Nonproliferative and Proliferative Lesions of the Rat and Mouse Skeletal Tissues (Bones, Joints, and Teeth)

Abstract

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) Project (www.toxpath.org/inhand.asp) is an initiative of the Societies of Toxicological Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in the skeletal tissues and teeth of laboratory rats and mice, with color photomicrographs illustrating examples of many common lesions. The standardized nomenclature presented in this document is also available on the internet (http://www.goreni.org/). Sources of material were databases from government, academic and industrial laboratories throughout the world.

Keywords: bone; diagnostic criteria; diagnostic pathology; joint; nomenclature; skeletal system; tooth.

Figure 1.

Fibro-osseous lesion (FOL), skull, mouse. Localized increases of bone trabeculae and osteoclasts with fibrous stroma proliferation within the marrow cavity. (A) Low magnification, (B) Higher magnification. Decalcified bone, H&E. Images courtesy of Dr. Jerrold Ward.

Figure 2.

Fibrous osteodystrophy (FOD), rat. Dense peri-trabecular fibrosis with prominent osteoblast rims along some bone surfaces (lower middle) and increased scalloping (erosion in shallow depressions [Howship’s lacunae]) associated with osteoclasts along other surfaces (upper middle). Decalcified bone, H&E. Image courtesy of Dr. Andrew Suttie.

Figure 3.

Increased bone, trabeculae, tibia, rat that had been given an anti-sclerostin antibody. Increased bone is characterized by trabecular hypertrophy (expanded thickness) in the metaphysis (B) compared to an untreated rat (A). Decalcified bone, H&E.

Figure 4.

Increased bone, cortex, diaphysis of a long bone, rat (B). The cortex is thicker relative to that of normal cortex in a rat long bone (A). Decalcified bone, H&E.

Figure 5.

Increased bone, periosteum and endosteum, metaphysis, tibia, rat. Decalcified bone, H&E. Image courtesy of Dr. Bing Ong.

Figure 6.

Increased osteoid, tibia, rat, following administration of high doses of 1,25 dihydroxy vitamin D₃. Abundant accumulation of osteoid (pale blue) lining the mineralized (black) matrix in trabeculae of the primary spongiosa in the metaphysis. Undecalcified section, von Kossa/MacNeal’s tetrachrome.

Figure 7.

Increased osteoid, cortex, tibia, rat. The increase is evident as a thick plaque of pale eosinophilic woven bone (A, decalcified bone, H&E) or bright red woven bone (B, undecalcified bone, modified trichrome) adjacent to the bone marrow.

Figure 8.

Increased osteoblastic surface, tibia, rat. Increased surface extent of osteoblasts, interpreted to be active in matrix synthesis, along the trabeculae of the primary spongiosa in a rat given recombinant human parathyroid hormone (PTH) (B), compared to control (A). Decalcified bone, H&E.

Figure 9.

Increased osteoclasts with fibrosis, genetically engineered mouse. Both changes follow the trabecular surfaces; the osteoclasts are very large, multinucleated elements with basophilic cytoplasm. Decalcified bone, H&E. Image courtesy of Dr. Jerrold Ward.

Figure 10.

Decreased bone, metaphysis, distal femur, rat. Both the number and size of trabeculae in the primary spongiosa are reduced markedly. Decalcified bone, H&E.

Figure 11.

Cyst, bone, rat. The cavity is lined by a continuous membrane (visible as a thin eosinophilic layer) while the wall is expanded by fibrous connective tissue. Decalcified bone, H&E. Image courtesy of Dr. Andrew Suttie.

Figure 12.

Necrosis, femoral head, rat. Empty osteocyte lacunae (arrowheads) are numerous in epiphyseal trabecular bone, while reactive woven bone (arrow) in the adjacent viable marrow is indicative of a tissue response. Decalcified bone, H&E.

Figure 13.

Fracture with callus, vertebrae of tail, mouse. (A) Lower magnification, (B) Higher magnification. The proliferating cartilage forms multiple, coalescing, pale blue nodules (center) spanning the gap between the ends of the displaced bone fragments. The sharp bony margins visible along the fracture line indicate that bony remodeling has yet to begin in earnest. Decalcified bone, H&E.

Figure 14.

Increased thickness, physis, tibia, rat that received a TGFβ1 inhibitor (B). Relative to an age-matched control rat (A), the treated animal exhibited increased thickness of the physeal hypertrophic zone along with altered staining of cartilagenous matrix (the latter indicating changes in matrix components indicative of dysplasia). Decalcified bone, Movat’s pentachrome stain. Images republished from Frazier et al (2007) by permission of SAGE.

Figure 15.

Increased thickness, physis, long bone, neonatal male rat that received the engineered fusion protein OPG-Fc (combining osteoprotegerin [OPG] and the constant region [Fc] of human immunoglobin), an inhibitor of RANKL (B). Relative to an age-matched control animal (A), the treated rat exhibits a hypertrophic lesion characterized by thickening and disorganization of the physeal hypertrophic zone with marked focal thickening (arrows) and increased trabecular bone. The two images are taken at the same magnification to highlight the thickened physis and overproduction of bone. Decalcified bone, Toluidine blue.

Figure 16.

Decreased thickness, physis, femur, rat. In images taken at the same magnification, the treated rat (B) has a slightly narrowed growth plate—confirmed subsequently by quantitative endpoints—compared to a control animal (A). Decalcified bone, H&E.

Figure 17.

Growth plate closed, female rats, 15-21 months of age. (A) With hyaline cartilage remnants, proximal tibia with red marrow (growth plate labelled with arrowheads). (B) and (C) Distal tibia with fatty marrow. (C) There is complete disappearance of the growth plate and fusion of the epiphysis and metaphysis. (B) Arrowheads mark the position of the ossified growth plate. Undecalcified bone, Von Kossa/MacNeal’s tetrachrome. Images courtesy of Dr. Thomas J. Wronski.

Figure 18.

Hyperplasia, chondrocyte with subchondral bone, calcified cartilage fractures, and collapse of the articular cartilage, femorotibial joint of a rat model of medial meniscal tear-induced osteoarthritis (OA). (A) Low magnification, (B) Higher magnification to demonstrate clonal clusters of hypertrophied chondrocytes. (As an approximate comparison, the normal appearance of chondrocytes in articular cartilage of the mouse femur is shown in Figure 9.) Decalcified bone, Toluidine blue.

Figure 19.

Hyperplasia, osteoblast, focal, femur with increased bone trabeculae, male rat given recombinant human parathyroid hormone (PTH). (A) Low magnification, (B) higher magnification. Note poorly demarcated areas of irregular trabecular bone with bone surfaces lined by plump cuboidal osteoblasts. Decalcified bone, H&E. Images republished from Jolette J et al. (2006), by permission of SAGE.

Figure 20.

Osteoma, mouse. (A) Low magnification, (B) higher magnification. (A) An expansile, well-demarcated, benign neoplasm of osteocytic or osteoblastic origin consisting of irregular lobules of well-differentiated bone separated by narrow bands of fibrous connective tissue. (B) The disorganized arrangement of lacunae in the woven bone of the well-differentiated benign neoplasm contrasts with the regular laminated architecture of the cortical bone (upper right quadrant). Decalcified bone, H&E.

Figure 21.

Osteoblastoma, proximal tibia, rat given recombinant human parathyroid hormone (PTH). (A) Low magnification, (B) higher magnification. A focal benign neoplasm of osteoblast origin with irregular borders replacing metaphyseal bone. The neoplastic cells in this lesion are more pleomorphic (i.e., less differentiated) than those in an osteoma. Decalcified bone, H&E. Images republished from Jolette J et al. (2006), by permission of SAGE.

Figure 22.

Osteofibroma, mouse. (A) Low magnification, (B) higher magnification. An expansile, highly cellular, mildly pleomorphic benign bone neoplasm that lacks tumor osteoid or other features of osteosarcoma but has a dense fibrous stroma. Decalcified bone, H&E.

Figure 23.

Osteosarcoma, mouse. (A) Low magnification, (B) higher magnification. An aggressively invasive, highly cellular, variably anaplastic malignant spindle cell neoplasm of bone characterized by formation of osteoid by tumor cells. Decalcified bone, H&E.

Figure 24.

Osteosarcoma, fibroblastic, tibia, rat given recombinant human parathyroid hormone (PTH). The tumor was lytic and produced scant tumor osteoid (arrows) but a fairly abundant fibrous stroma. Decalcified bone, H&E. Image republished from Jolette J et al. (2006), by permission of SAGE.

Figure 25.

Osteogenic fibrosarcoma, intramedullary, with increased bone in metaphysis, distal femur (*), rat administered recombinant human parathyroid hormone (PTH). (A) Low magnification, (B) higher magnification. This malignant tumor forms from fibroblasts within a bone, and thus does not produce osteoid. Decalcified bone, H&E. Radiographic evidence of focal osteolysis of the femoral epiphysis (arrowhead) with bone sclerosis of the metaphysis and diaphysis (left insert) is a common clinical presentation in osteosarcomas. Image republished from Jolette J et al. (2006), by permission of SAGE.

Figure 26.

Chondroma, nasal turbinate, rat. (A) Low magnification, (B) higher magnification. An expansile, benign tumor of chondrocyte or chondroblast origin formed of irregular lobules of disorganized hyaline cartilage. Decalcified bone, H&E.

Figure 27.

Chondrosarcoma, vertebra, rat. A large, highly expansile and destructive, malignant neoplasm of chondrocytic or chondroblastic origin. Decalcified bone, H&E.

Figure 28.

Chondrosarcoma, rat. Extensive pleomorphism is characteristic of malignant cells in this tumor. Decalcified bone, H&E.

Figure 29.

Osteochondroma, rat. (A) Low magnification, (B) higher magnification. A benign mixed mesenchymal neoplasm characterized by both cartilaginous and osseous components. The orderly cap of hyaline cartilage is a distinctive feature of this tumor. Decalcified bone, H&E.

Figure 30.

Chordoma, malignant, vertebral column, rat. This aggressive, lobulated neoplasm arises from notochord mesenchyme within the axial skeleton (commonly a vertebral body). Decalcified bone, H&E.

Figure 31.

Chordoma, malignant, rat. Lobules consist of densly packed aggregates of tumor cells separated by fibrous trabeculae. Spicules of bone encompassed by the tumor represent eroded remnants of bone rather than a product of the tumor cells. Decalcified bone, H&E.

Figure 32.

Chordoma, malignant, rat. Highly vacuolated cytoplasm (“physaliphorous cells”) is a characteristic feature of neoplastic cells within chordomas. Decalcified bone, H&E.

Figure 33.

Normal femorotibial joint (i.e., stifle, or “knee”), adult Lewis rat. This synovial joint features a narrow joint cavity (asterisk) that is partially filled by dense, fibrous cruciate ligaments (X) and triangular fibrocartilaginous menisci (M). Both the distal femur (F) and proximal tibia (T) have well-formed physes (arrows). Marrow cavities of these long bones generally are filled with hematopoietic precursors in healthy animals. Decalcified bone, H&E. Image republished from Bolon B et al. (2011) by permission of the publisher.

Figure 34.

Normal femorotibial joint (parasagittal section), 3-month-old mouse. This section shows articular surfaces, menisci, and synovium. Decalcified bone, H&E.

Figure 35.

Normal tibiotarsal joints (i.e. hock, or “ankle”), adult Lewis rat. These synovial joints demonstrate the characteristic thin synovial lining subtended by a thin fibrous joint capsule and abundant peri-articular soft tissue (in this case, white adipose tissue). The multiple joint cavities (asterisks) separate the articular surfaces of the navicular bone (N), talus (Ta), and distal tibia (Ti). In normal rodents, bone marrow cavities in this region typically contain white adipose tissue rather than hematopoietic cells. The deep digital flexor tendon (D) and calcaneus (C) are also shown. Decalcified bone, H&E. Image republished from Bolon B et al. (2011) by permission of the publisher.

Figure 36.

Normal distal interphalangeal joint, 10-week-old DBA/1JBomTac mouse. The joint cavity, synovium-lined cul-de-sacs, ligament-reinforced joint capsule, articular cartilage, subchondral bone, and transition zones are shown. Decalcified bone, H&E.

Figure 37.

Inflammation, distal interphalangeal joint, 10-week-old DBA/1JBomTac mouse. A minimal to mild, acute, neutrophil-dominated cellular infiltrate accompanied by fibrin distends the synovial cul-de-sacs and extends within the peri-articular connective tissue. The bone marrow contains the expected white adipose tissue but no inflammatory cells. Decalcified bone, H&E.

Figure 38.

Inflammation, distal interphalangeal joint, 10-week-old DBA/1JBomTac mouse. A mild to moderate, subacute infiltrate of neutrophils within the articular cavity and peri-articular connective tissue is associated with superficial erosion of the articular cartilage, disruption of the ligament-reinforced joint capsule, and incipient pannus formation. Decalcified bone, H&E.

Figure 39.

Inflammation, metatarsophalangeal joint, 10-week-old DBA/1JBomTac mouse. A moderate to marked, chronic infiltrate of neutrophils and macrophages accompanied by cellular debris obscures the natural boundaries of the joint; superficial erosion of articular cartilage, pannus formation, undermining of articular cartilage/subchondral bone, resorption of subchondral bone, and myelofibrosis are evident. The bone marrow is filled with inflammatory cells rather than white adipose tissue. Decalcified bone, H&E.

Figure 40.

Inflammation, metatarsophalangeal joint, 10-week-old DBA/1JBomTac mouse. This chronic lesion is characterized by complete loss of joint integrity; opposed bone ends are devoid of articular cartilage caps, and their medullary cavities are united by contiguous deposits of woven bone, fibrocartilage, and fibrous connective tissue. Decalcified bone, H&E.

Figure 41.

Osteophyte with degenerative joint disease (DJD), femorotibial joint, medial meniscal tear model of osteoarthritis (OA), rat. (A) On the left side of image, the medial tibial plateau (lower bone) and medial femoral condyle (upper bone) are devoid of articular cartilage, the subchondral bone plates at those sites are thickened, an osteophyte (arrow) projects above the eburnated surface of the medial tibial plateau, and a pseudocyst (arrowhead) is evident within the medial femoral condyle. Decalcified bone, H&E. (B) A toluidine blue-stained serial section of the specimen shown in (A), taken at the same magnification, showing that the osteophyte is formed mainly of cartilage.

Figure 42.

Osteophyte with degenerative joint disease (DJD), femorotibial joint, medial meniscal tear model of OA, rat. A higher magnification of the H&E-stained section in Figure 41A to highlight the loss of articular cartilage in the femur (left bone) and tibia (right bone) and osteophyte.

Figure 44.

Pseudocyst, femorotibial joint, medial meniscal tear model of OA, rat. The cavity within the medial femoral condyle (left bone) is designated a pseudocyst because it lacks the definitive cellular lining of a true cyst (shown in Figure 11). This lesion is found most frequently in the epiphyseal subchondral bone of joints with advanced degenerative joint disease, evident here through the loss of articular cartilage from the medial tibial plateau (right bone) and medial femoral condyle and osteophyte at the joint margin. Decalcified bone, H&E.

Figure 43.

Chondromucinous degeneration, sternebra, 10-week-old Sprague-Dawley rat. Multiple, discrete foci of matrix dissolution/fragmentation and chondrocyte loss are evident as pale, acellular areas within the cartilage of the synarthrosis. Decalcified bone, H&E.

Figure 45.

Synovial sarcoma, vertebra, tail, 165-day-old BALB/cJ mouse. (A) Low magnification, (B) higher magnification. (A) The architecture of a coccygeal vertebra is completely effaced by an expansile, cystic, and unencapsulated malignant neoplasm arising from synoviocytes. (B) The neoplasm is composed of a labyrinth of variably sized, interconnected spaces that contain a faintly stained, fine granular, eosinophilic substance and are bordered by papillary displays of monomorphic, histiocyte-like tumor cells (i.e., resembling type A synoviocytes) supported by a sparse collagenous stroma. Decalcified bone, H&E. Image courtesy of Dr. John Sundberg.

Figure 46.

Synovial sarcoma, vertebra, tail, 165-day-old BALB/cJ mouse. Higher magnification of the mass shown in Figure 45A. In this portion of the mass, the monomorphic, histiocyte-like cells are more solidly arranged and have indistinct cell borders. Individual cells are characterized by an oval, euchromatic nucleus and generally single nucleolus. Decalcified bone, H&E. Image courtesy of Dr. John Sundberg.

Figure 47.

Normal incisor, rat, showing ameloblasts (arrows), enamel (E), dentin (D), odontoblasts (O), pulp (P), and the periodontal ligament (PDL). Decalcified tooth, H&E.

Figure 48.

Degeneration and necrosis, ameloblast, with degeneration, odontoblast, mouse. Incisor showing ameloblast degeneration (short arrow) and necrosis (long arrow) as well as odontoblast degeneration (intermediate arrow). Degeneration is characterized by attenuation of the normal cell size, while necrosis is associated with destruction of the affected cells. Decalcified tooth, H&E.

Figure 49.

Periodontal pocket, rat. The potential space between the tooth and periodontium, which usually is spanned by the periodontal ligament, is disrupted by distension with impacted feed/bedding material and a hair cross section within the surrounding periodontal connective tissue. Decalcified tooth, H&E.

Figure 50.

Dentin niches (arrows), incisor, rat. This represents the localized failure of odontoblasts to form dentin. Decalcified tooth, H&E.

Figure 51.

Dentin niche, incisor, rat. Higher magnification of dentin niche region from Figure 50. Note the thin dentin layer, degeneration/loss of odontoblasts, and attempted repair seen as tertiary dentin (osteodentin) formation (arrows). Decalcified tooth, H&E.

Figure 52.

Dentin matrix alteration, incisor, rat. Dentin is not normal in morphology or staining, and it contains cellular inclusions. Decalcified tooth, H&E.

Figure 53.

Dental dysplasia (abnormal development), incisor, rat. This defect results from abnormal development of one or more odontogenic cell lineages and typically presents as a tooth socket containing a disorganized mass of dentin-like material surrounded by fragments of the original tooth and small islands of bone; because rodent incisors grow throughout life, this developmental anomaly may arise during adulthood, commonly in association with trauma. Decalcified tooth, H&E.

Figure 54.

Denticle, incisor, rat. These lesions represent abnormal formation of small tooth-like structures in the pulp cavity. Note odontoblasts along one edge (upper right), tubules within the dentin matrix, and central space containing degenerate ameloblasts and a small amount of enamel (purple) matrix. Decalcified tooth, H&E.

Figure 55.

Cyst, incisor, mouse. Odontogenic cysts are membrane-lined, fluid-filled cavities of unknown origin, typically arising at the apex of a tooth (seen here as a cross section at the upper left margin of the section). Decalcified tooth, H&E.

Figure 56.

Odontoma, rat. This lesion represents a developmental malformation (not neoplasm) in which all dental hard tissues including enamel (appears as clear spaces due to its loss during decalcification), dentin and cementum as well as odontoblasts, cementoblasts and dental pulp mesenchymal cells are present within a disorganized mass. Decalcified tooth, H&E.

Figure 57.

Ameloblastic odontoma, rat. This locally expansile neoplasm is comprised of proliferating, well-differentiated ameloblastoma-like epithelium located at the tumor periphery and minimal amounts of more centrally located dental hard tissues. Decalcified tooth, H&E.

Figure 58.

Ameloblastoma, rat. This locally expansile neoplasm consists of intersecting columns of mildly pleomorphic epithelial cells resembling the inner enamel epithelium encompassing aggregates of loosely arranged central cells similar to stellate reticulum. Decalcified tooth, H&E.

Figure 59.

Odontogenic fibroma, rat. This benign but locally expansile neoplasm is characterized by whorls of primitive-appearing, dental follicle-like mesenchyme separated by distinct areas of collagen formation. Decalcified tooth, H&E.

Figure 60.

Cementifying fibroma, mouse. This benign but locally expansile tumor features dense beds of neoplastic fibroblasts containing numerous cementicles (variably sized, irregular nodules of cementum). Decalcified tooth, H&E.

Figure 61.

Cementifying fibroma, mouse, higher magnification. Decalcified tooth, H&E.