Chondroblastomas appear as well-defined eccentric lucent lesions within the epiphyses of long bones. Additionally, they can occur in epiphyseal equivalents including apophyses and the patella (Turcotte et al. 1993). There are several radiographic characteristics which help distinguish chondroblastoma from other epiphyseal lucent lesions. On MRI, these lesions follow cartilage signal on all pulse sequences aside from occasional examples containing internal calcific matrix that demonstrates no signal. Additionally, painful lesions can demonstrate surrounding inflammatory response including bone marrow edema signal on MRI as well as bone marrow edema signal distant from the lesion (Figs. 2.3, 2.4, and 2.5). Biopsies show a benign cartilaginous neoplasm composed principally of sheets of mononuclear cells and osteoclast-type giant cells. The mononuclear cells frequently contain nuclear grooves which imparts a “coffee bean” appearance to the cells (Fig. 2.6). The presence of cartilaginous matrix and chicken-wire calcifications helps to facilitate the diagnosis. Not uncommonly, secondary aneurysmal bone cyst can develop and sometimes dominate the overall radiologic and histologic appearance to the extent that the diagnosis of chondroblastoma could be obscured (Fig. 2.6c).

Langerhans cell histiocytosis (LCH) is included within the differential of epiphyseal lesions in the pediatric population as these lesions can occur in all locations in long bones and in many other bones including the mandible, pelvis, ribs, and spine (Fig. 2.7). Epiphyseal lesions generally appear well circumscribed and lytic in appearance, potentially resembling chondroblastoma. LCH is a spectrum of disease and can have any radiographic appearance; lesions can have both an aggressive and nonaggressive radiographic features. In biopsies, LCH is characterized by distinctive histiocytes that are reactive for CD1a, Langerin, and S-100. The characteristic cells of LCH are often accompanied by mixed inflammatory cells, typically including predominantly eosinophils (Fig. 2.8), and can show histologic similarities with osteomyelitis as discussed further in Sect. 2.3.

In tubular bones, hematogenous osteomyelitis is usually localized to the metaphysis and may spread from the metaphysis through the growth plate to the epiphysis. In children a purely epiphyseal osteomyelitis is very rare; however, in infants younger than 15 months of age, epiphyseal osteomyelitis can occur more often given that metaphyseal vessels penetrate the growth plate and enter the epiphysis, allowing entry of causative organisms. The infection is usually subacute or chronic. An epiphyseal subacute or chronic osteomyelitis will generally appear lytic with sclerotic margin, overlapping with the appearance of other epiphyseal lesions. Metaphyseal osteomyelitis is discussed further in Sect. 2.3.

In histologic sections, GCT is characterized by multinucleated osteoclast-type giant cells (containing up to 50 nuclei) admixed with mononuclear cells (Fig. 2.9). While other giant cell-containing lesions enter the histologic differential diagnosis, the diagnosis of GCT is usually established by appropriate clinical and radiologic context in concert with the characteristic histologic features. This correlation is particularly important in GCT. The mononuclear cell population can show variable oval, round, or spindled morphology. The proportion of the giant cells and mononuclear cells can be variable between and within lesions, and lesions with few giant cells can present diagnostic challenges, particularly in a limited biopsy specimen (Fig. 2.9d). Necrosis, mitosis, and tumor emboli in vessels can all be seen in GCT, but they do not correlate with malignant progression. Areas of reactive bone can be seen in these lesions particularly if there is an associated fracture. In a subset of cases, secondary aneurysmal bone cyst changes can occur simulating a solid variant of aneurysmal bone cyst. Immunohistochemistry is of very limited use in the histologic differential diagnosis of GCT due to the lack of a specific marker (de la Roza 2011; Dickson et al. 2008).

Unicameral or simple bone cysts (UBC) appear lucent on radiographs. They demonstrate well-defined borders with a sclerotic rim and may show mild expansion of the overlying thinned bony cortex. They usually occur centrally within the medullary space near the metaphysis and may “migrate away” from the metaphysis into the diaphysis during bone growth. Although they are called unicameral bone cysts, more mature cysts can demonstrate internal septations (Fig. 2.10). On contrast-enhanced imaging, these cysts do have a rim of vascular lining which does enhance while the internal fluid component does not. Additionally, given their internal fluid structure, a characteristic “fallen fragment sign” may be demonstrated through a pathologic fracture involving a UBC with the bone fragment layering dependently within the fluid (Fig. 2.10). Unicameral bone cysts are asymptomatic unless complicated by fracture; these lesions are the most common cause of pathologic fracture in children. UBC has a characteristic gross yellowish color and clear appearance. These lesions are often removed in piecemeal and consist of multiloculated cystic spaces devoid of true lining. The cyst wall is fibrous which may contain variable amounts of fibrin, multinucleate giant cells, and sometimes cementoid material (Fig. 2.11).

Aneurysmal bone cysts (ABCs) on radiographs appear lucent with sharp margins, showing a “soap-bubble” lesion with thin sclerotic borders (Fig. 2.12). The bony cortex may be very thinned to the point of nonvisualization; however, no bony destruction is seen, similar to unicameral bone cysts. ABCs are usually multiloculated and may demonstrate lacelike internal matrix. On MRI, the lesion will also demonstrate characteristic fluid-fluid levels due to layering degraded blood products, similar to UBC (Fig. 2.12c). On contrast-enhanced imaging, the internal septa and the thin inner lining of the ABC will enhance, while the multiloculated fluid-containing spaces will not (Fig. 2.12d).

ABCs are grossly very hemorrhagic and sievelike, reminiscent of a sponge. Histologic section show multiloculated “cystic” spaces containing blood with no true lining with fibrous wall and variable amounts of osteoclastic-type giant cells, capillaries, spindle cells, and osteoid deposition that sometimes mineralize to form bone (Fig. 2.13). It is imperative to screen for secondary etiologies which may coexist in the same biopsy specimen.

An important differential diagnosis is telangiectatic osteosarcoma, which shares similar histologic features to ABCs. Telangiectatic osteosarcoma is characterized by multiple blood-filled cysts and microscopically shows tumor cells arranged along delicate networks of sinusoidal vessels. These features can mimic aneurysmal bone cyst; however, the high-grade pleomorphic cells with anaplasia, coagulative necrosis, atypical mitotic figures, and osteoid matrix are often readily identified in telangiectatic osteosarcoma (Fletcher et al. 2013). Conversely, aneurysmal bone cyst can also show osteoid formation which can undergo mineralization, representing an important histologic differential diagnosis from osteosarcoma. In these instances, the absence of malignant cytologic features is an important histologic clue to the diagnosis of aneurysmal bone cyst.

Conventional osteosarcoma can often be primarily diagnosed with radiography, with other imaging modalities typically reserved for staging and planning for surgical resection. Biopsy is performed for unequivocal confirmation of the diagnosis. In radiographs, osteosarcoma typically will appear as a large lesion with aggressive features showing a mixed lytic-sclerotic appearance, ill-defined margins, as well as bone destruction and a large soft tissue mass component. As a bone-forming tumor, conventional osteosarcoma classically has dense “cloud-like” matrix easily visible on radiographs (Fig. 2.14a, b). MRI can better delineate the soft tissue component and involvement of surrounding structures, useful for surgical planning (Fig. 2.14c). Additionally, osteosarcoma classically will demonstrate aggressive patterns of periosteal reaction including “sunburst” or “hair-on-end” pattern as well as “Codman triangles.” The sunburst pattern develops when growth of the lesion outpaces the ability of the periosteum to lay down new bone, and the Sharpey’s fibers stretch out in a divergent pattern from the bone (Fig. 2.14d), whereas “hair-on-end” periosteal reaction is oriented perpendicular to the bone. It is often seen with osteosarcoma but can also develop with other aggressive bony tumors such as Ewing sarcoma or osteoblastic metastases. The Codman triangles form on the edge of the periosteum in a fast-growing aggressive lesion or process. With aggressive lesions, the periosteum does not have time to completely ossify; thus, only the edge of the raised periosteum will ossify, producing the characteristic triangular appearance along the margins of the mass. While this is found often in osteosarcoma, this type of aggressive periosteal reaction can be found in many other aggressive lesions including Ewing sarcoma, osteomyelitis, metastatic disease, and other sarcomas. Osteosarcomas can occasionally appear purely lytic and exhibit little no periosteal reaction.

The histologic diagnosis of conventional osteosarcoma is established based on cells exhibiting malignant cytologic features associated with osteoid matrix material (Fletcher et al. 2013; Sanerkin 1980). Conventional osteosarcoma has a variety of histologic variants including osteoblastic, fibroblastic, chondroblastic, giant-cell rich, clear cell type, and epithelioid, yet none of these correlate with prognosis (Fig. 2.15) (Fletcher et al. 2013; Hauben et al. 2002). The malignant cells and associated osteoid permeate native bony trabeculae, often exhibiting anaplasia and atypical mitotic figures, and coagulative tumor necrosis involving the native bone trabeculae can be seen (Fig. 2.16). Osteoid matrix can be very focal or occasionally difficult to distinguish from other sclerosing sarcomas that produce thick collagen matrix. Generally, the role of immunohistochemistry in the diagnosis of osteosarcomas is limited and many pitfalls are known, including aberrant expression of markers such as cytokeratin that can mimic carcinoma (Okada et al. 2003). In cases where osteoid is scant or not easily discernible, immunohistochemical staining for SATB2 can be helpful to confirm bona fide osteoblastic differentiation (Fig. 2.17) (Conner and Hornick 2013). Recently, p16 expression has been shown to be predictive of tumor response to chemotherapy (Fig. 2.18) (Borys et al. 2012).

Osteoblastoma, especially aggressive forms, can show histologic features mimicking conventional osteosarcoma with plump epithelioid cells that can exhibit cytologic atypia. However, unlike osteosarcoma, osteoblastoma is typically a discrete lesion often in the diaphysis and does not invade surrounding native lamellar bone.

Parosteal osteosarcoma usually involves the metaphysis of long bones, most frequently the distal posterior aspect of the surface of the tibia. By definition, in the absence of dedifferentiation, parosteal osteosarcomas are low-grade malignant neoplasms composed of spindle cells with mild atypia which may manifest a cartilaginous cap thus mimicking an osteochondroma. However, parosteal osteosarcoma lacks the orderly arrangement typical of osteochondroma (Unni et al. 1976).

Small cell osteosarcoma is a poorly differentiated variant of osteosarcoma. Similar to conventional osteosarcoma, small cell osteosarcoma most often occurs in the metaphyseal region of long bones (Ayala et al. 1989; Green and Mills 2014; Nakajima et al. 1997) and can appear more lytic, lacking the typical “cloud-like” mineralization of the conventional osteosarcoma which contains more osteoid matrix (Fig. 2.19). Ewing sarcoma is more commonly diaphyseal and will be discussed further in Sect. 2.4. However, Ewing sarcoma can also present as a metaphyseal lesion with radiographic features that mimic osteosarcoma, including similar aggressive patterns of periosteal elevation such as Codman triangle (Fig. 2.20).