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. 2022 Oct 1;72(5):306-319.
doi: 10.30802/AALAS-CM-22-000037. Epub 2022 Sep 16.

Canine Idiopathic Arteriopathy, Appendicular Bone Infarcts, and Neoplastic Transformation of Bone Infarcts in 108 Dogs (Canis lupus familiaris)

Isabel A Jimenez  1 , Roy R Pool  2 , Kathleen L Gabrielson  3
Affiliations

Canine Idiopathic Arteriopathy, Appendicular Bone Infarcts, and Neoplastic Transformation of Bone Infarcts in 108 Dogs (Canis lupus familiaris)

Isabel A Jimenez et al. Comp Med. .

Abstract

Osteosarcoma (OSA) is the most common primary bone tumor in both dogs and humans. The dog is an important research model for OSA, yet dogs have much higher prevalence of bone tumors than do humans, a disparity that has yet to be explained. Neoplastic transformation of cells within or adjacent to bone infarcts into primary bone tumors has been described in humans but only sparsely characterized in the veterinary literature. In this study, 653 cases of canine bone infarcts were received through a referral veterinary osteopathology service over a 14-y period. We identified an idiopathic disorder affecting the nutrient artery, termed canine idiopathic arteriopathy (CIA), which to our knowledge has no direct counterpart in human medicine. This disorder was documented alongside ischemic necrosis of the medullary cavity in 114 bone infarcts in 108 dogs. We hypothesize that CIA precipitated an ischemic environment, resulting in development of a bone infarct down- stream of the abnormal artery. In 52% (59 of 114) of cases, bone infarcts demonstrated evidence of repair (termed reparative bone infarcts [RBI]), while in 48% (55 of 114) of infarcts, a bone tumor was also present, including pleomorphic sarcoma, OSA, fibrosarcoma, and chondrosarcoma. In some cases, a spectrum of tumors was present. We hypothesize that the ischemic infarct environment provoked bone marrow mesenchymal stem cells (MSCs) to attempt repair of the stroma, and in approximately half of cases, MSCs underwent neoplastic transformation (BINT) to produce tumors. The most common sites of bone infarcts were the distal femur, distal radius, proximal humerus, and distal tibia, coinciding with common sites of canine OSA. The authors propose that CIA leading to bone infarcts and infarct-derived tumors, in combination with possible underdiagnosis of canine bone infarcts and misdiagnosis of some RBI as neoplasia, may contribute to the higher reported proportion of bone tumors in dogs compared with humans.

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Figures

Figure 1.
Figure 1.
Transverse (A) and longitudinal oblique (B) sections of normal nutrient arteries, and examples of abnormal nutrient arteries (C-E) exhibiting various degrees of arterial mediolysis (arrows). A, B) The normal nutrient arteries have an intact flattened endothelial lining resting on an internal elastic lamina, a tunica media consisting of several layers of smooth muscle cells which allow for expansion to accommodate blood pressure fluctuations, and an external elastic lamina, as well as a narrow, indistinct tunica adventitia. Scale bar = 50 µm. C) An abnormal nutrient artery. The internal elastic lamina is indistinct. Within the tunica media, there is collagen deposition and patches of arterial mediolysis (absence of smooth muscle nuclei) (arrows). There is an increase in the ratio of the diameter of the tunica media to the diameter of the lumen. The tunica adventitia is expanded and inflammatory infiltrates are absent. Scale bar = 50 µm. D, E) Abnormal nutrient arteries with multiple areas of arterial mediolysis (arrows) and foci of disorganized, pyknotic smooth muscle nuclei within the tunica media. Vascular wall remodeling and collagen deposition are present and obscure the morphology of both the internal and external laminae. The vessels are bordered by infiltrates of mesenchymal cells with angular profiles, scant cytoplasm, and no cellular atypia. There are no inflammatory cells or neoplastic infiltrates. Scale bar = 50 µm. Brightness has been adjusted across all images.
Figure 2.
Figure 2.
Histologic examples of Zone 1 of bone infarcts. A) Low magnification image of partially remodeled fragment of necrotic cancellous bone. The marrow cavity is devoid of normal bone marrow elements and adipocytes, and contains a diffuse infiltrate of mesenchymal cells (MCs), ovoid stromal cells, and abundant collagen. Magnification = 100×. B) Low magnification image of infarcted bone in which necrotic fatty marrow and resorbed necrotic trabecular bone are being replaced by sheets of MCs and collagen. Osteoblasts (*) apply new woven bone to exposed necrotic bone surfaces and osteoclasts occupy resorption cavities (†). Magnification = 100×. C) High magnification image of ischemic bone fragments lined by osteoblasts (*) and surrounded by collagen and sheets of stromal cells without anaplastic features or mitotic figures. Magnification = 200×.
Figure 3.
Figure 3.
Zone 2 of bone infarcts (A, B) – Haphazard sheet of polyhedral and spindle cells are present within the marrow cavity. Adipose tissue is absent. Cells with angular profiles that lack mitotic figures are present alongside osteogenic cells, which are surrounded by spicules and islands of new woven bone. Magnification: A = 200×, B = 400×. Zone 3A of bone infarcts (C, D) – A fragment of necrotic remodeled cancellous bone is partially lined by osteoblasts and is surrounded by fibrous tissue of low cellular density and a low-density infiltrate of pleomorphic stromal cells. Adipose tissue and normal hematopoietic elements are absent. In some areas, stromal cells without cellular atypia (MCs that have differentiated into osteoblasts) form crude spicules of woven bone, analogous to the pattern of repair found in internal callus formation at the site of an unstable long bone fracture. Few, empty blood vessels are present. Magnification: C = 100×, D = 400×.
Figure 4.
Figure 4.
Zones of bone infarcts with neoplastic transformation (BINT). Zone 3B (A, B) – low-grade pleomorphic sarcoma: sheets of hyperchromatic polygonal and spindle-shaped cells surround fragments of remodeled ischemic cancellous bone. An adjacent population of hyperchromatic plump polygonal and spindle cells with prominent nucleoli exhibit few to no mitotic figures (*), and do not form matrix. Magnification: A = 200×, B = 400×. Zone 3C (C, D) – High-grade pleomorphic sarcoma: large, hyperchromatic polygonal and spindle-shaped cells with prominent nucleoli that exhibit variable numbers of mitotic figures (*) at different sites but have no matrix formation. In some areas, these cells are interspersed between strands of collagen (†). Magnification: 400×. Zone 3D (E, F) – Nascent osteosarcoma: Hyperchromatic, isolated cells that exhibit variation in size and shape and have stellate processes like those of osteoblasts, are visualized within small nodules of bone matrix (osteoid) (arrowhead). In some sections, these cells exhibit mitotic figures (*). Magnification: 400×.
Figure 5.
Figure 5.
Zone 3E (A, B) – high-grade osteosarcoma. Osteogenic tumor cells are characterized by marked pleomorphism (anisocytosis and anisokaryosis), prominent nucleoli, and one or more mitotic figures (*) in most high-power fields. These haphazardly arranged cells form are surrounded by large islands of bone matrix (osteoid) (arrowheads), and do not form normal bone architecture. Magnification: A = 200×, B = 400×.
Figure 6.
Figure 6.
Representative radiographic (A) and gross (B) images of a canine bone infarct with neoplastic transformation (BINT), demonstrating a zonal histologic pattern of tumorigenesis. Characteristics of Zones 1-3A are conserved among all bone infarcts. BINT in addition display features characterized by Zones 3B-3E. The approximate level of the nutrient foramen is indicated (arrowhead). MCs = mesenchymal cells.
Figure 7.
Figure 7.
Diagram demonstrating the overlap between sites of osteosarcoma (OSA), bone infarcts, and longer nutrient artery branches in the dog. Representative drawings of the major weight-bearing bones (humerus, radius, femur, tibia) of the canine appendicular skeleton. The ulna is also shown for anatomic context, although it is not a major weight-bearing bone in the dog. For each bone, the latest-closing physis (at the end of the bone with the longest growth period) is indicated with an open circle. The most common sites of canine OSA are indicated with an open square. The most common sites of bone infarcts, per the results of the current study, are indicated with a black triangle, along with the percentage of overall bone infarcts at that anatomic site. For each bone, a red line represents the most common location and course of the nutrient artery and its branches. Not shown are the supernumerary nutrient foramina documented in some bones.,,
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