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Histiocytic sarcoma (HS) is a rare yet lethal malignancy with no established standard of care therapies. A lack of pre-clinical models limits our understanding of HS pathogenesis and identification of therapeutic targets. Canine HS shares multiple clinical and genetic similarities with human HS, supporting its use as a unique translational model. Prior studies have investigated the immunogenicity of HS. Although increased tumor infiltrating lymphocyte (TIL) density is associated with favorable outcomes in canine HS, virtually all canine patients eventually succumb to progressive disease consistent with ultimate failure of anti-tumor immunity. To investigate potential regulators of the immune tumor microenvironment (TME), we undertook a comparative transcriptional approach of three long-lived cases of canine pulmonary HS with heavy T cell infiltrate and three short-lived cases of splenic HS that lacked significant T cell inflammation and compared these data to corresponding grossly normal tissues from dogs undergoing necropsy. This comparison identified PDCD1, encoding the immune checkpoint PD-1, and SPP1, encoding the secreted pro-tumorigenic protein osteopontin, as positive differentially expressed genes (DEGs) in canine HS. TXNIP, encoding the tumor suppressor TXNIP, was the most significant negative DEG. Comparative transcriptomic studies revealed conservation of enriched (including SPP1 ) and depleted (including TXNIP ) DEGs between canine and human HS patients. Immunohistochemistry demonstrated osteopontin in the TMEs of canine and human HS. Collectively, we uncover PD-1, osteopontin, and TXNIP as putative actionable targets in HS and further establish canine HS as a preclinical platform to screen novel immunotherapeutic approaches for this deadly disease.

Canine histiocytic sarcoma (HS) is a rare tumor with a poor prognosis. Rapid tumor growth often causes central hypoxia and starvation, impacting tumor progression. In the present study, HS cells were cultured under hypoxia and starvation for 1 and 3 days, simulating intermediate and central tumor zones, respectively. Cells were counted at each time point, followed by RNAseq analysis. Only hypoxia significantly reduced the cell number (p < 0.05). Short-term hypoxia altered 1645 differentially expressed genes (DEGs). Upregulated genes belonged to vasculature development, and downregulated genes to cell cycle processes. Short-term starvation affected 157 genes, mainly involving responses to stimuli. Prolonged hypoxia and starvation induced 1301 and 836 DEGs, respectively. Prolonged hypoxia upregulated genes mainly involved in immune responses, response to stimulus, adhesion, and angiogenesis. Prolonged starvation upregulated genes associated with signaling, adhesion, circulatory system development, and response to stimulus. Lipid metabolism and cell cycle pathways were downregulated under prolonged hypoxia and starvation, respectively. KEGG “pathways in cancer” were enriched under all conditions (adjusted p-values < 0.05). These findings indicate that hypoxia and starvation significantly alter the expression of genes involved in tumor progression. Further studies, namely post-translational analyses, are needed to elucidate the functional impact of these changes and identify potential therapeutic targets.

Histiocytic sarcoma (HS) is a rare and aggressive tumor in humans with no universally agreed standard of care therapy. Spontaneous canine HS exhibits increased prevalence in specific breeds, shares key genetic and biologic similarities with the human disease, and occurs in an immunocompetent setting. Previous data allude to the immunogenicity of this disease in both species, highlighting the potential for their successful treatment with immunotherapy. Quantification of CD3 tumor-infiltrating lymphocytes (TIL) in five cases of human HS revealed variable intra-tumoral T cell infiltration. Due to the paucity of human cases and lack of current model systems in which to appraise associations between anti-tumor immunity and treatment-outcome in HS, we analyzed clinical data and quantified TIL in 18 dogs that were previously diagnosed with localized HS and treated with curative-intent tumor resection with or without adjuvant chemotherapy. As in humans, assessment of TIL in biopsy tissues taken at diagnosis reveal a spectrum of immunologically “cold” to “hot” tumors. Importantly, we show that increased CD3 and granzyme B TIL are positively associated with favorable outcomes in dogs following surgical resection. NanoString transcriptional analyses revealed increased T cell and antigen presentation transcripts associated with prolonged survival in canine pulmonary HS and a decreased tumor immunogenicity profile associated with shorter survivals in splenic HS. Based on these findings, we propose that spontaneous canine HS is an accessible and powerful novel model to study tumor immunology and will provide a unique platform to preclinically appraise the efficacy and tolerability of anti-cancer immunotherapies for HS.

Background This report presents a case of esophageal and nodal metastasis in a primary pulmonary histiocytic sarcoma in a dog. Histiocytic sarcoma is a malignant neoplasm originating from histiocytic cells, characterized by its aggressive nature, high metastatic potential and high mortality rate. Pulmonary involvement occasionally results in pleural effusion and regional lymph node involvement, such as the tracheobronchial, sternal, and mediastinal lymph nodes. Thoracic radiography is the preferred complementary diagnostic test when respiratory disorders are suspected, as it can identify pulmonary masses and associated complications, such as pleural effusion. Similarly, ultrasonography can be used when pulmonary conditions are suspected, helping to differentiate lesions. Case presentation A one-year-old, intact male mixed-breed dog weighing 18 kg was referred for emergency clinical care due to severe inspiratory dyspnea. Thoracic radiography and ultrasonography revealed a large intrathoracic mass located in the mediastinum, displacing adjacent structures, along with associated pleural effusion. The primary diagnostic hypothesis was a neoplasm of cranial mediastinal origin. During the thoracocentesis procedure, the animal decompensated and died. Necropsy revealed a large, multilobulated tumor mass in the mediastinum, showing direct extension into the esophagus, as well as another nodule similar to the mediastinal mass in the left caudal lung lobe. Histopathological analysis supported the diagnosis of pulmonary histiocytic sarcoma with esophageal and nodal metastasis, confirmed through an immunohistochemical panel. Conclusions The involvement of cranial mediastinal and tracheobronchial lymph nodes, as well as the presence of pleural effusion, are common features associated with HS. However, the occurrence of esophageal metastases is considered uncommon, highlighting the uniqueness of this case, as well as supporting the potential for its occurrence. Thoracic radiography and ultrasonography played a crucial role in the initial suspicion of neoplasia, emphasizing their importance in early diagnostic approaches.

Histiocytic sarcoma (HS) is an incurable aggressive tumor, and no consensus has been made on the treatment due to its rare occurrence. Since dogs spontaneously develop the disease and several cell lines are available, they have been advocated as translational animal models. In the present study, therefore, we explored gene mutations and aberrant molecular pathways in canine HS by next generation sequencing to identify molecular targets for treatment. Whole exome sequencing and RNA-sequencing revealed gene mutations related to receptor tyrosine kinase pathways and activation of ERK1/2, PI3K-AKT, and STAT3 pathways. Analysis by quantitative PCR and immunohistochemistry revealed that fibroblast growth factor receptor 1 (FGFR1) is over-expressed. Moreover, activation of ERK and Akt signaling were confirmed in all HS cell lines, and FGFR1 inhibitors showed dose-dependent growth inhibitory effects in two of the twelve canine HS cell lines. The findings obtained in the present study indicated that ERK and Akt signaling were activated in canine HS and drugs targeting FGFR1 might be effective in part of the cases. The present study provides translational evidence that leads to establishment of novel therapeutic strategies targeting ERK and Akt signaling in HS patients.

Abstract Background Localized splenic histiocytic sarcoma (HS) in dogs is a poorly understood disease, and could have longer survival times than disseminated or hemophagocytic HS. Understanding the clinical behavior of localized splenic HS can refine treatment recommendations. Objective To describe the clinical characteristics and outcomes of dogs with localized splenic HS. Animals Fourteen client-owned dogs with histologically confirmed splenic HS that received splenectomy. Methods Multi-institutional retrospective case series—medical records of dogs with splenic HS were reviewed. Dog signalment, clinicopathologic data, primary and adjuvant treatments, and outcomes were obtained. Survival data were calculated using Kaplan-Meier analysis. Dog variables such as age, weight, platelet counts were reported using descriptive statistics. The Cox proportional hazards regression method was used to determine whether potential risk factors (weight, age, albumin level, hematocrit, and platelet count) were associated with PFI. Results Median survival time for the dogs in this study was 427 days. Twelve dogs received adjuvant lomustine-based chemotherapy. Five dogs (35.7%) were suspected or confirmed to have developed metastatic disease. Eleven dogs died of disease, 1 dog died of unrelated cause, and 2 dogs were alive at final follow-up. Conclusions and Clinical Significance Histiocytic sarcoma in dogs can manifest as a localized form in the spleen. Dogs with localized splenic HS treated with surgery ± chemotherapy can experience survival times over a year.

Histiocytic sarcoma (HS) is a rare and highly aggressive cancer in humans and dogs. In dogs, it has a high prevalence in certain breeds, such as Bernese mountain dogs (BMDs) and flat-coated retrievers. Hemophagocytic histiocytic sarcoma (HHS) is a unique form of HS that presents with erythrophagocytosis. Due to its rareness, the study of HHS is very limited, and mutations in canine HHS patients have not been studied to date. In previous work, our research group identified two major PTPN11/SHP2 driver mutations, E76K and G503V, in HS in dogs. Here, we report additional mutations located in exon 3 of PTPN11/SHP2 in both HS and HHS cases, further supporting that this area is a mutational hotspot in dogs and that mutations in tumors and liquid biopsies should be evaluated utilizing comprehensive methods such as Sanger and NextGen sequencing. The overall prevalence of PTPN11/SHP2 mutations was 55.8% in HS and 46.2% in HHS. In addition, we identified mutations in KRAS, in about 3% of HS and 4% of HHS cases. These findings point to the shared molecular pathology of activation of the MAPK pathway in HS and HHS cases. We evaluated the efficacy of the highly specific MEK inhibitor, cobimetinib, in canine HS and HHS cell lines. We found that the IC50 values ranged from 74 to 372 nM, which are within the achievable and tolerable ranges for cobimetinib. This finding positions cobimetinib as a promising potential candidate for future canine clinical trials and enhances our understanding of the molecular defects in these challenging cancers.

Abstract Background Intracranial neoplasia is relatively common in dogs and stereotactic radiotherapy, surgical debulking, or both, are the most successful treatment approaches. A key component of treatment planning involves delineating tumor margin on magnetic resonance imaging (MRI) examinations. How MRI signal intensity alterations relate to histological tumor margins is unknown. Objectives Directly compare histological brain sections to MRI sequence images and determine which sequence alteration best correlates with tumor margins. Animals Five dogs with glioma, 4 dogs with histiocytic sarcoma, and 3 dogs with meningioma. Methods Retrospective cohort study. Histological brain sections were registered to in vivo MRI scan images obtained within 7 days of necropsy. Margins of signal intensity alterations (T2-weighted, fluid-attenuating inversion recovery [FLAIR], T1-weighted and contrast enhancement) were compared directly to solid tumor and surgical margins identified on histology. Jacquard similarity metrics (JSM) and cross-sectional areas were calculated. Results In glioma cases, margins drawn around T2-weighted hyperintensity were most similar to surgical margins (JSM, 0.66 ± 0.17) when compared to other sequences. In both meningioma (JSM, 0.57 ± 0.21) and histiocytic sarcoma (JSM, 0.75 ± 0.11) margins of contrast enhancement were most similar to surgical margins. Conclusions and Clinical Importance Signal intensities correspond to tumor margins for different tumor types and facilitate surgical and radiation therapy planning using MRI images.

We report a rare case of a spontaneous composite tumour with the histopathological characteristics of B‐cell lymphoblastic lymphoma and histiocytic sarcoma in a 104‐week‐old male C57BL/6 mouse. It appeared to be a large, well‐circumscribed intra‐abdominal mass, presumably originating from a mesenteric lymph node. Histological examination revealed two distinct neoplastic cell populations, including small‐ to intermediate‐sized CD20‐ and Pax5‐positive lymphoid cells and large pleomorphic histiocytes expressing Iba1. Both cell types were strongly stained by proliferating cell nuclear antigen, which is indicative of high proliferative activity. No evidence of metastases was observed in other organs. While single cases of similar composite neoplasms have been reported in humans, this is the first documented case in a laboratory mouse. These findings expand the known spectrum of spontaneous hematopoietic tumours in aged mice and highlight the importance of comprehensive histopathological and immunophenotypic evaluation in diagnosing atypical lesions. This study describes a rare concurrent tumour composed of B‐cell lymphoblastic lymphoma and histiocytic sarcoma in a laboratory mouse. The two neoplastic components were clearly distinguished by distinct histopathological features and immunophenotypes, with CD20 and Pax5 expression in the lymphoblastic population and Iba1 positivity in the histiocytic component. This case highlights the diagnostic and interpretative challenges of composite hematopoietic neoplasms in ageing laboratory mice used in toxicologic pathology studies.

Histiocytic sarcomas refer to highly aggressive tumors with a poor prognosis that respond poorly to conventional treatment approaches. Oncolytic viruses, which have gained significant traction as a cancer therapy in recent decades, represent a promising option for treating histiocytic sarcomas through their replication and/or by modulating the tumor microenvironment. The live attenuated canine distemper virus (CDV) vaccine strain Onderstepoort represents an attractive candidate for oncolytic viral therapy. In the present study, oncolytic virotherapy with CDV was used to investigate the impact of this virus infection on tumor cell growth through direct oncolytic effects or by virus-mediated modulation of the tumor microenvironment with special emphasis on angiogenesis, expression of selected MMPs and TIMP-1 and tumor-associated macrophages in a murine xenograft model of canine histiocytic sarcoma. Treatment of mice with xenotransplanted canine histiocytic sarcomas using CDV induced overt retardation in tumor progression accompanied by necrosis of neoplastic cells, increased numbers of intratumoral macrophages, reduced angiogenesis and modulation of the expression of MMPs and TIMP-1. The present data suggest that CDV inhibits tumor growth in a multifactorial way, including direct cell lysis and reduction of angiogenesis and modulation of MMPs and their inhibitor TIMP-1, providing further support for the concept of its role in oncolytic therapies.