after the first surgery, the GCTB recurred locally. We started treatment with denosumab. During the first 5 months of treatment, we observed a demarcated area of osteosclerosis in the recurrent lesion, and the patient's clinical condition improved. At 6 months, however, the patient developed pain, and a rapidly growing mass was detected by computed tomography. An incisional biopsy was performed. Histologic analysis showed a high-grade osteosarcoma. The patient developed lung metastases and died soon after beginning chemotherapy. The mechanism of sarcomatous transformation of GCTB during denosumab therapy is unclear. These findings suggest that the scientific community should be aware of the possible malignant transformation of GCTB during denosumab treatment.

Paediatric chondrosarcomas: a retrospective review of 17 cases.

AIMS: Chondrosarcoma is primarily a tumour of adulthood and old age. Some studies indicate that survival is worse in paediatric than in adult chondrosarcomas. In view of the rarity of paediatric chondrosarcoma, few large studies are currently available. METHODS AND RESULTS: We evaluated the clinical, radiological and pathological features of a single institution series of chondrosarcomas presenting in patients younger than 17 years between 1981 and 2014. Seventeen patients with central (10), peripheral (five) and periosteal (two) chondrosarcoma were retrieved. The patients received various treatments according to the dimension, stage and grading of the lesions. Only two tumours, treated with resection, recurred after the first diagnosis, at 11 and 108 months, respectively. All patients but one were alive without disease at the time of the last follow-up (median: 148 months). The one patient who died of disease 27 months after diagnosis had a grade 2 central chondrosarcoma of the metacarpal bone. He was affected by Maffucci syndrome and developed multiple bone and lung metastases. CONCLUSIONS: Chondrosarcoma in children is rare but does exist, and is not limited to the head and neck region. Our findings do not support the current view that chondrosarcomas are more aggressive in children than in adults.

CIC-DUX4 fusion-positive round-cell sarcomas of soft tissue and bone: a single-institution morphological and molecular analysis of seven cases.

AIMS: Round-cell sarcomas lacking specific translocations represent a diagnostic challenge. The aim of this study was to describe seven cases of CIC-DUX4 fusion-positive sarcomas, including the first reported example arising primarily in bone. METHODS AND RESULTS: Patients ranged in age from 15 years to 44 years (median: 33 years). Six cases arose from the soft tissues, and one from the iliac bone. Morphologically, all cases showed an undifferentiated round-cell population with greater atypia and pleomorphism than Ewing sarcoma. Immunohistochemically, all tumours showed focal and weak positivity for CD99, and five of seven showed nuclear and/or cytoplasmic positivity for Wilms tumour 1. Five patients had lung metastases at presentation. All patients received chemotherapy according to Ewing sarcoma protocols. All but one patient (the one with a bone tumour) died of disease after a mean of 14.5 months from the diagnosis (range: 8-20 months). CONCLUSIONS: Our series confirms that CIC-DUX4 fusion-positive sarcomas are aggressive tumours with an adverse prognosis, and with clinical, histological and genetic differences from Ewing sarcoma. The best therapeutic approach needs to be investigated.

Primary pseudomyogenic haemangioendothelioma of bone: report of two cases.

Pseudomyogenic haemangioendothelioma (epithelioid sarcoma-like haemangioendothelioma) is a recently described, rarely metastasising neoplasm of the soft tissues that often presents as multiple discontinuous nodules in different tissue planes of a limb. This tumour type is extremely difficult to diagnose because no morphological evidence suggestive of endothelial differentiation is present to confirm a radiological suspicion of vascular neoplasm. All but one case published in the literature underline that bone involvement is secondary to deep and superficial soft tissue nodules. Here, we report two cases of primary bone pseudomyogenic haemangioendothelioma occurring in the radius and cuboid bone with a multifocal presentation.

Chondroblastoma-like osteosarcoma: a case report and review.

Chondroblastoma-like osteosarcomas are extremely rare malignancies having varying clinical, radiological and histological features. Their rarity causes challenges in both diagnosis and clinical management. They are often misdiagnosed as benign lesions. Their accurate diagnosis is important because they require adequate treatment. Misdiagnosed lesions or undertreatment may result in recurrences. We report a case of chondroblastoma-like osteosarcoma arising in the left first metatarsal bone with tarsometatarsal joint involvement in a 10-year-old boy for whom surgery with an original technique was planned after a multidisciplinary diagnostic review.

Meningeal hemangiopericytoma only diagnosed at the time of late bone metastasis.

Hemangiopericytoma is a rare neoplasm. Primary meningeal hemangiopericytomas account for 1 to 7% of all meningeal tumors. In the literature, meningeal hemangiopericytomas are mainly case reports, which confirm an aggressive behavior with a high rate of local recurrence and extracranial metastasis. Metastasis can be seen many years after initial surgical excision of the primary tumor, and the most common sites include the bone, liver and lung. We present a pathological study of four meningeal hemangiopericytomas with bone metastases. All patients are male with a mean age of 46.5 years. Metastases only involved bone. Three out of four lesions were initially misdiagnosed as meningiomas. Only one case was initially correctly diagnosed as meningeal hemangiopericytoma. All patients underwent surgery with complete resection. Only the patient immediately diagnosed with meningeal hemangiopericytoma received postoperative radiation therapy. Three patients had bone metastases without local recurrence including the one who received radiation therapy. One patient recurred locally after 7 years, and bone metastasis was found at the same time. Our cases confirm that meningeal hemangiopericytomas are a separate entity and have a high recurrence rate despite complete surgical resection, with extracranial metastases, mainly to bone, even after long intervals.

Lipofibromatosis: magnetic resonance imaging features and pathological correlation in three cases.

Lipofibromatosis is a rare, benign, but infiltrative, soft tissue tumor seen in children. We present three cases of lipofibromatosis, each with different magnetic resonance imaging features and correlate this with the histological findings. The patients comprised two males and one female who presented in infancy; at birth, 5 months, and 7 months of age. Clinically, the masses were painless and slow-growing. The masses ranged in size from 2 to 6 cm and involved the distal extremities in two cases (one foot, one wrist) and the trunk. Magnetic resonance imaging showed lipomatous lesions with varying amounts of adipose and solid components in each case. There were no capsules at the periphery of the lesions. One case showed a fat-predominant lesion, another an equal mixture of fat and solid tissue, and the third was predominantly solid. This was reflected in the histology, which showed corresponding features. Radiological and histopathological differential diagnoses are reviewed.

Radiofrequency ablation for non-spinal osteoid osteomas in 557 patients.

OBJECTIVES: To present the results of biopsy and computed tomography (CT) guided radiofrequency ablation (RFA) for non-spinal osteoid osteomas, and compare the results before and after procedural modifications. METHODS: We retrospectively studied 557 patients with non-spinal osteoid osteomas treated with biopsy and CT-guided RFA. In 68 patients we used 3-mm CT at 2-mm intervals, 19 G/5-mm active tip electrodes, and one 4-minute ablation at 90-93°C. In 489 patients we used contiguous 1-mm CT, 20 G/5-15-mm electrodes, ablation maintaining 60°C for 2 min followed by 14-15 min at 90-93°C, and multiple ablations in the same session for large and multiform lesions. RESULTS: 533/557 patients (96%) remained asymptomatic and 24/557 (4%) had recurrence; repeat RFA was successful in 22/24 patients (92%). Biopsy was non-diagnostic in 82%. With the modifications performed, success improved from 79% to 98%, recurrences reduced from 21% to 2% and complications from 5.9% to 0.2% (p < 0.001). All patients with large and multiform lesions treated with one ablation had recurrence, compared to no patient with similar lesions and multiple ablations in the same session. CONCLUSION: Electrode parameters, duration of ablation, morphology and size of osteoid osteomas are important for RFA. The above modifications are recommended for improved outcome.

Bilateral ischiofemoral impingement in a patient with hereditary multiple exostoses.

The skeletal anatomy of the hip provides two main locations for impingement: abnormal contact between the acetabulum and femur (femoroacetabular impingement) or between the ischium and femur (ischiofemoral impingement). We report a case of bilateral ischiofemoral impingement in a patient with hereditary multiple exostoses. The association of exostoses and femoral metaphyseal widening resulted in the narrowing of the ischiofemoral spaces. Pain was improved on the left side by resection of the ischial exostosis.

Unusual supero-medial iliac fatigue stress fracture.

Fatigue stress fractures are quite common in athletes, especially in women. They typically involve the lower extremities, but they have also been described in the pelvis and sacrum. Most of the time, they are radiographically occult at the beginning, and become visible only when the callus is detected. They are suspected owing to their clinical features, and investigated using magnetic resonance imaging (MRI) and computed tomography (CT). We present a case of unusual supero-medial iliac fatigue stress fracture in a 58-year-old amateur marathon runner woman presenting with a history of 1-month's worsening pain in the right buttock. Diagnosis was challenging. The early radiograph was normal, and the stress fracture was suspected by clinical features and MRI. Although the fracture was evident on the MRI, the findings were subtle and overlooked. The fracture was later confirmed by CT and radiograph, showing the reparative process.

Vascular bone tumors: a proposal of a classification based on clinicopathological, radiographic and genetic features.

The classification of vascular bone tumors remains challenging, with considerable morphological overlap spanning across benign to malignant categories. The vast majority of both benign and malignant vascular tumors are readily diagnosed based on their characteristic histological features, such as the formation of vascular spaces and the expression of endothelial markers. However, some vascular tumors have atypical histological features, such as a solid growth pattern, epithelioid change, or spindle cell morphology, which complicates their diagnosis. Pathologically, these tumors are remarkably similar, which makes differentiating them from each other very difficult. For this rare subset of vascular bone tumors, there remains considerable controversy with regard to the terminology and the classification that should be used. Moreover, one of the most confusing issues related to vascular bone tumors is the myriad of names that are used to describe them. Because the clinical behavior and, consequently, treatment and prognosis of vascular bone tumors can vary significantly, it is important to effectively and accurately distinguish them from each other. Upon review of the nomenclature and the characteristic clinicopathological, radiographic and genetic features of vascular bone tumors, we propose a classification scheme that includes hemangioma, hemangioendothelioma, angiosarcoma, and their epithelioid variants.

Selective arterial embolization of 36 aneurysmal bone cysts of the skeleton with N-2-butyl cyanoacrylate.

BACKGROUND: Aneurysmal bone cyst (ABC) is a lytic benign bone lesion representing about 1% of all primary bone tumors. The lesion causes pain and swelling, which are generally present for less than 3 months. METHODS: From April 2003 to April 2008 36 patients affected by aneurysmal bone cysts were treated by selective arterial embolization with N-2-butyl cyanoacrylate. The study population comprised 20 male and 16 female patients with an age range of 3.3-60.8 years. Nine lesions were localized in the appendicular skeleton (1 in the upper and 8 in the lower limb), 4 in the thoracic cage (1 rib lesion and 3 scapular lesions), 17 in the pelvis and 6 in the spine (1 thoracic and 5 sacral localizations). RESULTS: A total of 55 embolizations were performed: in 22 cases (61%) only one embolization was needed, whilst two embolizations were necessary in 9 cases (25%) and 3 in the remaining 5 patients (14%). The treatment was effective in 32 patients (94% ): follow-up was 0.9-5 years. In one patient, previously surgically treated, only the cyanoacrylate embolization turned out to be useful for healing the lesion. Another 7 patients underwent surgery during the study period. In the 55 procedures we performed we had 3 complications (5%): 2 cases of skin necrosis and 1 of transient paresis. CONCLUSIONS: Arterial embolization with cyanoacrylate may be the treatment of choice for aneurysmal bone cysts. Embolization is a less invasive, lower cost, simpler procedure than surgery and is easily repeatable.

Inflammation and infiltration: can the radiologist draw a line? MRI versus CT to accurately assess medullary involvement in parosteal osteosarcoma.

Cancer causes inflammation as it progresses through healthy tissue. The differentiation of tumoral growth from the surrounding inflammatory change is paramount in planning surgeries seeking to preserve function. This retrospective study aims at illustrating how a careful use of imaging (computed tomography (CT)/magnetic resonance imaging (MRI)) can help to draw the line between infiltration and inflammation. Out of 72 cases of parosteal osteosarcoma in our institution we selected 22 which had pretreatment imaging, and out of those, 14 that had both MRI and CT. Using Fisher's exact test, we evaluated the performance of each technique on accurately diagnosing medullary tumor infiltration, using histological analysis as a gold standard. All cases (14/14) demonstrated medullary abnormality on MRI, but only 6/14 (42.9%) demonstrated abnormality on CT. The 8/14 cases with MRI abnormality but no CT abnormality (57.1%) showed inflammation with no tumoral cells present on histological analysis. In the cases where the two examinations showed medullary abnormality (6/14) histology demonstrated tumoral infiltration. MRI demonstrated high sensitivity and negative predictive value, but low specificity and low positive predictive value and accuracy (P=1). CT demonstrated high sensitivity, specificity, high positive and negative predictive values and accuracy (P = 0.000333). MRI is highly sensitive for the detection of medullary abnormality but lacks specificity for tumor invasion. Correlation with CT is recommended in all cases of positive MR to add specificity for tumors. The adequate use of the two imaging methods allows to differentiate between inflammatory change and tumoral infiltration in POS, relevant for surgical planning.

High Dose Ifosfamide in Relapsed and Unresectable High-Grade Osteosarcoma Patients: A Retrospective Series.

Background: The evidence on high-dose ifosfamide (HD-IFO) use in patients with relapsed osteosarcoma is limited. We performed a retrospective study to analyze HD-IFO activity. Methods: Patients with osteosarcoma relapsed after standard treatment [methotrexate, doxorubicin, cisplatin +/- ifosfamide (MAP+/-I)] with measurable disease according to RECIST1.1 were eligible to ifosfamide (3 g/m2/day) continuous infusion (c.i.) days 1-5 q21d. RECIST1.1 overall response rate (ORR) (complete response (CR) + partial response (PR)), progression-free survival at 6-month (6m-PFS), duration of response (DOR), and 2-year overall survival (2y-OS) were assessed. PARP1 expression and gene mutations were tested by immunohistochemistry and next-generation sequencing. Results: 51 patients were included. ORR was 20% (1 CR + 9 PR). Median DOR was 5 months (95%CI 2-7). Median PFS, 6m-PFS, OS, and 2y-OS were 6 months (95%CI 4-9), 51%, 15 months (10-19), and 30%, respectively. A second surgical complete remission (CR2) was achieved in 26 (51%) patients. After multivariate analysis, previous use of ifosfamide (HR 2.007, p = 0.034) and CR2 (HR 0.126, p < 0.001) showed a significant correlation with PFS and OS, respectively. No significant correlation was found between outcomes and PARP1 or gene mutations. Conclusions: HD-IFO should be considered as the standard first-line treatment option in relapsed osteosarcoma and control arm of future trial in this setting.