Thromboembolic involvement and its possible pathogenesis in COVID-19 mortality: lesson from post-mortem reports.

The emergence of Coronavirus Disease 19 (COVID-19) as a pandemic has claimed hundreds of thousands of lives worldwide since its initial breakout. With increasing reports from clinical observations and autopsy findings, it became clear that the disease causes acute respiratory distress syndrome (ARDS), as well as a broad spectrum of systemic and multiorgan pathologies, including angiopathy, endothelialitis, and thrombosis. Coagulopathy is associated with the activity of megakaryocytes, which play crucial roles in modulating the platelet homeostasis. Only a few autopsy reports include findings on thrombosis formation and the presence of megakaryocytes. Here we review and summarize the possible involvement and the pathophysiology of the thromboembolic events in COVID-19 patients based on post-mortem reports. We reviewed post-mortem reports from March 2020 to September 2020. Eleven autopsy reports that demonstrated thromboembolic involvement findings, either macroscopically or microscopically, were included in this review. All studies reported similar pulmonary gross findings. Not all studies described thrombi formation and megakaryocyte findings. Pulmonary embolism, coagulopathy, severe endothelial injury, and widespread thrombosis are frequent in COVID-19 patients, following many patients with high-level D-Dimer, increased fibrinogen, abnormal prothrombic coagulation, and thrombocytopenia. Reports showed that thrombus was also found in the lower extremities' deep veins and the prostatic venous plexus. In conclusion, a complex interaction of SARS-CoV-2 virus invasion with platelets, leukocytes, endothelial cells, inflammation, immune response, and the possible involvement of megakaryocytes may increase the cumulative risk of thrombosis by a yet unclear cellular and humoral interaction.

Surgical Outcome and Oncological Survival of Osteofibrous Dysplasia-Like and Classic Adamantinomas: An International Multicenter Study of 318 Cases.

BACKGROUND: Osteofibrous dysplasia-like adamantinoma (OFD-AD) and classic adamantinoma (AD) are rare, neoplastic diseases with only limited data supporting current treatment protocols. We believe that our retrospective multicenter cohort study is the largest analysis of patients with adamantinoma to date. The primary purpose of this study was to describe the disease characteristics and evaluate the oncological outcomes. The secondary purpose was to identify risk factors for local recurrence after surgical treatment and propose treatment guidelines. METHODS: Three hundred and eighteen confirmed cases of OFD-AD and AD for which primary treatment was carried out between 1985 and 2015 were submitted by 22 tertiary bone tumor centers. Proposed clinical risk factors for local recurrence such as size, type, and margins were analyzed using univariable and multivariate Cox regression analysis. RESULTS: Of the 318 cases, 128 were OFD-AD and 190 were AD. The mean age at diagnosis was 17 years (median, 14.5 years) for OFD-AD and 32 years (median, 28 years) for AD; 53% of the patients were female. The mean tumor size in the OFD-AD and AD groups combined was 7.8 cm, measured histologically. Sixteen percent of the patients sustained a pathological fracture prior to treatment. Local recurrence was recorded in 22% of the OFD-AD cases and 24% of the AD cases. None of the recurrences in the OFD-AD group progressed to AD. Metastatic disease was found in 18% of the AD cases and fatal disease, in 11% of the AD cases. No metastatic or fatal disease was reported in the OFD-AD group. Multivariate Cox regression analysis demonstrated that uncontaminated resection margins (hazard ratio [HR] = 0.164, 95% confidence interval [CI] = 0.092 to 0.290, p < 0.001), pathological fracture (HR = 1.968, 95% CI = 1.076 to 3.600, p = 0.028), and sex (female versus male: HR = 0.535, 95% CI = 0.300 to 0.952, p = 0.033) impacted the risk of local recurrence. CONCLUSIONS: OFD-AD and AD are parts of a disease spectrum but should be regarded as different entities. Our results support reclassification of OFD-AD into the intermediate locally aggressive category, based on the local recurrence rate of 22% and absence of metastases. In our study, metastatic disease was restricted to the AD group (an 18% rate). We advocate wide resection with uncontaminated margins including bone and involved periosteum for both OFD-AD and AD. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Nikolay Ivanovich Pirogov (1810-1881): Anatomical research to develop surgery.

The 19th century Russian surgeon Nikolay Ivanovich Pirogov believed passionately in the importance of anatomy for surgeons. His interest in anatomy began as a medical student in Moscow. After graduating in 1828 Pirogov entered the postgraduate German-Baltic University of Dorpat (now Tartu in the Republic of Estonia) where he studied anatomy and surgery. After completing his study, he remained to research the consequences of ligation of the aorta in a series of animal experiments, which formed the core of his doctoral thesis. He wanted to determine the feasibility of aortic ligation as a treatment for patients with an aneurysm of the aorta or iliac artery. He discovered that success was only likely when the aorta was ligated between the two mesenteric arteries and the ligature gradually tightened, an approach surgically difficult in humans. Pirogov then spent 2 years at the Charité Hospital in Berlin before returning to Russia. In 1841, he was appointed Professor of Applied Anatomy and Surgery at the Imperial Medico-Surgical Academy in Saint Petersburg. He instituted the teaching of microscopy and histology to the medical curriculum and in 1846 formed the Institute for Applied Anatomy within the academy, where in addition to teaching medical students future teachers of anatomy in Russia were trained. Pirogov published extensively on anatomy, including several anatomical atlases, the most notable his three-dimensional atlas of topographical anatomy published in four volumes between 1852 and 1859. Today Pirogov's contributions to anatomy are remembered in a number of anatomical structures named after him. Clin. Anat., 33:714-730, 2020. © 2019 Wiley Periodicals, Inc.

Conjunctival Leiomyosarcoma, a Rare Neoplasm Always Originating at the Limbus? Report of a New Case and Review of 11 Published Cases.

PURPOSE OF THE STUDY: To describe the differential diagnosis and management of a rare conjunctival malignancy. PROCEDURES: A 79-year-old man presented with a conjunctival mass at the limbus. Excisional biopsy revealed a malignant mesenchymal tumor with myogenic differentiation. Six months later, three suspect lesions developed at the border of the previous excision. Pathological diagnosis pointed to a leiomyosarcoma. Adjuvant radiotherapy with strontium-90 brachytherapy was applied. After 3 years, there was neither recurrence nor distant metastases. A literature review revealed 11 cases of conjunctival leiomyosarcoma. RESULTS: All 12 cases seemed to originate at the limbal conjunctiva. Scleral invasion was found only in one patient with multiple previous resections. Corneal invasion was reported in two patients. Four patients had a globe-sparing resection. In two of them, margins were not tumor free and additional brachytherapy gave a tumor-free follow-up of 1 and 3 years. Four cases underwent an exenteration. CONCLUSION AND MESSAGE: Primary conjunctival leiomyosarcoma is a rare tumor with a favorable prognosis due to early detection and consequently limited size. Diagnosis involves histopathological investigation including immunohistochemistry. If possible, complete resection has the best prognosis. Adjunctive radiotherapy can be effective when the margins are not free and should be considered.

M-CSF and IL-34 expression as indicators for growth in sporadic vestibular schwannoma.

Macrophage colony stimulating factor and IL-34 are associated with clinical vestibular schwannoma progression. Investigating the biology behind vestibular schwannoma progression helps understanding tumor growth. Inflammation is important in the microenvironment of neoplasms. Macrophages are major players in the intratumoral infiltrate. These tumor-associated macrophages are known to stimulate angiogenesis and cell growth. M-CSF and IL-34 are cytokines that can regulate tumor-infiltrating macrophages. They are expressed by tumors and form potential targets for therapy. The goal of this study was to investigate these cytokines in vestibular schwannomas and to see if their expression is related to angiogenesis, macrophage numbers, cystic degeneration, and volumetric tumor progression. Immunohistochemical expression of M-CSF and IL-34 was analyzed in ten fast-growing vestibular schwannomas and in ten slow-growing vestibular schwannomas. Expression M-CSF and IL-34 were compared between fast- versus slow-growing and cystic versus non-cystic tumors. Data on macrophage numbers and microvessel density, known from earlier research, was also included. All tumors expressed M-CSF and its expression was higher in fast-growing tumors (p = 0.003) and in cystic tumors (p = 0.035). CD163 expression was higher in tumors with strong M-CSF expression (p = 0.003). All tumors expressed IL-34 as well, but no significant differences were found in relation to clinicopathological characteristics. This study demonstrated the expression of M-CSF and IL-34 in vestibular schwannomas. The results suggest that M-CSF is related to macrophage activity and tumor progression, making it a potential target for therapy. If a similar assumption can be made for IL-34 remains unclear.

The incidence, mutational status, risk classification and referral pattern of gastro-intestinal stromal tumours in the Netherlands: a nationwide pathology registry (PALGA) study.

Symptomatic gastrointestinal stromal tumours (GIST) are infrequent with an incidence of 12.7 per million inhabitants in the western population. We studied whether the incidence of GIST has further increased between 2003 and 2012 and assessed the frequency of mutations, risk groups, histological subtypes and immunohistochemistry results. From PALGA, the nationwide Dutch Pathology Registry, pathology excerpts from all patients with a GIST or GIST-like tumour between 2003 and 2012 were retrieved to calculate incidence rates. Full pathology reports were retrieved of resections in 2011 and 2012 to study the frequency of mutations, risk groups, histological subtypes and immunohistochemistry results. The incidence of GIST increased to 17.7 per million inhabitants in 2012 with a median age of 67 years. Mutational analysis was performed in 33.9% of patients with a resection between 2011 and 2012 (KIT mutation 67.5%, PDGFRA 16.3%, wild-type 11.4%). The percentage of high risk patients in the different risk classifications varied from 19.9% to 38.0% depending on the used classification. Only 35.9% of patients had diagnosis or revision of pathology diagnosis within three months in a designated GIST referral centre. No increase in proportion of central pathology reviews was found. Proportion of patients with mutational analysis increased over the years. The registered incidence of GIST, 17.7 per million inhabitants in 2012 in the Netherlands, is still rising. Despite incorporation in the ESMO GIST guidelines since 2008 for mutational testing and since 2010 for central review of pathology, both are performed in a minority of patients.

MRI appearances of atypical cartilaginous tumour/grade I chondrosarcoma after treatment by curettage, phenolisation and allografting: recommendations for follow-up.

AIMS: The purpose of this retrospective study was to differentiate between the MRI features of normal post-operative change and those of residual or recurrent disease after intralesional treatment of an atypical cartilage tumour (ACT)/grade I chondrosarcoma. PATIENTS AND METHODS: We reviewed the case notes, radiology and histology of 75 patients, who had been treated for an ACT/grade I chondrosarcoma by curettage, phenolisation and bone allografting between 1994 and 2005. The first post-operative Gd-enhanced MRI scan was carried out within one year of surgery. Patients had a minimum of two scans and a mean follow-up of 72 months (13 to 169). Further surgery was undertaken in cases of suspected recurrence. RESULTS: In 14 patients (18.6%) a second procedure was undertaken after a mean period of 59 months (8 to 114). Radio frequency ablation (RFA) was used in lesions of < 10 mm and curettage, phenolisation and bone grafting for those ≥ 10 mm. Only six of these (8% of total) had a histologically-proven recurrence. No increase in tumour grade was seen at time of recurrence. CONCLUSION: Based on this study, we have been able to classify the post-operative MRI appearances into four groups. These groups differ in follow-up, and have a different risk of recurrence of the lesion. Follow-up and treatment vary for the patients in each group. We present a flow diagram for the appropriate and safe follow-up for this specific group of patients. Cite this article: Bone Joint J 2016;98-B:1674-81.

CXCL14, CXCR7 expression and CXCR4 splice variant ratio associate with survival and metastases in Ewing sarcoma patients.

PURPOSE: Ewing sarcoma (EWS) is the second most common sarcoma of bone in children and young adults. Patients with disseminated disease at diagnosis or early relapse have a poor prognosis. Our goal was to identify novel predictive biomarkers for these patients, focusing on chemokines, specifically genes involved in the CXCR4-pathway because of their established role in metastasis and tumour growth. METHODS: Total RNA isolated from therapy-naïve tumour samples (n=18; panel I) and cell lines (n=21) was used to study expression of CXCR4-pathway related genes and CXCR4 splice variants (CXCR4-2: Small and CXCR4-1: Large) by RT-Q-PCR. Expression levels were correlated to overall survival (OS) and event free survival (EFS). Study results were validated in an independent series of 26 tumour samples (panel II) from therapy-naïve tumour samples. RESULTS: CXCL12, CXCR4, CXCR7 and CXCL14 were expressed and high CXCR7 and CXCL14 expression showed a positive correlation with EFS and OS and a negative correlation with metastasis development. Both splice variants CXCR4 were expressed in cell lines and tumour samples and CXCR4-1/CXCR4-2 ratio was significantly higher in tumour samples compared to cell lines and correlated with an improved EFS and OS. The results from the test panel were validated in an independent sample panel. CONCLUSIONS: We identified a set of genes involved in CXCR4 signalling that may be used as a marker to predict survival and metastasis development in Ewing sarcoma.

Novel splice variants of CXCR4 identified by transcriptome sequencing.

Chemokine receptor CXCR4 is involved in tumor growth, angiogenesis and metastasis. Its function is regulated in many ways and one of them is alternative splicing. We identified two novel coding splice variants (CXCR4-3 and CXCR4-4) of CXCR4 in Ewing sarcoma (EWS) cell lines by whole transcriptome sequencing and validated these with reverse transcriptase- PCR and Sanger sequencing. The novel splice variants were expressed at RNA level in Ewing sarcoma samples and in other tumor cell lines and placenta, but not in lung. Due to inclusion of an additional exon the new isoforms have a 70 and 33 amino acid elongation of the N-terminal end of CXCR4. For validation at protein and functional level, the identified isoforms and normal CXCR4 were cloned into an EYFP tagged vector and ectopically expressed in HEK293T cell line and EWS cell line A673. Of the novel isoforms CXCR4-3 showed cell membrane localization and a functional response after addition of CXCR4 ligand CXCL12a. CXCR4-4 showed strong cytoplasmic accumulation and no response to ligand treatment. The role of the newly discovered isoforms in CXCR4 signaling is likely to be limited. Our data stresses the importance of functional validation of newly identified isoforms.

Nikolay Ivanovich Pirogov: a surgeon's contribution to military and civilian anaesthesia.

A key figure in the development of anaesthesia in Russia was the surgeon Nikolay Ivanovich Pirogov (1810-1881). He experimented with ether and chloroform and organised the general introduction of anaesthesia in Russia for patients undergoing surgery. He was the first to perform systematic research into anaesthesia-related morbidity and mortality. More specifically, he was one of the first to administer ether anaesthesia on the battlefield, where the principles of military medicine that he established remained virtually unchanged until the outbreak of the Second World War.

EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment.

BACKGROUND: Four international study groups undertook a large study in resectable osteosarcoma, which included two randomised controlled trials, to determine the effect on survival of changing post-operative chemotherapy based on histological response. PATIENTS AND METHODS: Patients with resectable osteosarcoma aged ≤40 years were treated with the MAP regimen, comprising pre-operatively of two 5-week cycles of cisplatin 120 mg/m(2), doxorubicin 75 mg/m(2), methotrexate 12 g/m(2) × 2 (MAP) and post-operatively two further cycles of MAP and two cycles of just MA. Patients were randomised after surgery. Those with ≥10% viable tumour in the resected specimen received MAP or MAP with ifosfamide and etoposide. Those with <10% viable tumour were allocated to MAP or MAP followed by pegylated interferon. Longitudinal evaluation of quality of life was undertaken. RESULTS: Recruitment was completed to the largest osteosarcoma study to date in 75 months. Commencing March 2005, 2260 patients were registered from 326 centres across 17 countries. About 1334 of 2260 registered patients (59%) were randomised. Pre-operative chemotherapy was completed according to protocol in 94%. Grade 3-4 neutropenia affected 83% of cycles and 59% were complicated by infection. There were three (0.13%) deaths related to pre-operative chemotherapy. At definitive surgery, 50% of patients had at least 90% necrosis in the resected specimen. CONCLUSIONS: New models of collaboration are required to successfully conduct trials to improve outcomes of patients with rare cancers; EURAMOS-1 demonstrates achievability. Considerable regulatory, financial and operational challenges must be overcome to develop similar studies in the future. The trial is registered as NCT00134030 and ISRCTN 67613327.

Doxorubicin-based adjuvant chemotherapy in soft tissue sarcoma: pooled analysis of two STBSG-EORTC phase III clinical trials.

BACKGROUND: The EORTC-STBSG coordinated two large trials of adjuvant chemotherapy (CT) in localized high-grade soft tissue sarcoma (STS). Both studies failed to demonstrate any benefit on overall survival (OS). The aim of the analysis of these two trials was to identify subgroups of patients who may benefit from adjuvant CT. PATIENTS AND METHODS: Individual patient data from two EORTC trials comparing doxorubicin-based CT to observation only in completely resected STS (large resection, R0/marginal resection, R1) were pooled. Prognostic factors were assessed by univariate and multivariate analyses. Patient outcomes were subsequently compared between the two groups of patients according to each analyzed factor. RESULTS: A total of 819 patients had been enrolled with a median follow-up of 8.2 years. Tumor size, high histological grade and R1 resection emerged as independent adverse prognostic factors for relapse-free survival (RFS) and OS. Adjuvant CT is an independent favorable prognostic factor for RFS but not for OS. A significant interaction between benefit of adjuvant CT and age, gender and R1 resection was observed for RFS and OS. Males and patients >40 years had a significantly better RFS in the treatment arms, while adjuvant CT was associated with a marginally worse OS in females and patients <40 years. Patients with R1 resection had a significantly better RFS and OS favoring adjuvant CT arms. CONCLUSION: Adjuvant CT is not associated with a better OS in young patients or in any pathology subgroup. Poor quality of initial surgery is the most important prognostic and predictive factor for utility of adjuvant CT in STS. Based on these data, we conclude that adjuvant CT for STS remains an investigational procedure and is not a routine standard of care.

Gene expression profiling of giant cell tumor of bone reveals downregulation of extracellular matrix components decorin and lumican associated with lung metastasis.

Giant cell tumor of bone (GCTB) displays worrisome clinical features such as local recurrence and occasionally metastatic disease which are unpredictable by morphology. Additional routinely usable biomarkers do not exist. Gene expression profiles of six clinically defined groups of GCTB and one group of aneurysmal bone cyst (ABC) were determined by microarray (n = 33). The most promising differentially expressed genes were validated by Q-PCR as potential biomarkers in a larger patient group (n = 41). Corresponding protein expression was confirmed by immunohistochemistry. Unsupervised hierarchical clustering reveals a metastatic GCTB cluster, a heterogeneous, non-metastatic GCTB cluster, and a primary ABC cluster. Balanced score testing indicates that lumican (LUM) and decorin (DCN) are the most promising biomarkers as they have lower level of expression in the metastatic group. Expression of dermatopontin (DPT) was significantly lower in recurrent tumors. Validation of the results was performed by paired and unpaired t test in primary GCTB and corresponding metastases, which proved that the differential expression of LUM and DCN is tumor specific rather than location specific. Our findings show that several genes related to extracellular matrix integrity (LUM, DCN, and DPT) are differentially expressed and may serve as biomarkers for metastatic and recurrent GCTB.

Primary intraosseous manifestation of Rosai-Dorfman disease: 2 cases and review of literature.

Rosai-Dorman disease (RDD) is a rare disorder of proliferative histiocytes with an unknown etiology. It is also known as sinus histiocytosis with massive lymphadenopathy. Most patients present with painless cervical lymphadenopathy due to accumulation of histiocytes in the lymph nodes, often in conjunction with fever, elevated leukocyte count and erythrocyte sedimentation rate. Isolated skeletal involvement is very rare.

Zebrafish as a model for human osteosarcoma.

For various reasons involving biological comparativeness, expansive technological possibilities, accelerated experimental speed, and competitive costs, zebrafish has become a comprehensive model for cancer research. Hence, zebrafish embryos and full-grown fish have been instrumental for studies of leukemia, melanoma, pancreatic cancer, bone tumors, and other malignancies. Although because of its similarities to human osteogenesis zebrafish appears to be an appealing model to investigate osteosarcoma, only a few osteosarcoma specific studies have been accomplished yet. Here, we review interesting related and unrelated reports of which the findings might be extrapolated to osteosarcoma. More importantly, rational but yet unexplored applications of zebrafish are debated to expand the window of opportunities for future establishment of osteosarcoma models. Accordingly technological advances of zebrafish based cancer research, such as robotic high-throughput multicolor injection systems and advanced imaging methods are discussed. Furthermore, various use of zebrafish embryos for screening drug regimens by combinations of chemotherapy, novel drug deliverers, and immune system modulators are suggested. Concerning the etiology, the high degree of genetic similarity between zebrafish and human cancers indicates that affected regions are evolutionarily conserved. Therefore, zebrafish as a swift model system that allows for the investigation of multiple candidate gene-defects is presented.

Brostallicin versus doxorubicin as first-line chemotherapy in patients with advanced or metastatic soft tissue sarcoma: an European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group randomised phase II and pharmacogenetic study.

AIM: Brostallicin is a DNA minor groove binder that has shown activity in patients with soft tissue sarcoma (STS) failing first-line therapy. The present study assessed the safety and efficacy of first-line brostallicin in patients with advanced or metastatic STS >60 years or not fit enough to receive combination chemotherapy. A prospective explorative pharmacogenetic analysis was undertaken in parallel. METHODS: Patients were randomised in a 2:1 ratio between IV brostallicin 10mg/m(2) and doxorubicin 75 mg/m(2) once every 3 weeks for a maximum of six cycles. Disease stabilisation at 26 weeks (primary end-point) was considered a 'success'. Further testing of brostallicin was warranted if ≥ 35 'successes' were observed in the first 72 eligible patients treated with brostallicin. In addition, patients were genotyped for glutathione S transferase (GST) polymorphisms. RESULTS: One hundred and eighteen patients were included (79 brostallicin and 39 doxorubicin). Brostallicin was well tolerated in comparison to doxorubicin with less grade 3-4 neutropenia (67% versus 95%), grade 2-3 systolic dysfunction (0% versus 11%), alopecia (17% versus 61%) and grade 2-3 mucositis (0% versus 18%). For brostallicin versus doxorubicin, 'successes' were observed in 5/77 versus 10/36, progression free survival at 1 year was 6.5% versus 15.6%, objective response rate was 3.9% versus 22.2% and overall survival at 1 year was 50.5% versus 57.9%, respectively. Only GSTA1 genotype was significantly associated with success rate of doxorubicin treatment. CONCLUSION: Brostallicin cannot be recommended at this dose and schedule in this patient population as first-line therapy. GSTA1 genotype may be predictive for doxorubicin efficacy but warrants further study.

Results of a phase II pilot study of moderate dose radiotherapy for inoperable desmoid-type fibromatosis--an EORTC STBSG and ROG study (EORTC 62991-22998).

BACKGROUND: To determine the activity of radiotherapy in patients with inoperable desmoid-type fibromatosis (DF) a multicenter prospective phase II trial was carried out. MATERIALS AND METHODS: Patients with inoperable progressive disease of primary, recurrent or incompletely resected lesions received a dose of 56 Gy in 28 fractions. Follow-up MRI studies were carried out every 3 months for 2 years and thereafter every 6 months. The primary end point was local control rate at 3 years, estimated by a nonparametric method for interval-censored survival data. Secondary end points were objective tumor response, acute and late toxic effect. RESULTS: Forty-four patients (27 F/17 M) were enrolled from 2001 to 2008. Median age was 39.5 years. Main tumor sites included trunk 15 (34.1%) and extremities 27 (61.3%). Median follow-up was 4.8 years. The 3-year local control rate was 81.5% (90% one-sided confidence interval 74% to 100%). Best overall response during the first 3 years was complete response (CR) 6 (13.6%), partial response (PR) 16 (36.4%), stable disease 18 (40.9%), progressive disease 3 (6.8%) and nonassessable 1 (2.3%). Five patients developed new lesions. After 3 years, the response further improved in three patients: (CR 2, PR 1). Acute grade 3 side-effects were limited to skin, mucosal membranes and pain. Late toxic effect consisted of mild edema in 10 patients. CONCLUSIONS: Moderate dose radiotherapy is an effective treatment of patients with DF. Response after radiation therapy is slow with continuing regression seen even after 3 years.

The management of diffuse-type giant cell tumour (pigmented villonodular synovitis) and giant cell tumour of tendon sheath (nodular tenosynovitis).

Giant cell tumours (GCT) of the synovium and tendon sheath can be classified into two forms: localised (giant cell tumour of the tendon sheath, or nodular tenosynovitis) and diffuse (diffuse-type giant cell tumour or pigmented villonodular synovitis). The former principally affects the small joints. It presents as a solitary slow-growing tumour with a characteristic appearance on MRI and is treated by surgical excision. There is a significant risk of multiple recurrences with aggressive diffuse disease. A multidisciplinary approach with dedicated MRI, histological assessment and planned surgery with either adjuvant radiotherapy or systemic targeted therapy is required to improve outcomes in recurrent and refractory diffuse-type GCT. Although arthroscopic synovectomy through several portals has been advocated as an alternative to arthrotomy, there is a significant risk of inadequate excision and recurrence, particularly in the posterior compartment of the knee. For local disease partial arthroscopic synovectomy may be sufficient, at the risk of recurrence. For both local and diffuse intra-articular disease open surgery is advised for recurrent disease. Marginal excision with focal disease will suffice, not dissimilar to the treatment of GCT of tendon sheath. For recurrent and extra-articular soft-tissue disease adjuvant therapy, including intra-articular radioactive colloid or moderate-dose external beam radiotherapy, should be considered.

Smooth muscle actin expression in primary bone tumours.

Alpha isoform of smooth muscle actin (SMA) expression has been reported in giant cell tumour of bone (GCTB) and other benign and malignant bone tumours, but the pattern of SMA expression and the precise nature of SMA-expressing cells in these lesions is uncertain. We determined by immunohistochemistry the expression of SMA and other muscle and vascular markers in normal bone, GCTB and a wide range of primary benign and malignant bone tumours. Cultured stromal cells of GCTB, chondroblastoma (CB), and aneurysmal bone cyst (ABC) were also analysed for SMA expression. SMA was only noted in blood vessels in normal bone. SMA was expressed by mononuclear stromal cells (MSC) cultured from GCTB, ABC and CB. SMA was strongly and diffusely expressed by MSC in non-ossifying fibroma, fibrous dysplasia, and "brown tumour" of hyperparathyroidism. SMA expression was also noted in GCTB, ABC, CB, chondromyxoid fibroma, malignant fibrous histiocytoma of bone and osteosarcoma. Little or no SMA was noted in Langerhans cell histiocytosis, simple bone cyst, Ewing's sarcoma, osteoblastoma, osteoid osteoma, enchondroma, osteochondroma, chondrosarcoma, myeloma, lymphoma, chordoma and adamantinoma. Our findings show that there is differential SMA expression in primary bone tumours and that identifying the presence or absence of SMA is useful in the differential diagnosis of these lesions. The nature of SMA-expressing cells in bone tumours is uncertain but they are negative for desmin and caldesmon and could represent either myofibroblasts or perivascular cells, such as pericytes.