Veterinary Pathology

  • Osteopathology in the Equine Distal Phalanx Associated With the Development and Progression of Laminitis 20 agosto 2015
    Engiles, J. B., Galantino-Homer, H. L., Boston, R., McDonald, D., Dishowitz, M., Hankenson, K. D.
    Although the equine distal phalanx and hoof lamellae are biomechanically and physiologically integrated, bony changes in the distal phalanx are poorly described in laminitis. The aims of this study were (1) to establish a laminitis grading scheme that can be applied to the wide spectrum of lesions seen in naturally occurring cases and (2) to measure and describe changes in the distal phalanx associated with laminitis using micro–computed tomography (micro-CT) and histology. Thirty-six laminitic and normal feet from 15 performance and nonperformance horses were evaluated. A laminitis grading scheme based on radiographic, gross, histopathologic, and temporal parameters was developed. Laminitis severity grades generated by this scheme correlated well with clinical severity and coincided with decreased distal phalanx bone volume and density as measured by micro-CT. Laminitic hoof wall changes included progressive ventral rotation and distal displacement of the distal phalanx with increased thickness of the stratum internum–corium tissues with lamellar wedge formation. Histologically, there was epidermal lamellar necrosis with basement membrane separation and dysplastic regeneration, including acanthosis and hyperkeratosis, corresponding to the lamellar wedge. The changes detected by micro-CT corresponded to microscopic findings in the bone, including osteoclastic osteolysis of trabecular and osteonal bone with medullary inflammation and fibrosis. Bone changes were identified in horses with mild/early stages of laminitis as well as severe/chronic stages. The authors conclude that distal phalangeal pathology is a quantifiable and significant component of laminitis pathology and may have important implications for early detection or therapeutic intervention of equine laminitis.
  • Fibroblast Growth Factor 23: A New Dimension to Diseases of Calcium-Phosphorus Metabolism 20 agosto 2015
    Hardcastle, M. R., Dittmer, K. E.
    Traditionally, control of phosphorus in the body has been considered secondary to the tighter control of calcium by parathyroid hormone and vitamin D. However, over the past decade, substantial advances have been made in understanding the control of phosphorus by the so-called phosphatonin system, the lynchpin of which is fibroblast growth factor 23 (FGF23). FGF23 binds to the klotho/FGFR1c receptor complex in renal tubular epithelial cells, leading to upregulation of Na/Pi cotransporters and subsequent excretion of phosphorus from the body. In addition, FGF23 inhibits parathyroid hormone and the renal 1α-hydroxylase enzyme, while it stimulates 24-hydroxylase, leading to decreased 1,25-dihydroxyvitamin D3. FGF23 is intimately involved in the pathogenesis of a number of diseases, particularly the hereditary hypophosphatemic rickets group and chronic kidney disease, and is a target for the development of new treatments in human medicine. Little work has been done on FGF23 or the other phosphatonins in veterinary medicine, but increases in FGF23 are seen with chronic kidney disease in cats, and increased FGF23 expression has been found in soft tissue sarcomas in dogs.
  • Benign and Malignant Proliferative Fibro-osseous and Osseous Lesions of the Oral Cavity of Dogs 20 agosto 2015
    Soltero-Rivera, M., Engiles, J. B., Reiter, A. M., Reetz, J., Lewis, J. R., Sanchez, M. D.
    Ossifying fibroma (OF) and fibrous dysplasia (FD) are benign, intraosseous, proliferative fibro-osseous lesions (PFOLs) characterized by replacement of normal bone by a fibrous matrix with various degrees of mineralization and ossification. Osteomas are benign tumors composed of mature, well-differentiated bone. Clinical, imaging, and histologic features of 15 initially diagnosed benign PFOLs and osteomas of the canine oral cavity were evaluated. Final diagnoses after reevaluation were as follows: OF (3 cases), FD (4 cases), low-grade osteosarcoma (LG-OSA) (3 cases), and osteoma (5 cases). Histology alone often did not result in a definitive diagnosis for PFOL. OF appeared as a well-circumscribed, radiopaque mass with some degree of bone lysis on imaging. Most lesions of FD showed soft tissue opacity with bone lysis and ill-defined margins. Low-grade OSA appeared as a lytic lesion with a mixed opacity and ill-defined margins. Osteomas were characterized by a mineralized, expansile, well-circumscribed lesion. Although histologic features of PFOLs were typically bland, the lesions diagnosed as LG-OSA had some features of malignancy (eg, bone invasion or a higher mitotic index). Treatment varied widely. Of the 10 dogs with benign PFOL or osteoma with known outcome (10/12), 9 showed either complete response (6/10) or stable disease (3/10) after treatment. Of the 2 dogs with LG-OSA with known outcome, 1 showed complete response after curative intent surgery, but 1 patient had recurrence after partial maxillectomy. Definitive diagnosis of mandibular/maxillary PFOL is challenging via histopathologic examination alone, and accurate diagnosis is best achieved through assimilation of clinical, imaging, and histopathologic features.
  • An Update on the Pathogenesis of Osteochondrosis 20 agosto 2015
    Olstad, K., Ekman, S., Carlson, C. S.
    Osteochondrosis is defined as a focal disturbance in endochondral ossification. The cartilage superficial to an osteochondrosis lesion can fracture, giving rise to fragments in joints known as osteochondrosis dissecans (OCD). In pigs and horses, it has been confirmed that the disturbance in ossification is the result of failure of the blood supply to epiphyseal growth cartilage and associated ischemic chondronecrosis. The earliest lesion following vascular failure is an area of ischemic chondronecrosis at an intermediate depth of the growth cartilage (osteochondrosis latens) that is detectable ex vivo, indirectly using contrast-enhanced micro- and conventional computed tomography (CT) or directly using adiabatic T1 magnetic resonance imaging. More chronic lesions of ischemic chondronecrosis within the ossification front (osteochondrosis manifesta) are detectable by the same techniques and have also been followed longitudinally in pigs using plain CT. The results confirm that lesions sometimes undergo spontaneous resolution, and in combination, CT and histology observations indicate that this occurs by filling of radiolucent defects with bone from separate centers of endochondral ossification that form superficial to lesions and by phagocytosis and intramembranous ossification of granulation tissue that forms deep to lesions. Research is currently aimed at discovering the cause of the vascular failure in osteochondrosis, and studies of spontaneous lesions suggest that failure is associated with the process of incorporating blood vessels into the advancing ossification front during growth. Experimental studies also show that bacteremia can lead to vascular occlusion. Future challenges are to differentiate between causes of vascular failure and to discover the nature of the heritable predisposition for osteochondrosis.
  • Diversity of Histologic Patterns and Expression of Cytoskeletal Proteins in Canine Skeletal Osteosarcoma 20 agosto 2015
    Nagamine, E., Hirayama, K., Matsuda, K., Okamoto, M., Ohmachi, T., Kadosawa, T., Taniyama, H.
    Osteosarcoma (OS), the most common bone tumor, includes OS of the head (OSH) and appendicular OS (OSA). In dogs, it is classified into 6 histologic subtypes: osteoblastic, chondroblastic, fibroblastic, telangiectatic, giant cell, and poorly differentiated. This study investigated the significance of the histologic classification relevant to clinical outcome and the histologic and immunohistochemical relationships between pleomorphism and expression of cytoskeletal proteins in 60 cases each of OSH and OSA. Most neoplasms exhibited histologic diversity, and 64% of OS contained multiple subtypes. In addition to the above 6 subtypes, myxoid, round cell, and epithelioid subtypes were observed. Although the epithelioid subtypes were observed in only OSH, no significant difference in the frequency of other subtypes was observed. Also, no significant relevance was observed between the clinical outcome and histologic subtypes. Cytokeratin (CK) was expressed in both epithelioid and sarcomatoid tumor cells in various subtypes, and all CK-positive tumor cells also expressed vimentin. Vimentin and α-smooth muscle actin (SMA) were expressed in all subtypes. A few SMA-positive spindle-shaped tumor cells exhibited desmin expression. Glial fibrillary acidic protein–positive tumor cells were observed in many subtypes, and some of these cells showed neurofilament expression. Although OSH exhibited significantly stronger immunoreactivity for SMA than OSA, no significant difference in other cytoskeletal proteins was observed. Some tumor cells had cytoskeletal protein expression compatible with the corresponding histologic subtypes, such as CK in the epithelioid subtype and SMA in the fibroblastic subtype. Thus, canine skeletal OS is composed of pleomorphic and heterogenous tumor cells as is reflected in the diversity of histologic patterns and expression of cytoskeletal proteins.
  • Animal Models of Osteoarthritis: Comparisons and Key Considerations 20 agosto 2015
    McCoy, A. M.
    Osteoarthritis (OA) is unquestionably one of the most important chronic health issues in humans, affecting millions of individuals and costing billions of dollars annually. Despite widespread awareness of this disease and its devastating impact, the pathogenesis of early OA is not completely understood, hampering the development of effective tools for early diagnosis and disease-modifying therapeutics. Most human tissue available for study is obtained at the time of joint replacement, when OA lesions are end stage and little can be concluded about the factors that played a role in disease development. To overcome this limitation, over the past 50 years, numerous induced and spontaneous animal models have been utilized to study disease onset and progression, as well as to test novel therapeutic interventions. Reflecting the heterogeneity of OA itself, no single "gold standard" animal model for OA exists; thus, a challenge for researchers lies in selecting the most appropriate model to answer a particular scientific question of interest. This review provides general considerations for model selection, as well as important features of species such as mouse, rat, guinea pig, sheep, goat, and horse, which researchers should be mindful of when choosing the "best" animal model for their intended purpose. Special consideration is given to key variations in pathology among species as well as recommended guidelines for reporting the histologic features of each model.
  • Histologic, Clinical, and Radiologic Findings of Alveolar Bone Expansion and Osteomyelitis of the Jaws in Cats 20 agosto 2015
    Bell, C. M., Soukup, J. W.
    The objective of this study was to characterize clinical, radiologic, and histologic patterns of alveolar bone expansion and osteomyelitis in cats. Based on case materials submitted as surgical biopsy specimens, alveolar bone pathology was diagnosed in 28 cats. These cats had a total of 37 oral lesions with clinical and radiologic changes that involved bone and/or teeth, including periodontitis, bone expansion, tooth resorption, and/or chronic osteomyelitis; 32 lesions were evaluated by histopathology. Canine teeth were affected in 19 cats (27 affected teeth), with bilateral lesions in 5 (26.3%) cats. The caudal premolar and/or molar regions were affected in 10 cats (10 affected sites). All biopsy sites evaluated by a review of clinical images and/or radiographs had evidence of periodontitis. Clinical photographs showed expansion of alveolar bone in 13 of 16 (81%) biopsy sites evaluated. Radiologically, rarifying osseous proliferation of alveolar bone was seen at 26 of 27 (96%) biopsy sites, and tooth resorption occurred at 15 of 18 (83%) sites. Histologically, the tissue samples from canine sites had compressed trabeculae of mature remodeled bone, loose fibrous stroma with paucicellular inflammation, and mild proliferation of woven bone. Tissue samples from the premolar/molar biopsy sites were often highly cellular with mixed lymphoplasmacytic and chronic suppurative inflammation, ulceration with granulation tissue, and robust proliferation of woven bone. Alveolar bone expansion and osteomyelitis in cats occurs in conjunction with periodontal inflammation and frequently with tooth resorption.
  • Mouse Models of Rheumatoid Arthritis 20 agosto 2015
    Caplazi, P., Baca, M., Barck, K., Carano, R. A. D., DeVoss, J., Lee, W. P., Bolon, B., Diehl, L.
    Rheumatoid arthritis (RA) is a chronic debilitating autoimmune disorder characterized by synovitis that leads to cartilage and bone erosion by invading fibrovascular tissue. Mouse models of RA recapitulate many features of the human disease. Despite the availability of medicines that are highly effective in many patient populations, autoimmune diseases (including RA) remain an area of active biomedical research, and consequently mouse models of RA are still extensively used for mechanistic studies and validation of therapeutic targets. This review aims to integrate morphologic features with model biology and cover the key characteristics of the most commonly used induced and spontaneous mouse models of RA. Induced models emphasized in this review include collagen-induced arthritis and antibody-induced arthritis. Collagen-induced arthritis is an example of an active immunization strategy, whereas antibody- induced arthritis models, such as collagen antibody–induced arthritis and K/BxN antibody transfer arthritis, represent examples of passive immunization strategies. The coverage of spontaneous models in this review is focused on the TNF ARE mouse, in which arthritis results from overexpression of TNF-α, a master proinflammatory cytokine that drives disease in many patients.
  • Ellis-van Creveld Syndrome in Grey Alpine Cattle: Morphologic, Immunophenotypic, and Molecular Characterization 20 agosto 2015
    Muscatello, L. V., Benazzi, C., Dittmer, K. E., Thompson, K. G., Murgiano, L., Drogemuller, C., Avallone, G., Gentile, A., Edwards, J. F., Piffer, C., Bolcato, M., Brunetti, B.
    Ellis–van Creveld (EvC) syndrome is a human autosomal recessive disorder caused by a mutation in either the EVC or EVC2 gene, and presents with short limbs, polydactyly, and ectodermal and heart defects. The aim of this study was to understand the pathologic basis by which deletions in the EVC2 gene lead to chondrodysplastic dwarfism and to describe the morphologic, immunohistochemical, and molecular hallmarks of EvC syndrome in cattle. Five Grey Alpine calves, with a known mutation in the EVC2 gene, were autopsied. Immunohistochemistry was performed on bone using antibodies to collagen II, collagen X, sonic hedgehog, fibroblast growth factor 2, and Ki67. Reverse transcription polymerase chain reaction was performed to analyze EVC1 and EVC2 gene expression. Autopsy revealed long bones that were severely reduced in length, as well as genital and heart defects. Collagen II was detected in control calves in the resting, proliferative, and hypertrophic zones and in the primary and secondary spongiosa, with a loss of labeling in the resting zone of 2 dwarfs. Collagen X was expressed in hypertrophic zone in the controls but was absent in the EvC cases. In affected calves and controls, sonic hedgehog labeled hypertrophic chondrocytes and primary and secondary spongiosa similarly. FGF2 was expressed in chondrocytes of all growth plate zones in the control calves but was lost in most EvC cases. The Ki67 index was lower in cases compared with controls. EVC and EVC2 transcripts were detected. Our data suggest that EvC syndrome of Grey Alpine cattle is a disorder of chondrocyte differentiation, with accelerated differentiation and premature hypertrophy of chondrocytes, and could be a spontaneous model for the equivalent human disease.
  • Animal Models of Bone Metastasis 20 agosto 2015
    Simmons, J. K., Hildreth, B. E., Supsavhad, W., Elshafae, S. M., Hassan, B. B., Dirksen, W. P., Toribio, R. E., Rosol, T. J.
    Bone is one of the most common sites of cancer metastasis in humans and is a significant source of morbidity and mortality. Bone metastases are considered incurable and result in pain, pathologic fracture, and decreased quality of life. Animal models of skeletal metastases are essential to improve the understanding of the molecular pathways of cancer metastasis and growth in bone and to develop new therapies to inhibit and prevent bone metastases. The ideal animal model should be clinically relevant, reproducible, and representative of human disease. Currently, an ideal model does not exist; however, understanding the strengths and weaknesses of the available models will lead to proper study design and successful cancer research. This review provides an overview of the current in vivo animal models used in the study of skeletal metastases or local tumor invasion into bone and focuses on mammary and prostate cancer, lymphoma, multiple myeloma, head and neck squamous cell carcinoma, and miscellaneous tumors that metastasize to bone.