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Feline injection-site sarcomas (FISSs) are aggressive neoplasms that have been associated mostly with vaccination. Feline noninjection-site sarcomas (non-FISSs) are less frequently observed in cats and may arise in any anatomic site. This study aimed to determine the differences in the expression of the selected proteins (matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), cyclooxygenase-2 (COX-2), and P-glycoprotein (PGP)) and their correlation with the mitotic count in FISS and non-FISS, in order to characterize their immunohistochemical features. A preliminary study of eleven samples of FISS and eight samples of non-FISS was performed using immunohistochemistry. Among all the tested sarcomas, 80.4% of the tumors were positive for COX-2, 90.2% were positive for MMP-9, and 100% were positive for PGP. The results showed that the expressions of COX-2, MMP-9, and PGP were significantly higher in FISS than in non-FISS (COX-2-p ≤ 0.001; MMP-9-p ≤ 0.05; and PGP-p ≤ 0.05). A Spearman rank correlation analysis showed a moderate negative correlation between the expression of COX-2 and MMP-9 in FISS (r = -0.52). A strong negative correlation between COX-2 and PGP (r = -0.81), a moderate positive correlation between MMP-2 and MMP-9 (r = +0.69), and a moderate negative correlation between MMP-2 and PGP (r = -0.44) were observed in non-FISS. In summary, our study presents the immunohistochemical profile of the proteins involved with inflammation and carcinogenesis in FISS and non-FISS, which can contribute to expanding the knowledge of tumor biology.

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In this study, the immunohistochemical expression of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1), which could facilitate a novel approach to immunotherapy for feline injection site sarcomas (FISSs), was investigated. Treatment strategies based on the suppression of this pathway are possible for tumours expressing PD-1/PD-L1. In this context, FISSs were histologically classified, the grade of sarcoma and the intensity of lymphocyte infiltration determined and PD-1 and PD-L1 expression evaluated in tumours of different grade. Tumours were immunolabelled for vimentin, S100, smooth muscle actin and sarcomeric actin. Fibrosarcoma was diagnosed in eight cases, undifferentiated sarcoma in one case, liposarcoma in one case and rhabdomyosarcoma in one case. PD-1 expression was found mainly in lymphoid infiltrations and macrophage-like cells, while PD-L1 was found primarily in tumour cells and infiltrated macrophage-like cells. By Pearson correlation analysis, tumour differentiation was found to have a moderate correlation with PD-1 (P <0.05) and a high correlation with PD-L1 (P <0.01). Tumour grade had a low correlation with PD-1 and a moderate correlation with PD-L1 (P >0.05). A moderate correlation was also detected between PD-1 and PD-L1 (P <0.05). It was concluded that the increased expression of PD-1 and PD-L1 may be associated with poor tumour differentiation and, therefore, poor prognosis in FISS.

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Feline injection-site sarcomas (FISSs) are highly invasive malignant mesenchymal neoplasms that arise from injection sites in cats. Although the tumorigenesis of FISSs is still uncertain, there is a consensus that FISS is associated with chronic inflammation caused by irritation of injection-related trauma and foreign chemical substances. Chronic inflammation can provide a proper microenvironment for tumour development, which has been known as one of the risk factors of tumorigenesis in many tumours. To investigate the tumorigenesis of FISS and screen for its potential therapeutic targets, cyclooxygenase-2 (COX-2), an inflammation-enhancing enzyme, was selected as a target for this study. In vitro experiments using FISS- and normal tissue-derived primary cells and robenacoxib, a highly selective COX-2 inhibitor, were performed. The results demonstrated that expression of COX-2 could be detected in formalin-fixed and paraffin-embedded FISS tissues and FISS-derived primary cells. Cell viability, migration and colony formation of FISS-derived primary cells were inhibited, and cell apoptosis was enhanced by robenacoxib in a dose-dependent manner. However, susceptibility to robenacoxib varied in different lines of FISS primary cells and was not completely correlated with COX-2 expression. Our results suggest that COX-2 inhibitors could be potential adjuvant therapeutics against FISSs.

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BACKGROUND: Feline injection-site sarcomas (FISSs) are malignant mesenchymal tumors of different histotypes. The pathogenesis of FISS has been correlated with chronic inflammation, resulting in neoplastic transformation. Activation of the Janus kinase-signal transducer and activator of transcription 3 (STAT3) have been demonstrated to play a critical role in tumor development by regulating signaling pathways involved in cell proliferation, survival, metastasis, and angiogenesis in human medicine. To characterize the role of STAT3 in FISS, we first detected STAT3 and phosphorylated STAT3 in formalin-fixed and paraffin-embedded (FFPE) FISS tissues using immunohistochemical staining. RESULTS: STAT3 was detected in 88.9% (40/45) of FISS cases, and phosphorylated STAT3 was detected in 53.3% (24/45) of cases. However, the expression levels of both forms of STAT3 were not correlated with tumor grade. To study the role of STAT3 in tumor survival, two primary cells derived from FISSs of two cats exhibiting consistent immunophenotypes with their parental FFPE tissues were established. A dose-dependent inhibitory effect on cell proliferation was observed in both primary FISS cells treated with the STAT3 inhibitor, 5-hydroxy-9,10-dioxo-9,10-dihydroanthracene-1-sulfonamide. CONCLUSIONS: The STAT 3 may play an important role in the tumorigenesis of FISS and be a potential molecular therapeutic target for FISS.

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Papillary endothelial hyperplasia (PEH) is a rare soft tissue lesion arising from excessive reactive endothelial cell proliferation described in humans, dogs, and horses. PEH is considered a diagnostic challenge in humans, in which it is frequently misdiagnosed as angiosarcoma. We describe here PEH that developed at injection sites in 2 cats that were initially misdiagnosed as feline injection-site sarcoma by cytology and as subcutaneous angiosarcoma by histopathology. Morphologic features included sharp demarcation from surrounding tissues, and a layered microscopic architecture with an outer fibrous capsule from which emerged fibrovascular stalks covered by a monolayer of factor VIII-related antigen and CD31-positive flat-to-plump endothelial cells. Both lesions had a cystic core containing abundant erythrocytes and fibrin. PEH lesions did not recur in either case. Immunohistochemistry for α-smooth muscle actin and desmin demonstrated that the capsule was devoid of smooth muscle cells, excluding an intravascular origin. PEH in these cats was hypothesized to have developed extravascularly following trauma related to injection. We wish to provide awareness of PEH in domestic cats and of the risk of misdiagnoses leading to overtreatment.

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OBJECTIVES: This study set out to determine the average temperature of skin and soft tissue tumors in cats using infrared thermography and to investigate correlations between thermographic findings and tumor type. Correlations between thermographic findings, histologic subtype and tumor grade were also investigated in cases of feline injection site sarcoma (FISS). METHODS: Thermographic images of normal skin and skin overlying neoplastic lesions were prospectively obtained. Following thermographic assessment, tumors were resected and submitted to histopathologic and immunohistochemical analysis. Mean temperatures detected in tumoral areas were compared between different tumor types and between FISSs of different histologic subtypes and grades. RESULTS: Thermograms obtained from 11 healthy cats and 31 cats presenting with skin and soft tissue tumors (eight benign and 23 malignant tumors, including 21 FISSs) were evaluated in this study. Thermal behavior varied widely in normal skin, as well as in skin overlying neoplastic lesions. Mean temperatures were significantly higher in malignant compared with benign tumors (35.4 ± 1.8ºC and 34.5 ± 1.7ºC respectively; P = 0.01), with a temperature above 34.7ºC being associated with malignancy (sensitivity 76%, specificity 80%; P = 0.01). Temperatures detected in FISS did not differ significantly according to histologic subtype (P = 0.91) or tumor grade (P = 0.46), or between primary and recurring tumors (P = 0.25). CONCLUSIONS AND RELEVANCE: Infrared thermography proved to be a sensitive and effective method for detection of temperature differences between malignant and benign skin and soft tissue tumors in cats. Thermographic assessment may contribute to diagnosis and prognostic estimation in feline oncologic patients.

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OBJECTIVES: The aim of this retrospective descriptive study was to determine the effectiveness of using iridium implants in addition to surgery in cats with feline injection-site sarcomas (FISSs) in terms of time to progression and disease-specific survival and to identify prognostic factors for patient outcome. METHODS: Medical records of cats presented at our institution with FISS were reviewed. Inclusion criteria included histologic diagnosis of a tumor type associated with post-injection neoplastic development, tumor located at a site associated with vaccination, no other therapies prior to the administration of brachytherapy with the exception of surgery and adequate follow-up data. RESULTS: Twenty-two cats with FISS were treated with surgery and brachytherapy delivered by postoperative iridium-192 interstitial implants. Radiation doses ranged from 4000 to 6000 cGy (median dose 5079.55 cGy), with most doses delivered over 7 days. The median number of surgeries prior to brachytherapy was one (range 1-4). The complications associated with postoperative brachytherapy were typically mild, although four cats developed more severe complications. The median time to progression for all cats was 619 days and disease-specific survival time for all cats was 1242 days. The 1 and 2 year tumor-free rates in these cats were 63.6% and 40.9%, respectively. The local failure rate was 54.5% and the distant failure rate was 13.6% due to lung metastasis. There was a significant difference in time to progression of cats that had a single surgery performed prior to brachytherapy and those that had multiple surgeries (undefined vs 310 days; P = 0.01). There were no other statistically significant identified prognostic factors. CONCLUSIONS AND RELEVANCE: These data suggest that the addition of brachytherapy postoperatively in cats with FISS was well tolerated and is comparable to other forms of adjuvant therapy.

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Feline injection site sarcoma (FISS) is a mesenchymal neoplasm with highly malignant characteristics. These tumours originate in anatomical sites where there has been previous parenteral administration of medicinal substances or implantation of medical devices. The aim of this study was to investigate the epidemiological and pathological features associated with FISS in the southern region of Brazil. The database of the Department of Veterinary Pathology of the Federal University of Rio Grande do Sul was searched for excisional and incisional biopsy samples compatible with FISS submitted between 2007 and 2017. Biopsy reports were reviewed and epidemiological information, including breed, age and sex of affected cats, as well as gross findings including anatomical location and size of the tumour and the presence of tissue invasion, were extracted. Eighty-nine samples were selected based on the established criteria. Most animals were of undefined breed and were female cats with a median age of 10 years. Grossly, 84.8% of the tumours were >2 cm in diameter. Regarding anatomical location, 34.9% of the tumours were located in the subcutaneous tissue of the thoracic wall, 29.2% in the flank, 21.3% in the interscapular region and 14.6% in the limbs. Histologically, the tumours originated in the subcutaneous tissue and were diagnosed as malignant mesenchymal neoplasms. Most were compatible with fibrosarcomas, but variants with features of pleomorphic sarcoma or chondrosarcoma were recognized. All tumours exhibited areas of necrosis and peripheral inflammatory infiltrate, composed predominantly of lymphocytes, plasma cells and macrophages. The results of this study suggest the need for dissemination of information on FISS epidemiology and guidelines for management of this tumour to veterinarians in the region.

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BACKGROUND: Chronic inflammation has been implicated in sarcomagenesis. Among various factors, activation of nuclear factor-kappa B (NF-κB) signaling pathway has been documented being able to target genes associated with tumor progression and up-regulate the expression of tumor-promoting cytokines and survival genes in several human solid tumors. Feline injection sites sarcomas (FISS) are malignant entities derived from the mesenchymal origin. The disease has been considered to be associated with vaccine adjuvant, aluminum, which serves as a stimulus continuously inducing overzealous inflammatory and immunologic reactions. To understand the contribution of NF-κB in FISS, detection of activated NF-κB in paraffin-embedded specimens, in vitro establishment of primary cells derived from FISS, and evaluation of the effects of the NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), on primary tumor cells were conducted. RESULTS: In this study, nuclear expression of NF-κB p65 was detected in 83.3% of FISS cases and not correlated with tumor grading, sex, and age. Primary cells derived from FISS in three cats exhibiting same immunohistochemical characteristics as their original tumor were successfully established. The NF-κB inhibitor, DHMEQ, was able to prevent nuclear translocation of NF-κB p65, inhibit cell proliferation, migration, and colonization in dosage-dependent manners, and induce cell apoptosis in these primary FISS cells. CONCLUSIONS: High expression rate of nuclear NF-κB p65 in FISS cases and dose-dependent inhibitory effects on the growth of FISS primary cells treated with NF-κB inhibitor suggested that NF-κB might be a potential molecular therapeutic target for FISS.

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Computed tomographic angiography (CTA) and magnetic resonance imaging (MRI) have been described as methods for preoperative surgical planning in cats with feline injection site sarcomas (FISS), however, few published studies have compared these modalities. The objective of this retrospective, secondary analysis study was to determine if imaging features of FISS on CTA and MRI are predictive of neoplastic peritumoral projections. Archived data from a previous prospective study were retrieved for 10 cats with FISS. All cats had been evaluated in a single anesthetic episode with MRI and dual phase CT (CTA) imaging followed by surgical removal. Histopathological grading and targeted histopathology of imaging-identified peritumoral projections were performed. Two observers evaluated the CTA and MRI studies for FISS shape, margination, size, enhancement pattern, postcontrast uniformity, pre- and postcontrast margination, the number of muscles involved, mass mineralization, and bone lysis. Metal was present in the imaging field of three of 10 cats, resulting in one nondiagnostic MRI. Peritumoral projections were detected in all cats with both imaging modalities, and most were benign. At least one neoplastic peritumoral projection was detected in six cats using MRI, five cats using CTA, and three cats with both modalities. Higher grade FISS were larger than low grade using MRI, and FISS were larger using MRI. Other FISS imaging features using MRI and CTA were similar. Findings supported use of either MRI or CTA for detecting neoplastic peritumoral projections in cats with FISS. Authors recommend CTA for cats with known metallic objects in the scan field.

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Feline injection site sarcomas (FISSs) are mesenchymal neoplasms that develop at the sites of delivery of vaccines or other injectable products. Vaccine adjuvants can trigger an intense and persistent inflammatory response that may lead to neoplastic transformation. The proinflammatory role of cyclo-oxygenase (COX)-2 is well known and its overexpression has prognostic value in multiple neoplastic processes. One hundred and seventeen FISSs were evaluated for the degree of inflammation and anaplasia. Immunohistochemistry was used to determine the expression of COX-2 in these sarcomas. There was a significant association between the degree of inflammation and the expression of COX-2 by neoplastic cells. COX-2 expression was lower in tumours with higher degrees of anaplasia. These findings may be useful in predicting the sensitivity of FISSs to treatment with COX-2 inhibitors. The potential therapeutic use of such agents could then be restricted to tumours with lower degrees of anaplasia.

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Proteomic analyses are rapid and powerful tools that are used to increase the understanding of cancer pathogenesis, discover cancer biomarkers and predictive markers, and select and monitor novel targets for cancer therapy. Feline injection-site sarcomas (FISS) are aggressive skin tumours with high recurrence rates, despite treatment with surgery, radiotherapy, and chemotherapy. Doxorubicin is a drug of choice for soft tissue sarcomas, including FISS. However, multidrug resistance is one of the major causes of chemotherapy failure. The main aim of the present study was to identify proteins that differentiate doxorubicin-resistant from doxorubicin-sensitive FISS using two-dimensional gel electrophoresis (2DE), followed by matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF MS) analysis. Using the three-dimensional (3D) preclinical in ovo model, which resembles features of spontaneous fibrosarcomas, three significantly (p ≤ 0.05) differentially expressed proteins were identified in tumours grown from doxorubicin-resistant fibrosarcoma cell lines (FFS1 and FFS3) in comparison to the doxorubicin-sensitive one (FFS5): Annexin A5 (ANXA5), Annexin A3 (ANXA3), and meiosis-specific nuclear structural protein 1 (MNS1). Moreover, nine other proteins were significantly differentially expressed in tumours grown from the high doxorubicin-resistant cell line (FFS1) in comparison to sensitive one (FFS5). This study may be the first proteomic fingerprinting of FISS reported, identifying potential candidates for specific predictive biomarkers and research targets for doxorubicin-resistant FISS.

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Feline injection site sarcoma is a malignant neoplasm with digitiform projections into muscular planes that are ill recognized during physical examination and may compromise tumor margin demarcation. This study compared tumoral size of 32 cats measured by different methods, and evaluated the CT density of 10 tumoral tissues (Hounsfield unit) based on histograms. Tumor axes were measured by physical examination and CT images. Larger craniocaudal axis measurements were obtained following multiplanar reconstruction of pre- and post-contrast CT images (p=0.049 and p=0.041 respectively); dorsoventral axis measurements taken from post-contrast CT images were also larger (p=0.010). Tumor volume estimates increased following contrast-enhancement. Histograms tended to produce two peaks: one in the fat and another in the soft tissue attenuation range. Multiplanar reconstructed post-contrast CT images provided clearer definition of tumor margins and more judicious determination of tumor size. A tendency of common FISS attenuation profile could be described.(AU)

O sarcoma de aplicação felino (SAF) é uma neoplasia maligna que geralmente apresenta projeções digitiformes para planos musculares adjacentes, dificilmente reconhecidos ao exame físico, o que pode comprometer a real identificação das suas margens. Este estudo comparou as dimensões tumorais de 32 SAFs mensurados por diferentes métodos (exame físico e por imagens de tomografia computadorizada) e avaliou a densidade tomográfica em unidades Hounsfield de 10 dessas neoplasias, com base em histogramas. As medidas no eixo craniocaudal foram maiores quando obtidas após reconstrução multiplanar de imagens tomográficas, tanto na fases pré como após administração de meio de contraste (p=0,049 e p=0,041, respectivamente). As medições tomográficas no eixo dorsoventral obtidas na fase pós-contraste também foram maiores, quando comparadas com as imagens pré-contraste (p=0,010). Estimativas do volume tumoral foram maiores após a fase contrastada. Os histogramas das densidades tumorais tenderam a produzir dois picos: o primeiro no intervalo de valores de densidade gordura e o segundo no intervalo correspondente a tecidos moles. As imagens tomográficas pós-contraste com reconstrução multiplanar demarcaram com mais clareza as margens do tumor e definiram de forma mais criteriosa o seu tamanho. Uma tendência de perfil de atenuação comum para o SAF pôde ser descrita com esse estudo.(AU)

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Feline injection-site sarcomas are malignant skin tumours with a high local recurrence rate, ranging from 14% to 28%. The treatment of feline injection-site sarcomas includes radical surgery, radiotherapy and/or chemotherapy. In our previous study it has been demonstrated that doxorubicin conjugated to glutathione-stabilized gold nanoparticles (Au-GSH-Dox) has higher cytotoxic effects than free doxorubicin for feline fibrosarcoma cell lines with high glycoprotein P activity (FFS1, FFS3). The aim of the present study was to assess the effectiveness of intratumoural injection of Au-GSH-Dox on the growth of tumours from the FFS1 and FFS3 cell lines on chick embryo chorioallantoic membrane. This model has been utilized both in human and veterinary medicine for preclinical oncological studies. The influence of intratumoural injections of Au-GSH-Dox, glutathione-stabilized gold nanoparticles and doxorubicin alone on the Ki-67 proliferation marker was also checked. We demonstrated that the volume ratio of tumours from the FFS1 and FFS3 cell lines was significantly (p < 0.01) decreased after a single intratumoural injection of Au-GSH-Dox, which confirms the positive results of in vitro studies and indicates that Au-GSH-Dox may be a potent new therapeutic agent for feline injection-site sarcomas.

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Feline injection-site sarcoma (FISS) is commonly treated with surgery and radiation therapy. Despite aggressive therapy, FISS has a high recurrence rate. The true benefit of adjuvant chemotherapy is not known. DNA damage response mechanisms help protect against genomic instability but can also promote chemoresistance. In order to determine whether DNA damage is a feature of FISS, we evaluated tumour tissues with γH2AX immunohistochemistry. H2AX is phosphorylated to form γH2AX following DNA double strand breaks. Seventeen FISS specimens were evaluated prospectively. DNA damage ranged from 2.18 to33.7%, with a median of 16.2%. Significant differences were noted between cats (P < 0.0001). Mitotic index ranged from 0 to 57 with a median of 13 and did not correlate with γH2AX positivity (P = 0.2). Further studies are needed to determine if γH2AX expression may predict chemosensitivity and have independent value as a prognostic factor.

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