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.

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.

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.

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.

Epithelioid hemangioma of bone: A unique case with multifocal metachronous bone lesions.

Epithelioid hemangioma of bone is a rare vascular neoplasm with a ubiquitous distribution. To date, up to 25% epithelioid hemangioma of bone presents synchronous bone lesions. We report a unique case of epithelioid hemangioma with multifocal metachronous bone lesions without any fatal outcome observed after a long period. Importantly, a strong nuclear expression of FOSB antibody was detected by immunohistochemical analysis. In this case, the pathologic and radiologic findings are also described. We suggest that epithelioid hemangioma can present multifocal metachronous bone lesions without producing a fatal outcome.

Imaging of Upper Limb Tumors and Tumorlike Pathology.

Bone and soft tissue sarcomas are uncommon tumors that can occur within the upper extremity as well as elsewhere within the body. However, certain histopathological subtypes have increased affinity for the upper limb and even certain sites within the arm and hand. Other benign masses and tumor mimics, such as infection and traumatic lesions, are more common and imaging appearances can sometimes overlap with malignant lesions making diagnosis difficult. In this article, we explore the current options for imaging of these lesions as well as typical imaging appearances of the more common upper limb tumors.

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.

Intraosseous papillary intralymphatic angioendothelioma (PILA): one new case and review of the literature.

BACKGROUND: Papillary intralymphatic angioendothelioma (PILA) is a locally aggressive, rarely metastasizing vascular tumor, generally occurring in the soft tissues, with less than 40 cases described in the literature and only three cases reported in bone. CASE PRESENTATION: We describe the case of a 51-year-old male with an intraosseous PILA of the proximal edge of his left clavicle and two other lesions evident on imaging. The patient was treated with marginal resection of the clavicle lesion but was lost to follow-up 1 month after surgery. CONCLUSIONS: PILA can also occur in bone, albeit very rarely, and has to be considered in the differential diagnosis of vascular bone tumors.

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.

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.

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.

Soft Tissue Tumors Rarely Presenting Primary in Bone; Diagnostic Pitfalls.

Primary bone sarcomas represent extremely rare entities. The use of now abolished labels, such as malignant fibrous histiocytoma and hemangiopericytoma, has significantly hampered the chance of identifying specific entities. It is now accepted that a broad variety of mesenchymal malignancies most often arising on the soft tissue may actually present as primary bone lesions. A more accurate morphologic partition is justified based on availability of distinct therapeutic options. An integrated diagnostic approach represents the only way to achieve a correct classification. In consideration of the significant complexity, primary bone sarcomas should ideally be handled in the context of expert centers.

Erratum to: Osteosarcoma follow-up: chest X-ray or computed tomography?

[This corrects the article DOI: 10.1186/s13569-017-0067-5.].

Osteosarcoma follow-up: chest X-ray or computed tomography?

BACKGROUND: In patients with relapsed osteosarcoma, the surgical excision of all metastases, defined as second complete remission (CR-2), is the factor that mainly influences post-relapse survival (PRS). Currently a validated follow-up policy for osteosarcoma is not available, both chest X-ray and computed tomography (CT) are suggested for lung surveillance. The purpose of this study is to evaluate whether the type of imaging technique used for chest surveillance, chest X-ray or CT, influenced the rate of CR-2 and prognosis in patients with recurrent osteosarcoma. METHODS: Patients up to 40 years with extremity osteosarcoma enrolled in consecutive clinical trials and treated at the Rizzoli Institute from 1986 to 2009 were identified. Only patients who had lung metastases alone as first pattern of recurrence were considered for the analysis. The rate of CR-2, overall survival (OS) and PRS were the end-points of the study. RESULTS: The median follow-up was 47 months (1-300), 215 patients were eligible. Lung metastases were detected by chest X-ray in 100 (47%) patients, by CT in 112 (52%) and by symptoms in 3 (1%). CR-2 rate was 60% for patients followed by X-rays and 88% for those followed by CT (p < .0001). 5-year PRS was 30% (95% CI 21-39) in the X-ray group and 49% (95% CI 39-59) in the CT group (p = .0004). 5-year OS was 35% (95% CI 26-44) in the X-ray group and 60% (95% CI 51-70) in the CT group (p = .004). CONCLUSIONS: A follow-up strategy with chest CT leads to a higher rate of CR-2 and significantly improves PRS and OS in osteosarcoma, compared to chest X-ray.

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.

Ewing sarcoma in patients over 40 years of age: a prospective analysis of 31 patients treated at a single institution.

PURPOSE: Patients with Ewing sarcoma who are 40 years old or older are usually excluded from clinical trials. For this reason, information on this subset of patients is limited. METHODS: Clinical characteristics and treatment-related variables of patients aged 40 years or more, with a diagnosis of Ewing sarcoma, treated at the authors' institution had been prospectively collected since 1999. RESULTS: Thirty-one patients were identified, with ages ranging from 40 to 70 years (median 45 years). Twenty-six (84%) had localized disease, 4 patients presented with lung metastases, and 1 patient had multiple metastases (bone, lung, abdominal nodes, and bone marrow). The primary tumors were skeletal in 19 (61%) patients, while 12 (39%) had extraskeletal disease. All patients received chemotherapy according to regimens similar to those adopted in younger patients, based on doxorubicin, cyclophosphamide, etoposide, vincristine, dactinomycin, and ifosfamide. All patients experienced grade 4 leukopenia (100%); red blood cells or platelets transfusions were needed in 50% and 16% of patients, respectively. Toxicity-related dose reduction was required in 13 patients (43%). The 5-year overall survival (OS) was 54% for the whole group. In patients with complete remission, 5-year disease-free survival was 57%. Survival was different for patients with skeletal and extraskeletal Ewing sarcoma (5-year OS: 64% vs 40%, p = 0.2). CONCLUSIONS: In older patients, the incidence of extraskeletal Ewing sarcoma is high. Intensive chemotherapy treatment can be recommended in this group. The high chemotherapy toxicity can be justified by expected results, similar to those of younger patients.

Translational research in diagnosis and management of soft tissue tumours.

Finding a soft tissue mass in the superficial regions is a common event in daily clinical practice. Correct management of the diagnostic process is crucial to avoid blunders. Diagnosis is posed by pathology, although both imaging and a better understanding of the cellular and molecular mechanisms play an important a role in the characterization, staging and follow-up of soft tissue masses. Cellular and molecular mechanisms can explain either the development of chemo-resistance and the underlying pre- and post-surgery metastasis formation. These are mandatory to improve prognosis and unveil novel parameters predicting therapeutic response. Imaging mainly involves ultrasound and MR and is fundamental not only in diagnosis but also in the first step of therapy: the biopsy. Novel imaging techniques like Ultrasound Elastosonography, Dynamic Contrast-Enhanced MR imaging (DCE), Diffusion Weighted MR imaging (DWI) and MR Spectroscopy (MRS) are discussed. This paper aims at reviewing and discussing pathological methods and imaging in the diagnosis of soft tissue masses underscoring that the most appropriate treatment depends on advanced molecular and radiological studies.

Recurrence After Marginal Excision for Atypical Lipomatous Tumors Versus Lipomas of the Extremities.

This study reviewed the medical records of 90 patients with lipomas (47 patients) and atypical lipomatous tumors (ALT)/well-differentiated liposarcomas (WDL) (43 patients) of the extremities treated from 2006 to 2012. All patients had preoperative biopsy and postoperative histologic analysis of the tumors; surgical margins were marginal in all cases. Histologic sections of the tissue blocks from the excised specimens were re-reviewed for all patients; a consensus with postoperative histologic analysis was confirmed. Molecular chromosome analysis was performed on fluorescence in situ hybridization in tissue sections from the tissue blocks in all cases for the purpose of this study; a ratio greater than 2 was considered to represent murine double-minute 2 (MDM2) amplification consistent with a diagnosis of ALT/WDL. Mean follow-up was 52 months (range, 14-96 months). Local recurrence and metastasis rates and the relationship of patient age and sex with tumor size and location were evaluated. None of the patients with lipomas experienced local recurrence compared with 6 patients (13.9%) with ALT/WDL who experienced local recurrence within a mean of 48 months (range, 33-96 months); this difference was statistically significant. None of the patients in either group experienced metastasis prior to the study period. Local recurrence did not correlate statistically with patient age or sex, or with tumor size or location. [Orthopedics. 2016; 39(4):e610-e614.].

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.