Department of Pathology, Sinai Hospital of Baltimore Pathology, Baltimore, MD, USA
KeywordsOsteosarcomaChondrosarcomaOsteoidOsteochondromaEnchondrom aGiant cell tumor of the boneChondroblastom aEwing sarco ma
For tumors of the bone , involving the bone, or simulating the bone, the radiograph is the gross examination. Just as in vascular lesions, a well-differentiated neoplasm may be classified as benign or low-grade malignant largely by the degree to which it infiltrates or invades the surrounding tissue or bone. In the bone, this infiltration of the periphery is best assessed by a radiologist or an experienced bone pathologist. General features are:
Benign and slow-growing lesions tend to be clearly defined, well circumscribed, and walled off by a layer of reactive bone (a thin dense sclerotic rim on x-ray). Benign things also tend to evoke a thick and smooth periosteal reaction (thickening of the cortex). Note that some benign processes can still make large tumor masses that dramatically expand the bone—aneurysmal bone cyst, for example.
Aggressive lesions , which include infectious or malignant lesions, tend to be poorly circumscribed, reflecting their infiltration of surrounding marrow. Aggressive lesions tend to produce an onionskin, spiculated, or discontinuous periosteal reaction. They may also erode through the cortex of the bone and spill into the soft tissue.
The second major principle is that primary bone tumors are rare and mainly occur in young adults and kids. For any patient over 50, the first three things in the differential for a bony lesion are metastasis, metastasis, and metastasis. Number four is a hematopoietic malignancy such as multiple myeloma. Metastatic carcinoma to the bone may consist of very rare tumor cells in a background of fibrosis, so dense fibrosis in the marrow space should always be screened with a cytokeratin stain.
The third major principle is that lytic (radiolucent) lesions, as described radiologically, just mean that something is replacing or destroying the bone. That something may be fluid, as in a simple cyst, or granulation tissue in infection, or a benign or malignant non-bone-forming tumor. Blastic lesions are radiodense and imply that the bone is being added to the lesion, either by tumor (a bone-forming tumor) or as a reaction (such as in metastatic prostate carcinoma or in Paget’s disease of the bone). The terms lytic and blastic/sclerotic refer to changes seen on x-ray or CT scan, which are the preferred modalities for seeing calcified or ossified tissues. MRI is preferable for visualizing soft tissues, while a bone scan can highlight other skeletal lesions that may be involved by the same process.
As a side note, when grossing any bone specimens, before automatically placing it in decalcification solution, it is important to know the clinical situation. Was this biopsy performed to diagnose a suspected metastatic carcinoma in a patient with a history of carcinoma, or is this a workup of a primary bone tumor? If it is for a metastatic workup, will any molecular/FISH testing be needed for potential treatment (i.e., EGFR, ALK, ROS1 in lung cancer or Her2 in breast cancer)? Bone biopsies that have been decalcified in acid solution may be unsuitable for molecular studies. Gentler decalcification methods are available, although slower.
Starting with some basic histology, how does the bone form? In the fetus, the main pathway is by endochondral ossification, in which new bone is laid down on the cartilage scaffolding. You can see this process at any growth plate, as the edge of the cartilage plate ossifies into a layer of the bone. However, in the membranous bones of the skull and in the adult at sites of repair, the first step is the synthesis of osteoid (a salmon-pink acellular matrix ) by osteoblasts and its subsequent mineralization with calcium hydroxyapatite. This immature bone has a disorganized collagen framework and is called woven bone (Figure 30.1). Continuing development and remodeling produces the bone with organized layers or lamellae of collagen visible as parallel seams within the trabeculae or cortex; this mature configuration is called lamellar bone (Figure 30.1). Polarization, or even lowering the condenser, can highlight the contrast between mature and woven bone. Neoplastic or reactive bone is almost always woven-type; fragments of lamellar bone within a lesion are entrapped native bone.
Types of bone. (a) Woven bone is laid down in thick primitive trabeculae (arrow) of osteoid, which undergoes mineralization and acquires a purple tinge (arrowhead) which may vary depending on the extent of tissue decalcification. Osteocytes (within the osteoid seams) and osteoblasts (lining the seams) can be seen in the oval. (b) Lamellar bone, seen here under polarized light, has parallel arrays of collagen (purple arrow) indicating mature bone. Immature woven bone (arrowhead) shows no organization of the collagen.
Second, how do we look at the bone on the slide? Most histologic sections of the bone are decalcified, so the pink fragments of the “bone” you see are the osteoid left behind. Calcium salts are dark purple on H&E. In lesions with osteoid formation, which may include anything from reactive metaplastic bone to fibrous dysplasia to osteosarcoma , the osteoid (pink) can be differentiated from collagen or amyloid (also pink) by the process of mineralization, seen as a purple tinge within the seams of osteoid. Dystrophic calcification in soft tissue, such as tumoral calcinosis, is not the same as bone formation. Heterotopic bone formation, such as in myositis ossificans, is true bone, but is not neoplastic.
The trickiest thing about bone tumors is that quite a lot of them lay down reactive bone as part of the process, yet are not true bone-forming tumors: the bone is just a bystander. Determining whether you are looking at reactive bystander bone versus a tumor-forming bone is critical and difficult. A basic rule of thumb is that malignant osteoid is fairly distinctive and defines the tumor as an osteosarcoma . Every other pattern is nonspecific and may be seen in benign or malignant or reactive processes, so context is key.
Malignant osteoid pattern:
A lacelike deposition of osteoid surrounding atypical and malignant-appearing spindle cells (Figure 30.2). The cells should appear to be secreting little moats of osteoid that surround them and coalesce into lacelike islands of osteoid, which in turn may mineralize.
Malignant osteoid. The osteoid is visible as pink soup among the tumor cells (arrow), which are secreting it in a haphazard fashion without trabecular organization. Pleomorphic tumor cells identify this as malignant (arrowheads), which makes this an osteosarcoma . Note the completely irrelevant giant cell (white arrow), which can be seen in any bone tumor.
Finding this in the context of a high-grade sarcoma = osteosarcoma .
Nonspecific osteoid patterns:
Well-formed, mature, lamellar bone (almost always benign)
Interlacing fingers of woven bone with prominent osteoblastic rimming and minimal atypia (usually benign; Figure 30.3)
Osteoblastic rimming in heterotopic ossification. Between layers of cartilage (C) and muscle (M), there is a layer of woven bone with prominent osteoblastic rims (arrows) outlining the seams. This often indicates reactive bone formation.
Little islands of osteoid in the context of either of the first two, without cellular atypia
Any of these three patterns may be seen in non-bone-forming tumors (like giant cell tumor of the bone), in fracture repair , in an inflammatory response, in benign bone-forming tumors (like an osteoma), and in very low-grade osteosarcomas (e.g., parosteal osteosarcoma ). Therefore, they are nonspecific, and you’ll need other information to help you make the diagnosis.
Epiphysis : the end of the long bone, adjacent to the joint surface
Physis : another term for the cartilaginous growth plate
Metaphysis : the “shoulder” of the bone between epiphysis and shaft
Diaphysis : the shaft of the bone
Cortical or compact bone : the dense structural outer layer of the bone
Medullary cavity : the inner core of the diaphysis, with marrow
Trabecular or cancellous bone : mature spicules of bone, “spongy” bone
Lamellar bone : mature bone, with concentric or layered architecture
Woven bone : immature seams of bone
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Bone-Forming Tumors (Table 30.1)
Osteoid osteoma is a common benign bone-forming neoplasm characterized by a small (<1.5 cm) radiolucent nidus of woven bone rimmed by prominent osteoblasts and surrounded by a dense sclerotic zone (Figure 30.4). The nidus is the source of intense bone pain. It is rarely seen on a slide these days, as radiofrequency ablation is an effective treatment. Osteoblastoma is essentially the same lesion histologically but is larger (>1.5 cm). The osteoblasts within these lesions are plump and amphophilic, and the pattern of osteoid deposition may be alarming at high power, but there should not be any atypia.
Malignant but indolent
Malignant and aggressive
Osteosarcoma, conventional type
Small cell osteosarcoma
Osteoid osteoma or osteoblastoma (depending on size). At the nidus of the lesion, osteoid is laid down in seams by benign osteoblasts (arrows). The hyaline pink substance can be identified as osteoid by the dark purple tinge of mineralization.
At the other end of the spectrum lies osteosarcoma . Conventional osteosarcoma is the stereotypical high-grade osteogenic sarcoma that classically arises in the femur or tibia of a young person. It is a heterogeneous malignant bone-forming tumor composed of (1) malignant cells (spindle cell, round cell, or pleomorphic) and (2) malignant osteoid (Figure 30.5). High-grade osteosarcomas have multiple morphologic variants, including osteoblastic (bone forming), chondroblastic (cartilage forming), and fibroblastic (predominantly fibrous), telangiectatic (a very aggressive variant with prominent blood lakes), and small cell (very hard to distinguish from Ewing sarcoma ). The osteoid is laid down in a lacelike pattern, the classic malignant osteoid as described above. The relative amount of osteoid and nonspecific sarcoma varies by case; sometimes the osteoid is very focal. The unifying and defining feature is the production of osteoid by tumor cells, as immunostains are not usually helpful. Resections of osteosarcoma are usually done post-chemotherapy, at which time the goal is quantifying the amount of viable tumor that remains. Rarely , a high-grade soft tissue or visceral sarcoma will show osteosarcomatous differentiation; the histologic appearance is the same.
Osteosarcoma. (a) Some tumors may show extensive osteoid, with small tumor cells that are difficult to identify as sarcoma (arrow). The lacelike osteoid deposition helps to make the diagnosis. (b) A poorly differentiated tumor can be difficult to identify as osteosarcoma because of the focal and subtle production of osteoid (arrowhead).
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