An overview of canine histiocytic disorders - Veterinary Medicine
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An overview of canine histiocytic disorders
The disorders that arise from histiocyte proliferation range from benign, self-resolving lesions to malignant, life-threatening sarcomas and include a newly identified splenic and bone marrow macrophage disorder. These clinicians give you the information you'll need to readily differentiate and manage these disorders.


Most dogs with localized histiocytic sarcoma present with a rapidly growing, localized soft tissue mass.18 The limbs are most commonly affected,1 with the tumor site close to a joint because the tumor cells originate from dendritic cells in the synovial lining.20 Primary lesions can also develop from the stomach,24 spleen, liver, lungs, pancreas, or central nervous system.25-27 Most dogs are middle-aged to older, with overrepresentation by flat-coated retrievers,22 rottweilers, and golden retrievers.18 Presenting complaints secondary to local invasion of the primary tumor are often nonspecific (anorexia, weight loss, lethargy) unless they are related to the organ systems involved. These system-related signs often include lameness and swelling of the affected limb (musculocutaneous), coughing and dyspnea (respiratory), or seizures and paralysis (neurologic).3 Localized histiocytic sarcoma is highly metastatic, with metastasis documented in 91% of cases at necropsy.20

Despite age distributions and breed predilections (Bernese mountain dogs, retrievers, and rottweilers) similar to that of the localized form, disseminated histiocytic sarcoma most often affects the spleen, liver, lungs, bone marrow, and lymph nodes.1 In one study, 85% of dogs with histiocytic sarcoma presented with visceral involvement.21 Nonspecific clinical signs predominate, and widespread involvement is frequently noted at presentation.1 Common clinicopathologic abnormalities identified at diagnosis include anemia (29%), thrombocytopenia (22%), hypoalbuminemia (27%), and mild to moderate liver enzyme activity elevations (34%), reflecting the widespread nature of this disease.21 Less commonly reported abnormalities include neutrophilia, hypercalcemia, and hyperglobulinemia (< 10% to 20% of cases).21,28

Hyperferritinemia. Hyperferritinemia, which has been identified in people with malignant histiocytosis,29,30 was reported in a dog with disseminated histiocytic sarcoma.31 Ferritin is an iron storage protein found in low concentrations in normal serum.32 Ferritin production by neoplastic cells is thought to be the pathogenesis of hyperferritinemia in disseminated histiocytic sarcoma,32 and serum ferritin concentrations have been investigated as a marker of disease activity.33 Although all dogs with histiocytic tumors had mildly to markedly elevated serum ferritin in this study, ferritin concentrations above the reference range were found in dogs with hemolytic anemia, hemolymphatic neoplasia, inflammation, and hepatic disease.33 Hyperferritinemia alone cannot distinguish among these diseases.33 However, if hyperferritinemia is present at diagnosis, it may be a useful marker of disease remission and progression, warranting additional prospective studies.


The etiopathology of localized and disseminated histiocytic sarcomas is unknown, but the clearly defined canine breed predilections point toward a genetic or molecular mechanism.34 The ras family of oncogenes regulates several intracellular growth-promoting pathways, and ras oncogenes are mutated, leading to protein overexpression in up to 30% of human cancers.35 A member of the ras oncogene family, c-N-ras, was investigated in Bernese mountain dogs, and no activating mutations were found to explain the prevalence of histiocytic sarcoma in this breed.36 Dysregulation of other receptor tyrosine kinase (RTK) signaling pathways—kit/stem-cell factor (SCF), Flt3/Flt3 ligand (Flt3L), and Met/hepatocyte growth factor (HGF)—have been investigated in established histiocytic sarcoma cell lines and histiocytic tumor samples for their potential role in the malignant transformation of dendritic cells.34 While all cell lines and tumor samples expressed messenger RNA encoding the receptors and their respective ligands, none of the samples expressed gene mutations in regions known to frequently undergo mutations in other human and canine neoplasms.34 Furthermore, inhibition of signaling by an RTK inhibitor, SU11654, did not result in growth inhibition in vitro. That indicates that these pathways are not critical to histiocytic sarcoma cell survival and proliferation, and the use of RTK targeted therapy in the clinical setting is unlikely to be beneficial in treating histiocytic sarcomas.34


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