We assessed the frequency of programmed death-ligand 1 (PD-L1) expression by immunohistochemistry (IHC) in a cohort of 522 sarcomas from 457 patients, incuding a subset of 46 patients with 63 matched ...samples from local recurrence or metastases with primary tumours and/or metachronous metastases. We also investigated the correlation of PD-L1 with the presence and degree of tumour-infiltrating lymphocytes (TILs) in a subset of cases. IHC was performed using the PD-L1 SP263 companion kit (VENTANA) on tissue microarrays from an archival cohort. Evaluation of PD-L1 and TILs was performed on full sections for a subset of 23 cases. Fisher's exact and Mann Whitney test were used to establish significance (P <0.05). PD-L1 positive expression (≥1%) was identified in 31% of undifferentiated pleomorphic sarcomas, 29% of angiosarcomas, 26% of rhabdomyosarcomas, 18% of myxofibrosarcomas, 11% of leiomyosarcomas and 10% of dedifferentiated liposarcomas. Negative expression was present in all atypical lipomatous tumous/well-differentiated lipoasarcomas, myxoid liposarcomas, synovial sarcomas, pleomorphic liposarcomas, and Ewing sarcomas. PD-L1 IHC was concordant in 81% (38 of 47) of matched/paired samples. PD-L1 IHC was discordant in 19% (9 of 47 matched/paired samples), displaying differences in the proportion of cells expressing PD-L1 amongst paired samples with the percentage of PD-L1-positive cells increasing in the metastatic/recurrent site compared to the primary in 6 of 9 cases (67%). Significant correlation between PD-L1 expression and the degree of TILs was exclusively identified in the general cohort of leiomyosarcomas, but not in other sarcoma subtypes or in metastatic/recurrent samples. We conclude that the prevalence of PD-L1 expression in selected sarcomas is variable and likely to be clone dependent. Importantly, we demonstrated that PD-L1 can objectively increase in a small proportion of metastases/recurrent sarcomas, offering the potential of treatment benefit to immune checkpoint inhibitors in this metastatic setting.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Blau syndrome (BS) is a rare autosomal dominant familial granulomatous inflammatory disease presenting in early childhood with dermatitis, arthritis and uveitis. Early-onset sarcoidosis represents ...the sporadic form, and both are characterised by mutations in the CARD15/NOD2 gene on chromosome 16. We describe a 38-year-old man with known BS who presented for orthopaedic review following right-sided patellar dislocation. MRI of the injured knee demonstrated diffuse synovitis and prominent fatty tissue resembling lipoma arborescens with evidence of recent patellar dislocation. Synovectomy was performed and confirmed granulomatous synovitis. Knee imaging findings are described for the first time. Combining distinct morphological bone changes with synovitis which resembles lipoma arborescens and histology which includes sarcoidal-type granulomatous synovitis should lead the radiologist and pathologist to consider the diagnosis of BS.
Background The pathophysiologic mechanisms behind proliferation of fibroblasts and deposition of dense collagen matrix in idiopathic frozen shoulder remain unclear. Accumulation of advanced glycation ...end products (AGEs) with cross-linking and stabilization of collagen has been hypothesized to contribute to this pathophysiologic process. This study investigated whether the immunoreactivity of AGEs is higher in patients with idiopathic frozen shoulder than in the control groups. Methods Shoulder capsule samples were collected from 8 patients with idiopathic frozen shoulder, 6 with unstable shoulders (control 1), and 8 with rotator cuff tears (control 2). The samples were hematoxylin and eosin stained and analyzed by immunohistochemistry using antibodies against AGEs. Immunoreactivities were rated in a blinded fashion from none (0) to strong (3). Immunohistochemical distribution within the capsule was noted. Results Frozen shoulder patients had greater frequency and severity of self-reported pain ( P = .02) than rotator cuff tear patients and more restricted range of motion in all planes ( P < .05) than patients of the instability and rotator cuff tear groups. Hematoxylin and eosin–stained capsular tissue from frozen shoulder showed fibroblastic proliferation, increased numbers of adipocytes, and increased subsynovial vascularity. Immunoreactivity of AGEs was stronger in frozen shoulder capsules (2.8) than in instability (0.3; P = .0001) and rotator cuff tear (1.1; P = .016) capsules. Conclusion This study highlights a potential role for AGEs in the pathogenesis of frozen shoulder. The overexpression of AGEs may explain the fibroblastic proliferation and deposition of collagen matrix in idiopathic frozen shoulder. Level of evidence Basic Science Study; Histology
Background Our understanding of the pathogenesis of frozen shoulder and why it is so painful is undetermined. This study investigated the expression of neuronal proteins in the capsular tissue of ...frozen shoulder. Methods Shoulder capsular samples were collected from 8 patients with idiopathic adhesive capsulitis and 10 patients with a rotator cuff tear but no stiffness (controls). Samples were analyzed by immunohistochemistry using antibodies against protein gene product 9.5 (PGP9.5), a general nerve marker; growth associated protein 43 (GAP43), a nerve growth marker; nerve growth factor receptor p75; and CD34, an endothelial cell marker. Results Samples from frozen shoulders showed subsynovial hypercellularity and fibroblastic proliferation, with increased expression of nerve growth factor receptor p75 and CD34 compared with controls. Nerves positive for PGP9.5 and GAP43 were more abundant in samples of frozen shoulder (2.8 ± 0.2 and 2.4 ± 0.4 per field; P < .01) compared with controls (1.6 ± 0.3 and 1.3 ± 0.3 per field; P < .05). Expression of neuronal proteins followed that of CD34. Conclusion Increased expression of nerve growth factor receptor and new nerve fibers were found in the shoulder capsular tissue of patients with frozen shoulder compared with those without a frozen shoulder. These data suggest that neoinnervation and neoangiogenesis in the shoulder capsule are important events in the pathogenesis of frozen shoulder and may help explain the often-severe pain of patients with frozen shoulder.
In this study we used the Illumina Infinium Methylation array to investigate in a cohort of matched archival human tissue samples (n = 32) from 14 individuals with soft tissue sarcomas if genome-wide ...methylation changes occur during metastatic and recurrent (Met/Rec) disease. A range of sarcoma types were selected for this study: leiomyosarcoma (LMS), myxofibrosarcoma (MFS), rhabdomyosarcoma (RMS) and synovial sarcoma (SS). We identified differential methylation in all Met/Rec matched samples, demonstrating that epigenomic differences develop during the clonal evolution of sarcomas. Differentially methylated regions and genes were detected, not been previously implicated in sarcoma progression, including at PTPRN2 and DAXX in LMS, WT1-AS and TNXB in SS, VENTX and NTRK3 in pleomorphic RMS and MEST and the C14MC / miR-379/miR-656 in MFS. Our overall findings indicate the presence of objective epigenetic differences across primary and Met/Rec human tissue samples not previously reported.
Objective
To describe the imaging and histopathological findings and provide an overview of a recently described and rare cause of bone sclerosis.
Materials and methods
Five cases of intra-osseous ...hibernoma of bone that presented over the last year. The imaging and histopathology is reviewed.
Results
All cases were identified in asymptomatic middle-aged to elderly adults as incidental findings with bone sclerosis in the axial skeleton. MRI showed lesions that were T1 hypointense to subcutaneous fat and hyperintense to skeletal muscle and one showed contrast enhancement. Glucose avidity was demonstrated on FDGPET in both cases tested and isotope bone scan performed in three cases showed strong positivity in two, but uptake was inconspicuous in one case.
Conclusions
Intra-osseous hibernoma is a rare cause of sclerotic bone lesions, predominating in the axial skeleton of middle-aged and elderly adults. They have a non-aggressive appearance on CT and on MRI are T1 hypointense to subcutaneous fat and hyperintense to skeletal muscle. They are usually T2 hyperintense and may show peripheral contrast enhancement. They may show increased glucose avidity on FDGPET and may or may not be positive on isotope bone scans. We suspect that with ever-increasing use of a variety of imaging techniques, particularly in a setting of staging for malignant disease, more such cases will come to light. This diagnosis should be added to the differential diagnosis of sclerotic bone lesions.
Purpose and Experimental Design: Telomeres of tumor cells may be maintained by telomerase or by alternative lengthening of telomeres (ALT). The standard ALT
assay requires Southern analysis of high ...molecular weight genomic DNA. We aimed to establish and validate an ALT assay suitable
for archived paraffin-embedded tumors and to use it to examine the prevalence and clinical significance of ALT in various
types of tumors that are often telomerase negative.
Results: To assay for ALT, we detected ALT-associated promyelocytic leukemia (PML) bodies (APBs) by combined PML immunofluorescence
and telomere fluorescence in situ hybridization. APBs are PML nuclear domains containing telomeric DNA and are a known hallmark of ALT in cell lines. The APB
assay concurred with the standard ALT assay in 62 of 62 tumors and showed that 35% of 101 soft tissue sarcomas (STS), 47%
of 58 osteosarcomas (especially younger patients), 34% of 50 astrocytomas, and 0% of 17 papillary thyroid carcinomas were
ALT positive (ALT+). The prevalence of ALT varied greatly among different STS subtypes: malignant fibrous histiocytomas, 77%;
leiomyosarcomas, 62%; liposarcomas, 33%; synovial sarcomas, 9%; and rhabdomyosarcomas, 6%. ALT correlated with survival in
glioblastoma multiforme and occurred more often in lower-grade astrocytomas, but ALT+ and ALT− sarcomas were equally aggressive
in terms of grade and clinical outcome.
Conclusion: The APB assay for ALT is suitable for paraffin-embedded tumors. It showed that a substantial proportion of STS, osteosarcomas,
and astrocytomas, but not papillary thyroid carcinomas use ALT. APB positivity correlated strongly with survival of patients
with astrocytomas.
Mesenchymal chondrosarcoma (MC) is a rare sarcoma that typically arises in adolescents and young adults and characteristically harbours a HEY1-NCOA2 gene fusion. A recent study has shown that NKX3.1 ...immunohistochemistry (IHC) is highly specific and sensitive in MCs. NKX3.1 is a nuclear marker expressed in prostatic tissue and is widely used in most laboratories to determine prostatic origin of metastatic tumours. In the current study we investigated whether this stain can be used in the diagnostic workup of MC, as it may assist in triaging cases for further molecular testing, by assessing its expression in a cohort of MCs and in a wide spectrum of sarcoma types. Furthermore, we aimed to elucidate if expression of NKX3.1 by MCs is related to androgen receptor (AR) expression. We identified NKX3.1 positive nuclear staining in 9 of 12 individual patients of MC (n=20 of 25 samples when taking into account separate episodes). Four of the five negative specimens had been previously subjected to acid-based decalcification. NKX3.1 was negative in 536 samples from 16 non-MC sarcomas derived from largely tissue microarrays (TMAs). Overall, we identified 80% sensitivity and 100% specificity for NKX3.1 IHC in MCs. The sensitivity increased to 95.2% when acid-based decalcified specimens were excluded from the analysis. No correlation between NKX3.1 expression and AR IHC was identified. In summary, our findings indicate that NKX3.1 nuclear positivity is highly sensitive and specific for MC, provided that ethylenediaminetetraacetic acid (EDTA)-based rather than acid-based decalcification is used for sample processing. NKX3.1 IHC in the right clinical and histopathological setting can potentially be sufficient for the diagnosis of MC, reserving molecular confirmation only for equivocal cases.
CIC-rearranged sarcoma is a recently established, ultra-rare, molecularly defined sarcoma subtype. We aimed to further characterise clinical features of CIC-rearranged sarcomas and explore clinical ...management including systemic treatments and outcomes.
A multi-centre retrospective cohort study of patients diagnosed between 2014-2019.
Eighteen patients were identified. The median age was 27 years (range 13-56), 10 patients were male (56%), 11 patients (61%) had localised disease and 7 patients had advanced (metastatic or unresectable) disease at diagnosis. Of 11 patients with localised disease at diagnosis, median overall survival (OS) was 40.6 months and the 1-, 2- and 5-year OS estimates were 82%, 64% and 34% respectively. Nine patients (82%) underwent surgery (all had R0 resections), 8 (73%) patients received radiotherapy to the primary site (median dose 57Gy in 28 fractions), and 8 (73%) patients received chemotherapy (predominantly Ewing-based regimens). Metastases developed in 55% with a median time to recurrence of 10.5 months. In patients with advanced disease at diagnosis, median OS was 12.6 months (95% CI 5.1-20.1), 1-year OS was 57%. Median progression-free survival was 5.8 months (95% CI 4.5-7.2). Durable systemic therapy responses occurred infrequently with a median duration of systemic treatment response of 2.1 months. One durable complete response of metastatic disease to VDC/IE chemotherapy was seen. Responses to pazopanib (n = 1) and pembrolizumab (n = 1) were not seen.
In this series, CIC-rearranged sarcomas affected young adults and had a high incidence of presenting with, or developing, metastatic disease. The prognosis overall was poor. In advanced disease, durable systemic therapy responses were infrequent.
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