Most pathologic fractures associated with bone tumors present with a clear history of minor or trivial trauma and a previous clinical history of underlying lesions. However, diagnostic problems would be met in the bone tumor with a fracture through a previously unknown bony lesion which is not easily detectible due to concealed lesion by the spiral or oblique fracture on radiograph, and in unrecognized stress or fatigue fracture without a history of memorable trauma. A complete comprehensive understanding of remarkable microscopic sequences of fracture repair is essential for a correct diagnosis of bone tumors with unrecognized concealed fractures because the histologic findings include exclusive growth of primitive mesenchymal cells in the beginning and primitive chondro-osteoid matrix without osteoblastic rimming in the next phase, both of which can be easily misinterpreted as sarcoma. However, the absolute criterion for malignancy including mitotic figures and frank pleomorphism are never seen in fracture callus. Several histologic features useful for differentiation of fracture callus from osteosarcoma (OSA) were described. Fracture callus exhibits a typical zonal architecture with areas of immature cartilage merging with woven bone and myofibroblasts, whereas OSA tends to be more diffuse. Maturing woven bone in fractures forms trabeculae with prominent rimming, which connect together and produce variable-sized circles. But OSA produces a more lace-like pattern of woven bone embedding individual tumor cells and lacks well-formed trabeculae. Lastly, the space between woven bone trabeculae consists of a mixture of vascular and reactive fibroblastic cells in maturing fracture, whereas there is largely a matrix in the stroma of OSA [1]. The repair process after general fracture goes through four stages including formation of hematoma at the fracture ends, formation of a fibrocartilaginous callus, formation of a bony callus, and remodeling and addition of compact bone, which make histologic features vary greatly with time. The chronologic stages can be considerably overlapped [2]. (A) Hematoma formation (days 1 to 5): The hematoma immediately following the fracture releases pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), bone morphogenetic proteins (BMPs), interleukins, and platelet-derived growth factors (PDGF), which recruit macrophages, monocytes, and lymphocytes to remove damaged, necrotic tissue. (B) Fibrocartilaginous callus formation (days 5 to 11): The VEGF initiates angiogenesis and recruits local fibroblasts and capillaries to form granulation tissue or pro-callus. The cytokines also recruit further primitive mesenchymal cells and differentiate pluripotential cells into immature fibroblasts, osteoblasts, and chondroblasts which lay down collagen-rich fibrocartilaginous and osteoid matrices mimicking fibrosarcoma, chondrosarcoma, or OSA. (C) Bony callus formation (days 11 to 28): The cartilaginous callus begins to undergo enchondral ossification. The cartilaginous callus is resorbed and begins to calcify by further differentiation of chondroblasts, chondroclasts, as well as osteoblasts and osteoclasts with RANK-L expression. A hard, calcified callus of immature bone forms at the end of the stage. (D) Bone remodeling (day 18 onward, lasting months to years): The “coupled remodeling” results from a balance of resorption by osteoclasts and new bone formation by osteoblasts. The process of bone remodeling usually lasts for many months to years, ultimately resulting in the regeneration of the normal bone structure with reconstituted marrow [2–6]. Mirra dated more precisely the callus tissues of each phase based on pathologic specimens in which a specific fracture event occurred days to weeks before evaluation [7]. He described the microscopic findings of the healing process timed on a week-to-week basis during the first 2 months. The process begins with a primitive explosive growth of mesenchymal cells which can be easily confused with a sarcoma and finishes with completely normal lamellar bone and reconstituted marrow. The timing of the biopsy is very important because the histologic features of callus are quite different depending on the event stages after fracture. Particularly during the early phase, the callus tissue exhibits granulation tissue with reactive myofibroblastic cells, extensive local hemorrhage, or variable necrosis and primitive osteoid often with chondroid, which may distinguish an incipient stress or fatigue fracture from an OSA difficulty. However, the callus tissue matures significantly during the next 3 weeks after injury and does not simulate a sarcoma anymore. The callus may present with mixed areas of older and younger histology, possibly from unperceived repeated minor injuries. The normal histologic phases of fracture healing are summarized in Table 2.1 and presented in Fig. 2.1 based on Mirra’s description with addition of exact dates after fracture in my practice. (1) Within first week: Immediately after injury (less than 3 days), extensive local hemorrhage, fibrin exudate, and varying degrees of necrosis occur in association with neutrophils and lymphocytes at 24 hours, and macrophages at 48–72 hours to remove damaged, necrotic tissue. From 3 to 5 days, granulation tissue is formed with explosive proliferation of mesenchymal cells embedded in a loose myxomatous and fibrinoid matrix. The cells are stellate or spindle-shaped which migrate and anchor to fibrin strands. The overall shape is likened to a “tissue culture-like” appearance. The individual cells are plump with pleomorphic nuclei in size and shape, which may simulate an undifferentiated sarcoma (Fig. 2.1a). By the end of the week (6–7 days), the mesenchymal cells are more spindled and higher in number, which are tightly packed together forming a mass of poorly differentiated cells and infiltrate surrounding muscle fibers. In addition, other ominous cytologic features of high nuclear to cytoplasmic ratio, larger nucleoli, and high number of mitoses can more easily make a misdiagnosis of high-grade sarcoma (Fig. 2.1b, c). (2) 1–2 weeks: Sometime between 7 and 10 days, early fine wisps of primitive osteoid surrounded by ominous stromal cells often with chondroid can be seen. The cells can be plump and chromatin rich, but nuclear and cytoplasmic features are monotonous from cell to cell, which seem to be “regularly ominous.” Initially, the osteoid shows no osteoblastic rimming that may simulate that seen in OSA. But calcium deposition of the osteoid begins within 1–3 days, in which the osteoid converts to primitive woven bone. Some fields reveal masses of primitive chondroid to cartilage simulating chondrosarcoma (Fig. 2.1d). (3) 2–3 weeks: A single row of the plump osteoblasts begins to rim along the periphery of maturing woven bone spicules. Woven bone trabeculae with osteoblast rimming and less cellular marrow are connecting together and begin to form variable-sized circles (Fig. 2.1e). (4) 3–4 weeks: During this phase, most osteoid is converted trabeculae of mature woven bone with a prominent osteoblastic rimming. The bony trabeculae join each other forming variable-sized circles designated as the Roman aqueduct sign. The sign can be also seen in osteoid osteoma, osteoblastoma, or injury-related lesions such as myositis ossificans. There are prominent thin-walled, dilated, capillaries, so-called injury vessels representing a maturate granulation tissue following the injury (Fig. 2.1f). (5) 4–6 weeks: The intertrabecular tissues become hypocellular with a few spindle cells, prominent capillaries, and loose pre-marrow fat appearance (Fig. 2.1g). (6) 6–7 weeks: The histologic features can be overlapped with those of 4–6 weeks after fracture. The osteoblasts produce lamellar bone rather than woven bone leading to a peripheral network of lamellar bone laid down over the primitive woven bone spicules, which pattern is an important sign of benign bone production and is never seen in OSA. The stroma becomes bubbly to vacuolated and begins to produce primitive fat marrow early in the sixth week (Fig. 2.1h). (7) Over 8 weeks: The marrow exhibits further maturation with fat cells and hematopoietic cells appearing completely normal. With time, the bone is progressively replaced with pure mature lamellar bone spicules by a harmony of osteoblastic activity and osteoclastic remodeling.