Transcriptomic subtyping of malignant peripheral nerve sheath tumours highlights immune signatures, genomic profiles, patient survival and therapeutic targets.

BACKGROUND: Malignant peripheral nerve sheath tumour (MPNST) is an aggressive orphan disease commonly affecting adolescents or young adults. Current knowledge of molecular tumour biology has been insufficient for development of rational treatment strategies. We aimed to discover molecular subtypes of potential clinical relevance. METHODS: Fresh frozen samples of MPNSTs (n = 94) and benign neurofibromas (n = 28) from 115 patients in a European multicentre study were analysed by DNA copy number and/or transcriptomic profiling. Unsupervised transcriptomic subtyping was performed and the subtypes characterized for genomic aberrations, clinicopathological associations and patient survival. FINDINGS: MPNSTs were classified into two transcriptomic subtypes defined primarily by immune signatures and proliferative processes. "Immune active" MPNSTs (44%) had sustained immune signals relative to neurofibromas, were more frequently low-grade (P = 0.01) and had favourable prognostic associations in a multivariable model of disease-specific survival with clinicopathological factors (hazard ratio 0.25, P = 0.003). "Immune deficient" MPNSTs were more aggressive and characterized by proliferative signatures, high genomic complexity, aberrant TP53 and PRC2 loss, as well as high relative expression of several potential actionable targets (EGFR, ERBB2, EZH2, KIF11, PLK1, RRM2). Integrated gene-wise analyses suggested a DNA copy number-basis for proliferative transcriptomic signatures in particular, and the tumour copy number burden further stratified the transcriptomic subtypes according to patient prognosis (P < 0.01). INTERPRETATION: Approximately half of MPNSTs belong to an "immune deficient" transcriptomic subtype associated with an aggressive disease course, PRC2 loss and expression of several potential therapeutic targets, providing a rationale for molecularly-guided intervention trials. FUNDING: Research grants from non-profit organizations, as stated in the Acknowledgements.

Long-term outcome after surgical resection of non-high-risk gastrointestinal stromal tumours without adjuvant therapy.

BACKGROUND: Gastrointestinal stromal tumour (GIST) is the most common intra-abdominal sarcoma. Risk classification systems, commonly the modified National Institutes of Health consensus criteria, identify tumour properties relating to patient outcomes. However, owing to limited long-term evidence, most guidelines recommend up to 10-year follow-up for all risk groups except very low-risk GIST. METHODS: This retrospective multicentre study included patients who had complete resection of primary, non-metastatic GIST from three Scandinavian sarcoma centres: Gothenburg (2004-2020), Stockholm (2000-2019), and Oslo (2000-2017). Medical records were reviewed for clinical details regarding diagnosis, treatment, and follow-up, and recurrence-free and disease-specific survival evaluated. RESULTS: The total cohort consisted of 1213 patients with GIST. High-risk patients and those treated with tyrosine kinase inhibitors were excluded. The remaining 649 patients were included in the present analysis: 118 with very low-, 381 with low-, and 150 with intermediate-risk GISTs. Five-year recurrence-free survival rates were 100, 98.5, and 100 per cent for the intermediate-, low-, and very low-risk groups respectively (P = 0.246). Disease-specific survival rates 10 years after surgery were 100, 98.4, and 100 per cent for the intermediate-, low-, and very low-risk groups respectively (P = 0.262). CONCLUSION: Patients with completely resected non-high-risk GISTs have an excellent long-term outcome, irrespective of risk group. Follow-up programmes to detect disease recurrences in these patients are probably not indicated.

Gastrointestinal stromal tumours (GISTs) originate from the muscle layer of the gastrointestinal tract. They are divided into risk groups according to size, location, and how quickly they grow. Patients with GIST, regardless of risk group, have been followed with imaging for several years after their tumour has been successfully removed with an operation. The aim of this study was to evaluate whether follow-up is necessary for patients in the lower-risk groups. Six hundred and forty-nine patients with GISTs from the lower-risk groups were followed for 5 years (median). Only 1.2 per cent of the patients experienced a recurrence of their cancer. It was concluded that patients with GIST in the lower-risk groups do not need follow-up with imaging after a successful operation.

The spectrum and frequency of histopathological diagnosis of oral diseases in Oslo: Implications to oral pathology syllabus.

INTRODUCTION: To assure knowledge and skills in diagnostic work of oral diseases a continuously updated curriculum is essential. The first aim of the present study was to evaluate the spectrum and frequency of oral histopathological diagnoses signed out by oral pathologists at the Department of Pathology, Oslo University Hospital (OUS), Norway during a two-year period. The second aim was to compare the spectrum of histopathological diagnoses with the content of the current syllabus in oral pathology at the Faculty of Dentistry, University of Oslo (UiO). MATERIALS AND METHODS: In this retrospective cross-sectional study, all histological diagnosis signed out during 2015 and 2016 were included. All histopathological reports were analysed with regard to clinical information and histopathological diagnosis. The spectrum of histopathological diagnoses was compared to the diagnoses presented in lectures and courses for dental and dental hygienist students at UiO. RESULTS: Three thousand four hundred and two histopathological reports (47% males and 53% females) were included. The diagnoses were categorised into eight disease groups and the three most frequent disease groups were cysts, benign tumours/reactive lesions, and white, red, ulcerative and vesiculobullous lesions. The lateral periodontal cyst was more frequent than expected. CONCLUSIONS: We conclude that a minor revision of the syllabus is needed, although the most frequent oral conditions presented in this study are well covered in the oral pathology teaching in Oslo. A more clinical related teaching approach should be considered by categorising oral diseases according to, for example location and age groups.

Validation of a novel risk score to predict early and late recurrence in solitary fibrous tumour.

BACKGROUND: Current risk models in solitary fibrous tumour (SFT) were developed using cohorts with short follow-up and cannot reliably identify low-risk patients. We recently developed a novel risk model (G-score) to account for both early and late recurrences. Here, we aimed to validate the G-score in a large international cohort with long-term follow-up. METHODS: Data were collected from nine sarcoma referral centres worldwide. Recurrence-free interval (RFi) was the primary endpoint. RESULTS: The cohort comprised 318 patients with localised extrameningeal SFTs. Disease recurrence occurred in 96 patients (33%). The estimated 5-year RFi rate was 72%, and the 10-year RFi rate was 52%. G-score precisely predicted recurrence risk with estimated 10-year RFi rate of 84% in low risk, 54% in intermediate risk and 36% in high risk (p < 0.001; C-index 0.691). The mDemicco (p < 0.001; C-index 0.749) and SalasOS (p < 0.001; C-index 0.674) models also predicted RFi but identified low-risk patients less accurate with 10-year RFi rates of 72% and 70%, respectively. CONCLUSIONS: G-score is a highly significant predictor of early and late recurrence in SFT and is superior to other models to predict patients at low risk of relapse. A less intensive follow-up schedule could be considered for patients at low recurrence risk according to G-score.

Real-world evidence on perioperative chemotherapy in localized soft tissue sarcoma of the extremities and trunk wall; a population-based study.

BACKGROUND: Data from the real-world setting on perioperative chemotherapy in high-risk, localized soft tissue sarcoma (STS) is limited. Real-world data (RWD) includes data derived from patients treated outside clinical trials and often captures long-term follow-up not recorded in clinical trials. The aim of this study was to provide population-based, real-world evidence on perioperative chemotherapy in localized STS. MATERIAL AND METHODS: Adult patients with localized STS in the extremities or trunk wall treated at Oslo University Hospital, Oslo, Norway from 1998 to 2017 were included in the study. Data were extracted from a prospectively maintained database, supplemented by retrospective review of medical records. RESULTS: The total study cohort included 806 patients, of whom 154 (19%) received perioperative chemotherapy. A regimen with anthracycline and ifosfamide was given in 141 of 154 cases (92%). During long-term follow-up two patients developed secondary malignancies, cardiac toxicity was registered in 11 patients (7%) and renal toxicity in 12 patients (8%). Seventy-one of 154 patients (46%) were treated outside of clinical trials and constituted the RWD cohort. The median age at surgery was slightly lower and there were more synovial sarcomas and fewer myxofibrosarcomas in the RWD cohort. No difference in chemotherapy dose intensity was observed. The estimated 5-year metastasis-free survival (MFS) in all patients receiving perioperative chemotherapy was 58%. In the RWD cohort 5-year MFS was 53% and in the clinical study cohort 61% (HR 1.24; 95% CI 0.77-2.00). CONCLUSION: Long-term outcome after perioperative chemotherapy was comparable for patients treated in routine clinical practice to those in clinical trials. Secondary malignancy and cardiac toxicity were observed. The risk of serious late side effects should be included in the decision process on perioperative chemotherapy.

Improving public cancer care by implementing precision medicine in Norway: IMPRESS-Norway.

BACKGROUND: Matching treatment based on tumour molecular characteristics has revolutionized the treatment of some cancers and has given hope to many patients. Although personalized cancer care is an old concept, renewed attention has arisen due to recent advancements in cancer diagnostics including access to high-throughput sequencing of tumour tissue. Targeted therapies interfering with cancer specific pathways have been developed and approved for subgroups of patients. These drugs might just as well be efficient in other diagnostic subgroups, not investigated in pharma-led clinical studies, but their potential use on new indications is never explored due to limited number of patients. METHODS: In this national, investigator-initiated, prospective, open-label, non-randomized combined basket- and umbrella-trial, patients are enrolled in multiple parallel cohorts. Each cohort is defined by the patient's tumour type, molecular profile of the tumour, and study drug. Treatment outcome in each cohort is monitored by using a Simon two-stage-like 'admissible' monitoring plan to identify evidence of clinical activity. All drugs available in IMPRESS-Norway have regulatory approval and are funded by pharmaceutical companies. Molecular diagnostics are funded by the public health care system. DISCUSSION: Precision oncology means to stratify treatment based on specific patient characteristics and the molecular profile of the tumor. Use of targeted drugs is currently restricted to specific biomarker-defined subgroups of patients according to their market authorization. However, other cancer patients might also benefit of treatment with these drugs if the same biomarker is present. The emerging technologies in molecular diagnostics are now being implemented in Norway and it is publicly reimbursed, thus more cancer patients will have a more comprehensive genomic profiling of their tumour. Patients with actionable genomic alterations in their tumour may have the possibility to try precision cancer drugs through IMPRESS-Norway, if standard treatment is no longer an option, and the drugs are available in the study. This might benefit some patients. In addition, it is a good example of a public-private collaboration to establish a national infrastructure for precision oncology. Trial registrations EudraCT: 2020-004414-35, registered 02/19/2021; ClinicalTrial.gov: NCT04817956, registered 03/26/2021.

Cytogenetic and molecular analyses of 291 gastrointestinal stromal tumors: site-specific cytogenetic evolution as evidence of pathogenetic heterogeneity.

Gastrointestinal stromal tumor (GIST) is a mesenchymal neoplasm with variable behavior. An increased understanding of the tumor pathogenesis may improve clinical decision-making. Our aim was to obtain more data about the overall chromosome aberrations and intratumor cytogenetic heterogeneity in GIST. We analyzed 306 GIST samples from 291 patients using G-banding, direct sequencing, and statistics. Clonal chromosome aberrations were found in 81% of samples, with 34% of 226 primary tumors demonstrating extensive cytogenetic heterogeneity. 135 tumors had simple (≤5 changes) and 91 had complex (>5 changes) karyotypes. The karyotypically complex tumors more often were non-gastric (P < 0.001), larger (P < 0.001), more mitotically active (P = 0.009) and had a higher risk of rupture (P < 0.001) and recurrence (P < 0.001). Significant differences between gastric and non-gastric tumors were found also in the frequency of main chromosome losses: of 14q (79% vs. 63%), 22q (38% vs. 67%), 1p (23% vs. 88%), and 15q (18% vs. 77%). Gastric PDGFRA-mutated tumors, compared with gastric KIT-mutated, had a lower incidence of 22q losses (18% vs. 43%) but a higher rate of 1p losses (42% vs. 22%). The present, largest by far karyotypic study of GISTs provides further evidence for the existence of variable pathogenetic pathways operating in these tumors' development.

Outcome in dedifferentiated chondrosarcoma for patients treated with multimodal therapy: Results from the EUROpean Bone Over 40 Sarcoma Study.

INTRODUCTION: The role of chemotherapy for patients with dedifferentiated chondrosarcoma (DDCS) is still under discussion. Here, we present the outcome in patients with DDCS treated with intensive chemotherapy from the EUROpean Bone Over 40 Sarcoma Study. MATERIALS AND METHODS: The chemotherapy regimen included doxorubicin, ifosfamide and cisplatin. Postoperative methotrexate was added in case of poor histological response. Toxicity was graded based on the National Cancer Institute expanded common toxicity criteria, version 2.0, and survival was analysed using Kaplan-Meier curves, log-rank tests and univariate Cox regression models. RESULTS: Fifty-seven patients with DDCS (localised, 34 [60%]; metastatic, 23 [40%]) aged 42-65 years were included. Surgical complete remission (SCR) was achieved in 36 (63%) patients. The median overall survival (OS) was 24 months (95% confidence interval, 22-25), and the 5-year OS was 39%. Patients with extremity localisation had a 5-year OS of 49% compared with 29% in patients with a central tumour (P = 0.08). Patients with localised disease had a 5-year OS of 46%, whereas patients with metastatic disease had a 5-year OS of 29% (P = 0.12). Patients in SCR had a 5-year OS of 49%, whereas patients not in SCR had a 5-year OS of 23% (P = 0.004). Chemotherapy toxicity was considerable but manageable. There was no treatment-related death, and 39 (70%) patients received ≥6 cycles of the planned nine chemotherapy cycles. CONCLUSIONS: Adding intensive chemotherapy to surgery for treatment of DDCS is feasible and shows favourable survival data compared with previous reports. With the limitations of data from a non-controlled trial, we conclude that chemotherapy could be considered in the management of patients aged >40 years.

Clinical and molecular implications of NAB2-STAT6 fusion variants in solitary fibrous tumour.

Solitary fibrous tumour (SFT) is a mesenchymal neoplasm characterised by pathognomonic NAB2-STAT6 gene fusions. The clinical implications and prognostic value of different fusion variants has not been clarified. In the current study, we explore the clinicopathological, prognostic and molecular differences between tumours with different fusions. Thirty-nine patients with localised, extrameningeal SFT were included, of whom 20 developed distant recurrence and 19 were without recurrence after long term follow-up. Capture-based RNA sequencing identified 12 breakpoint variants, which were categorised into two groups based on the STAT6 domain composition in the predicted chimeric proteins. Twenty-one of 34 (62%) sequenced tumours had fusions with most of the STAT6 domains intact and were classified as STAT6-Full. Thirteen tumours (38%) contained only the transactivation domain of STAT6 and were classified as STAT6-TAD. Tumours with STAT6-TAD fusions had a higher mitotic count (p=0.016) and were associated with inferior recurrence-free interval (p=0.004) and overall survival (p=0.012). Estimated 10-year recurrence-free survival was 25% for patients with STAT6-TAD tumours compared to 78% for the STAT6-Full group. Distinct transcriptional signatures between the fusion groups were identified, including higher expression of FGF2 in the STAT6-TAD group and IGF2, EGR2, PDGFRB, STAT6 and several extracellular matrix genes in STAT6-Full tumours. In summary, we demonstrate that NAB2-STAT6 fusion variants are associated with distinct clinicopathological and molecular characteristics and have prognostic significance in extrameningeal SFT.

Primary uterine ectomesenchymoma harboring a DICER1 mutation: case report with molecular analysis.

Ectomesenchymoma is an exceedingly rare biphasic malignant tumor characterized by the presence of mesenchymal and neuroectodermal elements. The majority of patients are infants or children. We describe the first case of this entity diagnosed as a primary uterine tumor. A 72-year-old female presented with post-menopausal bleeding. Dilatation and curettage showed irregular mesenchymal proliferation of uncertain nature. In the hysterectomy specimen, a myxoid spindle cell tumor with areas of skeletal muscle and neural differentiation was found in the uterus, with direct invasion of the small intestine, and biphasic differentiation into rhabdomyosarcoma and ganglioneuroblastoma was unequivocally seen in a lymph node metastasis. The morphological findings were validated by immunohistochemistry. Massive parallel sequencing identified TP53, PTEN, and DICER1 mutations in the tumor. This report describes the presence of ectomesenchymoma in an unusual primary organ and in an uncharacteristic age and presents novel data regarding the genetic characteristics of this tumor.

Preoperative accelerated radiotherapy combined with chemotherapy in a defined cohort of patients with high risk soft tissue sarcoma: a Scandinavian Sarcoma Group study.

BACKGROUND: We recently reported outcomes from a Scandinavian Sarcoma Group adjuvant study (SSG XX group A) conducted on localized and operable high risk soft tissue sarcoma (STS) of the extremities and trunk wall. SSG XX, group B, comprised of patients in a defined cohort with locally advanced STS considered at high risk for intralesional surgery. These patients received preoperative accelerated radiotherapy, together with neoadjuvant and adjuvant chemotherapy. Herein we report the results of this group B. METHODS: Twenty patients with high-grade, locally advanced and deep STS located in lower extremities (n = 12), upper extremities (5) or trunk wall (3) were included. The median age was 59 years and 14 patients were males. The treatment regimen consisted of 6 cycles of doxorubicin (60 mg/m2) and ifosfamide (6 g/m2), with three cycles given neoadjuvantly, and preoperative radiotherapy (1, 8 Gyx2/daily to 36 Gy) between cycles 2 and 3. After a repeated MRI surgery was then conducted, and the remaining 3 chemotherapy cycles were given postoperatively at 3 weeks intervals. Survival data, local control, toxicity of chemotherapy and postoperative complications are presented. RESULTS: Median follow-up time for metastasis-free survival (MFS) was 2.8 years (range 0.3-10.4). The 5-year MFS was 49.5% (95% confidence interval [CI] 31.7-77.4). The median follow-up time was 5.4 years (range 0.3-10.4) for overall survival (OS). The 5-year OS was 64.0% (95% CI 45.8-89.4). The median tumour size was 13 cm, with undifferentiated pleomorphic sarcoma (n = 10) and synovial sarcoma (n = 6) diagnosed most frequently. All patients completed surgery. Resection margins were R0 in 19 patients and R1 in 1 patient. No patients had evidence of disease progression preoperatively. Three patients experienced a local recurrence, in 2 after lung metastases had already been diagnosed. Eleven patients (55%) had postoperative wound problems (temporary in 8 and persistent in 3). CONCLUSIONS: Preoperative chemotherapy and radiotherapy were associated with temporary wound-healing problems. Survival outcomes, local control and toxicities were deemed satisfactory when considering the locally advanced sarcoma disease status at primary diagnosis. Trial registration This study was registered at ClinicalTrials.gov Identifier NCT00790244 and with European Union Drug Regulating Authorities Clinical Trials No. EUDRACT 2007-001152-39.

Cytogenetic and Molecular Study of an Adult Sclerosing Rhabdomyosarcoma of the Extremity: MYOD1-mutation and Clonal Evolution.

BACKGROUND: Spindle cell/sclerosing rhabdomyosarcoma is a genomically heterogeneous, uncommon subtype of rhabdomyosarcoma, particularly rare in adults. Its MYOD1-mutant variant is aggressive irrespective of age. Cytogenetic data on spindle cell/sclerosing rhabdomyosarcoma are sparse and disparate. MATERIALS AND METHODS: Cytogenetic and molecular analyses were performed on an adult sclerosing rhabdomyosarcoma. RESULTS: The karyotype of the sclerosing rhabdomyosarcoma displayed clonal evolution corresponding to two hyperdiploid clones: 48,XY,+i(19)(p10),+22/48,idem,der(9)t(2;9)(q21~22;p21). The changes were gain of chromosome 19 with the overrepresentation of 19p arm, gain of chromosome 22, gain of the 2q arm, and loss of 9p21. Mutation analysis revealed a homozygous c.T365G (p.L122R) mutation of the MYOD1 gene, but none of PIK3CA. CONCLUSION: To our knowledge, this is the first adult MYOD1-mutant sclerosing rhabdomyosarcoma studied cytogenetically. The only other reported sclerosing rhabdomyosarcoma with MYOD1 mutation and abnormal karyotype was pediatric. Since these tumors are highly aggressive, further studies unravelling their cytogenetic and molecular characteristics are warranted.

Accurate 3-gene-signature for early diagnosis of liposarcoma progression.

BACKGROUND: Well- and dedifferentiated liposarcoma (WD/DDLPS) are rare mesenchymal malignant tumors that account for 20% of all sarcomas in adults. The WD form is a low-grade malignancy with a favourable prognosis which may progress to DDLPS, a high-grade aggressive counterpart. WDLPS is referred to as atypical lipomatous tumour (ALT) when localised in extremities, due to its better prognosis. Currently the final differential diagnosis to distinguish between more aggressive and less aggressive form is based on post-surgical histological examination and no molecular biomarkers for early detection are available. METHODS: Quantitative polymerase chain reaction (qPCR) analysis of 11 metabolic genes involved in general and adipose tissue-specific metabolism, was performed on ALT (= 8), WDLPS (= 9) and DDLPS (= 20) samples. Subsequent statistical analysis was carried out to determine genes that most accurately can predict DDLPS differential diagnosis. Selected genes were further validated in a separate cohort by qPCR and the data statistically analysed. Deep sequencing was performed on DDLPS specimen from the metastatic patient and on five random WDLPS specimens. RESULTS: We established a three-gene signature based on PNPLA2, LIPE and PLIN1, which identified DDLPS with 100% sensitivity and 90% specificity, even in specimens from the WD component of DDLPS tumors. Interestingly, the PNPLA2 gene is deleted in 45% of DDLPS samples analyzed under TCGA project, and the deletion is associated with significantly lower PNPLA2 expression level. However, other mechanisms causing loss or downregulation of the expression of these three genes may be involved. Moreover, the significantly lower level of PNPLA2 is associated with R1 surgical margins, compare to R0 margins, which suggests the more invasive tumor phenotype in the absence of PNPLA2. CONCLUSIONS: The identified metabolic signature allows highly accurate differential diagnosis between WD- and DDLPS even in samples containing lipid droplets, a marker of differentiation, which makes it very suitable for the use on biopsies. In respect to the pathogenesis of the disease, our results give a new insight into possible molecular mechanisms involved and support the recent observation that deletion of PNPLA2 is a novel factor in liposarcoma progression.

Risk stratification for central conventional chondrosarcoma of bone: A novel system predicting risk of metastasis and death in the Cancer Registry of Norway cohort.

BACKGROUND AND OBJECTIVES: Interobserver variability in histological grading of central conventional chondrosarcoma (CCCS) limits the quality of patient information and research progression. We aim to quantify known and new prognostic variables and propose a risk stratification model. METHOD: We selected 149 cases from the Cancer Registry of Norway. Cox proportional hazard models were estimated. Based on these results a dichotomous risk classification was proposed and presented by Kaplan-Meier estimates for rates of local recurrence, metastasis, and disease-specific survival. RESULTS: The influence of axial skeletal location (Hazard ratio [HR] = 19.06), a soft tissue component ≥1 cm (HR = 13.45), and histological grade 3 (HR = 16.46) are all significant in predicting the rate of metastasis. The creation of a variable combining axial skeletal location and a soft tissue component ≥1 cm strongly predicts the risk of metastasis (HR = 14.02; P < .001) and death (HR = 2.74; P = .030) at multivariate analysis, making the histological grade insignificant. Together with metastasis at diagnosis (HR = 285.65; P < .001), this forms the basis of our proposed risk stratification, producing a small high-risk group (39 cases with 33% risk of metastasis) and a large low-risk group (103 cases with 2% risk of metastasis) without a histological grade. CONCLUSION: Axial skeletal location and a soft tissue component ≥1 cm combined divides a CCCS cohort into low- and high-risk groups without a histological grade.

FOS-ANKH and FOS-RUNX2 Fusion Genes in Osteoblastoma.

BACKGROUND/AIM: Osteoblastoma is a rare benign tumor of the bones in which recurrent rearrangements of FOS have been found. Our aim was to investigate two osteoblastomas for possible genetic aberrations. MATERIALS AND METHODS: Cytogenetic, RNA sequencing, and molecular analyses were performed. RESULTS: A FOS-ANKH transcript was found in the first tumor, whereas a FOS-RUNX2 was detected in the second. Exon 4 of FOS fused with sequences either from intron 1 of ANKH or intron 5 of RUNX2. The fusion events introduced a stop codon and removed sequences involved in the regulation of FOS. CONCLUSION: Rearrangements and fusions of FOS show similarities with those of HMGA2 (a feature of leiomyomas and lipomas) and CSF1 (tenosynovial giant cell tumors). The replacement of a 3'-untranslated region, controlling the gene's expression, by a new sequence is thus a common pathogenetic theme shared by FOS, HMGA2, and CSF1 in many benign connective tissue tumors.

A novel risk score to predict early and late recurrence in solitary fibrous tumour.

AIMS: Solitary fibrous tumours (SFTs) are rare mesenchymal neoplasms with recurrence rates of 10-30%. Current risk stratification systems for extrameningeal SFTs are based on cohorts with limited follow-up and are not suitable for prediction of late recurrences. In this study we aimed to develop a prognostic model accounting for both early and late recurrences using a relatively large patient cohort with long-term follow-up. METHODS AND RESULTS: Clinicopathological factors were analysed in a cohort of 100 extrameningeal, STAT6-positive SFTs. Median follow-up for overall survival (OS) and recurrence-free interval (RFi) were 121 and 84 months, respectively. Disease relapse occurred in 31% of patients and median time to recurrence was 63 months. In univariate analysis mitotic count, necrosis, male gender and presence of severe atypia and pleomorphism were associated with inferior RFi. Mitotic count, necrosis and male gender were independent predictors of recurrence in multivariate analysis. Previously published risk models were also statistically associated with RFi in our cohort, but failed to reliably identify low-risk patients due to poor prediction of late recurrences. A novel risk score based on mitotic count, necrosis and gender was able to stratify patients into low-, intermediate- and high-risk groups for both early and late recurrences. CONCLUSIONS: In this cohort of patients with extrameningeal SFT and long-term follow-up mitotic count, necrosis and gender were independent prognostic markers of recurrence. We propose a novel risk score based on these factors and accounting for late recurrences, which should be validated in external cohorts with sufficient follow-up time.

Chronic Expanding Hematoma with a t(11;19)(q13;q13) Chromosomal Translocation.

BACKGROUND/AIM: Chronic expanding hematoma is defined as a hematoma that gradually expands over 1 month or longer, is without neoplastic features on histological sections, and does not occur in the setting of coagulopathy. The pathogenetic mechanism behind its development is unknown, nor is anything known about its genetic features. CASE REPORT: A 49-year-old man noted a tender lump close to the right femoral trochanter. Examination of a core needle biopsy showed a fibrous capsule with fibrinoid material on one side. The patient underwent surgery with removal of a cystic, encapsulated structure with central bleeding and proliferating vessels in the fibrous capsule. The reactive fibroblasts were without any sign of atypia. Genetic analyses were performed on this chronic expanding hematoma. RESULTS: G-Banding analysis of short-term cultured cells from the chronic expanding hematoma yielded a karyotype with a single clonal chromosome abnormality: 46,XY,t(11;19)(q13;q13)[8]/46,XY[10]. RNA sequencing and examination of the sequencing data using five different programs did not identify fusion genes related to the translocation. CONCLUSION: The acquired translocation t(11;19)(q13;q13) suggested that chronic expanding hematoma is a neoplastic lesion. Since the translocation did not lead to any fusion genes, one can speculate that it causes deregulation of gene expression.

Fusion of the COL1A1 and FYN Genes in Epithelioid Osteoblastoma.

BACKGROUND/AIM: Epithelioid osteoblastoma is a rare benign tumor of the bone. Its pathogenesis is unknown and little is known regarding its genetic features. MATERIALS AND METHODS: Cytogenetic, RNA sequencing, reverse transcription polymerase chain reaction (RT-PCR), genomic PCR, and Sanger sequencing analyses were performed on an epithelioid osteoblastoma. RESULTS: G-banding analysis of short-term cultured tumor cells yielded a normal male karyotype in all examined metaphases. RNA sequencing detected a fusion of COL1A1 from 17q21 with FYN from 6q21. Both RT-PCR and genomic PCR together with Sanger sequencing verified the presence of a COL1A1-FYN fusion gene. In the COL1A1-FYN chimeric transcript, exon 43 of COL1A1 was fused to exon 2 of FYN. The genomic junction occurred in introns 43 and 1 of COL1A1 and FYN, respectively. CONCLUSION: A COL1A1-FYN fusion gene was found in an epithelioid osteoblastoma resulting in deregulation of FYN. Whether COL1A1-FYN represents a consistent genetic feature of epithelioid osteoblastomas, remains to be seen.

Chondrosarcoma in Norway 1990-2013; an epidemiological and prognostic observational study of a complete national cohort.

BACKGROUND: Knowledge of chondrosarcoma (CS) of bone to date is based on institutional reports and registry publications with limits in reporting, detail and quality of data. METHOD: We have performed a retrospective search of CS of bone in the National Cancer Registry in Norway from 1990-2013, cross checked against local tumor databases with further quality control and supplementation of all data from clinical files. The time period is defined by the routine use of axial imaging in clinical practice. A total of 311 cases are included. We performed 108 pathological reviews and 223 radiological reviews. The manuscript was prepared according to the STROBE checklist for strengthening of observational studies. We performed uni-/multivariate cox analyses to define independent prognostic variables from the main cohort of central CS of bone. RESULTS: The incidence of CS of bone in Norway is 2.85/million/yr. for both sexes overall, rising to 3.45/million/yr. in the last 5-year period. There is an increase in the most common central CS subtype, stronger for women than for men. Central CS had, in general 10-15% local recurrence rates, all evident by 5 years while metastasis rate increases with location and grade. Exceptions are extremity grade 1 CS which displayed no metastatic events and axial grade-3 disease with high rates (50%) of both local and metastatic relapse. Peripheral CS had limited metastatic potential (2%), but rates of local relapse (13%) continue to appear towards 10 years of follow up. Malignancy grade 3 independently predicts rate of metastasis and presence of soft tissue component predicts local recurrence, metastasis and survival. CONCLUSION: Rates of local recurrence, metastasis and disease specific survival follow clear patterns depending on subtype, location and grade allowing better tailoring of follow-up regimes. Malignancy grade 3 and the presence of a soft tissue component independently predict behavior for central CS of bone.