Joints:  Location at which bones connect

Normal anatomy:  There are 2 types Synovial or nonsynovial.

Synovial joints (also known as diarthroses):  Space between ends of bones formed by endochondral ossification.  They are covered by hyaline cartilage, strengthened by dense fibrous capsule continuous with periosteum of bones and an inner synovial membrane, and reinforced by ligaments and muscles.  These are "movable" joints.

Nonsynovial joints (also known as synarthrosis):  Space between end of bones without a joint space present.  They provides structural integrity and may be fibrous (cranial sutures, bonds between roots of teeth and jaw bones) or cartilaginous (manubriosternalis and pubic). These are mostly "immovable" joints.

Bursae:  Small synovial fluid-filled sac lined by synovial membrane that are found when muscles, tendons and skin glide over bony prominences, and functions as a cushion. between bones and tendons and/or muscles around a joint. This helps to reduce friction between the bones and allows free movement.

Menisci (also known as "semi-lunar" cartilages — referring to their half-moon, crescent shape):  Crescent-shaped fibrocartilaginous structure that, in contrast to articular disks, only partly divides a joint cavity, and function toserve to disperse friction in the knee joint, particularly that between the lower leg (tibia) and the thigh (femur).

"Joint" by Madhero88 - Own work. Licensed under CC BY-SA 3.0 via Commons https://commons.wikimedia.org/wiki/File:Joint.svg#/media/File:Joint.svg

Synovial membrane forms boundary of joint space.  It lacks basement membrane, overlies vascularized loose connective tissue stroma --> quick exchange between blood and synovial fluid.

Synoviocytes: Fibroblast-like cells also associated with macrophages that cover synovial membrane and produce proteins, hyaluronic acid (lubricant, nutrition for cartilage). 1-4 cells deep and are not present over articular cartilage.  Positive stains:  VCAM-1, vimentin, CD68. Negative stains:  Cytokeratin, S-100, actins, desmin, CD34, LCA.

https://en.wikipedia.org/wiki/Cartilage#/media/File:Cartilage_polarised.jpg

Hyaline cartilage: Cartilage that is hyaline (transparent) and is composed of type 2 collagen, water, proteoglycans, chondrocytes.  It has no blood supply, no lymphatics, no innervation.  However, it is covered externally by a fibrous perichondrium, whichcontains vessels that provide the cartilage with nutrition.

Chondrocytes: synthesize and digest matrix; secrete inactive enzymes and enrich matrix with enzyme inhibitors

https://en.wikipedia.org/wiki/Tendon#/media/File:Tendon_

Tendons (or sinew):  Tough band of fibrous connective tissue composed of closely packed type 1 collagen fibers and surrounded by connective tissue. They connects muscle to bone.

Ligaments:  Fibrous connective tissue that connects bones to other bones join. Similar to tendon and fasciae; all three are made of collagen. 

Fascia: Fibrous connective tissue that connects muscles to other muscles.  Similar to tendon and ligaments; all three are made of collagen. 

Collagen: arranged in arches to allow cartilage to resist tensile stresses and to transmit vertical loads.

Diseases of the Joints:

Synovial Hyperplasia:  Etiology:  Associated with irritants within the joint (torn cartilage, chipped bone) and inflammatory process (rheumatoid arthritis).  Pathogenesis:  Epithelial hyperplasia in response to injury. Epidemiology:  Common, and particulary in cases of injury to joints and of arthritic diseases.  

Gross: Congested, thickened, granular synovium.

Micro:   Multiple layers of synovium +/-inflammation, foreign material, hemorrhage, and/or scar.

Ganglion/Cyst:  

Micro: Dense fibrous tissue, with no synovial or epithelial lining +/-inflammation if associated with rupture.

https://en.wikipedia.org/wiki/Ganglion_cyst#/media/File:Ganglion_Cyst,_Hand.jpg

Neoplastic Diseases of Bone:

• Bone Forming Tumors:
  
  • Benign Bone Forming Tumors: Bone Island, Osteoma, Osteoid Osteoma,   Osteoblastoma
  • Malignant Bone Forming Tumors:  Osteosarcoma:
• Cartilage Forming Tumors:  
  
  • Benign Cartilage Forming Tumors:  Osteochondroma, Periosteal Chondroma,    Chondroblastoma, Chondromyxoid Fibroma, Enchondroma
  • Malignant Cartilage Forming Tumors:  Conventional Chondrosarcoma, Clear Cell Chondrosarcoma, Dedifferentiated Chondrosarcoma. Mesenchymal Chondrosarcoma
  • Fibroblastic and Fibrohistiocytic Tumors
• Fibroblastic and Fibrohistiocytic Tumors:
  • Fibrous Lesions:  Non-ossifying fibroma (metaphysical fibrous defect, fibrous cortical defect), Desmoplastic Fibroma, Fibrosarcoma of Bone
  • Fibrohistiocytic Lesions:  Benign Fibrous Histiocytoma of Bone, Malignant Fibrous Histiocytoma of Bone
• Ewing Sarcoma
• Hematopoietic Tumors of Bone: Plasma Cell Myeloma, Lymphoma of Bone, Hodgkin Lymphoma of Bone:
• Vascular tumors of Bone:  Hemangioma, Epithelioid Hemangioendothelioma, Angiosarcoma·      Giant cell Tumor of Bone:
• Notochordal Tumor: Chordoma
• Adamantinoma:
•  Bone Tumors of Miscelllaneous Type or Uncertain Lineage:
  • Fibrous Lesions:  Fibrous Dysplasia, Osteofibrous Dysplasia
  •  Cystic Lesions:  Aneurysmal Bone Cyst, Simple (unicameral/solitary) Bone Cyst, Intraosseous Ganglion, Langerhans Cell Histiocytosis, Erdheim-Chester Disease
• Metastases Involving Bone:

https://commons.wikimedia.org/wiki/File:Gray349.png#/media/File:Gray349.png

Rheumatoid arthritis:  

Histology: Dense perivascular inflammatory infiltrate of T lymphocytes, plasma cells (often with eosinophilic cytoplasmic inclusions called Russell bodies), macrophages; inflammation extends to subchondral bone (relatively specific for rheumatoid arthritis); proliferative synovitis with synovial cell hyperplasia and hypertrophy, lymphoplasmacytic infiltrate with variable germinal centers, necrobiotic nodules and fibrosis; increased vascularity with hemosiderin deposition; organizing fibrin floating in joint space as rice bodies; neutrophils present on synovial surface; osteoclasts present in bone forming cysts; erosions, osteoporosis; pannus formation (synovium, synovial stroma with inflammatory cells, granulomatous tissue, fibroblasts), progressing to fibrous ankylosis (bridges joints), then ossifying to form bony ankylosis; minimal evidence of repair (proliferative cartilage, sclerotic bone or osteophytes).

Degenerative joint disease: Also called osteoarthritis

Osteoarthritis. Features include (1) eroded cartilage, in this case nearly absent, and irregular mineralization of the cartilage, seen here as a dark purple stain; (2) thickening of the subchondral bony trabeculae; (3) myxoid degeneration of the subchondral bone, forming cyst-like spaces; and (4) some residual hematopoietic marrow.

Metastatic calcification: AKA calcium hydroxyapatite deposition in soft tissue, tumoral calcinosis.

Synovial hyperplasia and heavy lymphoplasmacytic infiltrate in rheumatoid arthritis.

Histology: Calcium deposits are associated with inflammatory cells and giant cells.

DDx:  Dystrophic calcification (dead tissue that is not rapidly absorbed; associated with coagulation necrosis, caseous necrosis, fat necrosis).

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Tumoral calcinosis with a characteristic mixture of calcified material, histiocytes, and multinucleated giant cells.

Gout and gouty arthritis:

Histology: Ghost chondrocytes (no nuclei) or necrotic chondrocytes, marked irregularity of tidemark; irregular thinning, fragmentation and fibrillation of thinned cartilage; subchondral cysts with mucoid fluid surrounded by sclerotic bone; usually no significant inflammatory component although advanced cases have synovial hyperplasia with lymphoid follicles; may have associated sterile acute subchondral inflammation.

Histology: Early: Edematous synovium with acute and chronic inflammatory infiltrate; late - tophi (large aggregates of urate crystals, granulomatous inflammation, hyperplastic fibrotic synovium); gout crystals are long, slender, needle shaped, but difficult to visualize with routine staining because they are dissolved during formalin processing (crystals are water soluble); easier to identify on scrape or with alcohol fixation. With chronic disease, urate deposits may be present in soft tissue, ligaments, skin.  Gouty deposits may be surrounded by fibrous tissue and be rimmed by histiocytes and giant cells.

DDx: deposition of calcium pyrophosphate, calcium phosphate, talc, methyl methacrylate (prosthetic joints).

Spiked rods of uric acid crystals from a synovial fluid sample photographed under a microscope with polarized light. Formation of uric acid crystals in the joints is associated with gout.

By Bobjgalindo - Own work, GFDL, https://commons.wikimedia.org/w/index.php?curid=5653456

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Calcium pyrophosphate crystal deposition disease (CPPD): Also called pseudogout, chondrocalcinosis.

Micrograph showing crystal deposition in an intervertebral disc.

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=17159746

Histology: Small rectangular (rhomboid) crystals that are weakly positive birefringent; may have histiocytic and giant cell reaction around these crystals.

DDx:   crystal deposition: gout, deposition of calcium phosphate, talc, methyl methacrylate (prosthetic joints).

Pigmented villonodular synovitis (PVNS): Also called tenosynovial giant cell tumor-diffuse type. Called pigmented villonodular synovitis (PVNS) when occurs near a joint.  

Fibrous histiocytoma of tendon sheath: Also called tenosynovial giant cell tumor, giant cell tumor of tendon sheath, nodular tenosynovitis, xanthogranuloma, benign synovioma. Solitary, slow-growing, painless nodule on tendon sheaths of flexor surfaces of wrists/fingers, ankle/toes.

Histology: Diffuse expansive sheets of cells with infiltrative borders and variable cellularity. Also hyperplastic synovium with papillary projections composed of foamy histiocytes and hemosiderin containing macrophages. Large clefts, pseudoglandular or alveolar spaces lined by synovial cells, osteoclast-like multinucleated (10-70 nuclei) giant cells, epithelioid cells. Abundant collagen may be present, but lymphocytes and plasma cells are sparse. Also giant hemosiderotic granules (2-3x diameter of RBC), giant siderophages. May have 5+ mitotic figures/10 HPF, rarely chondroid metaplasia. Malignant if nodular and solid invasive growth plus large cells with large nuclei, prominent nucleoli, necrotic areas and atypical mitotic figures.

Malignant giant cell tumor of tendon sheath-diffuse type:  Histiology:  Benign areas with gradual or abrupt change to frank sarcoma containing pleomorphic, spindle or enlarged oval cells resembling MFH, fibrosarcoma, myxosarcoma or giant cell tumor with large nuclei and prominent nucleoli.  Also necrosis and atypical mitotic figures.

 Immunostains: Positive: CD68 (stromal and giant cells).  Negative: S100, CD45/LCA, EMA, keratin, HMB45, CD34, desmin, smooth muscle actin.

DDx: Hemosiderotic synovitis (associated with hemophilia and intraarticular bleeding, no mononuclear or giant cell nodular cellular proliferation, hemosiderin primarily in synovial lining cells), fibrosarcoma, synovial sarcoma.

4x PVNS:  sheets of rounded synovial-like cells admixed with multinucleated giant cells and xanthoma cells with hemosiderin

10x PVNS:  collections of xanthoma cells intermixed with round cells and multinucleated giant cells

20x PVNS:  rounded synovial-like cells admixed with multinucleated giant cells

20x PVNS:   hemosiderin/siderophages

Dissolved crystals seen as pale deposits with feathery texture, surrounded by reactive fibroblasts, mononuclear cells and foreign body giant cell reaction.

Hemosiderotic synovitis:  Associated with hemophilia and intraarticular bleeding, no mononuclear or giant cell nodular cellular proliferation, hemosiderin primarily in synovial lining cells.

Synovial lipomatosis:  Also called Hoffa’s disease.

Histology: Synovial hyperplasia with unremarkable fat extending to synovial lining; occasional chronic inflammatory infiltrate.

DDx:  PVNS, rheumatoid arthritis.

Fibroma of tendon sheath:

Histiology: Lobulated, with lobules divided by narrow cleft like spaces; nodules composed of fibroblasts; narrow vessels, large amounts of dense collagenous tissue, markedly hyalinized; may have foci of myxoid change; compared to fibrous histiocytoma of tendon sheath is less cellular with no xanthoma cells and no giant cells.

Synovial chondromatosis:  Also called synovial chondrometaplasia, synovial osteochondromatosis.  Secondary disease:  Associated with degenerative joint disease - growth of fragments of articular cartilage.  Initially intrasynovial disease without loose bodies; then intrasynovial proliferation and free loose bodies, then multiple free osteochondral bodies without intrasynovial disease.  No atypia.

Histology: Cartilage cells with variable atypia or binucleated forms within synovium; clusters of chondrocytes are often arranged in lobules; no underlying arthritis.

DDx: Secondary synovial chondrometaplasia due to degenerative joint disease, neuropathic arthropathy or osteochondritis dissecans (no lobulation, clustering or atypia), chondrosarcoma (not within a joint, no characteristic clustering pattern, marked myxoid change, spindling of nuclei), cartilaginous loose bodies (more common, but associated with arthritis).

Detritic Synovitis:

Histology:  Particles of synthetic material in the synovium are associated with an intense histiocytic and foreign body giant cell reaction.  The histiocytes are oval and rounded and have abundant eosinophilic foamy to granular cytoplasm. Nuclei are central and round and lack nucleoli. Mitoses are not seen. Additional histologic findings include papillary fibrocartilaginous metaplasia of the synovial surface, sheets of coagulative necrosis without inflammation, aggregates of hemosiderin-laden macro- phages, and, in a few cases, reactive myofibroblastic prolifer- ations that resemble nodular-proliferative fasciitis.  Stromal infiltrates of neutrophils are correlated strongly with bacte- rial infection surrounding the prosthesis.

Loose bodies: May form if portion of articular cartilage (detached cartilage or cartilage/bone within joint space with necrotic calcified centers, may become attached to synovial membrane, revascularize and convert to viable bone) breaks off; has the tide mark of articular cartilage, has evidence of prior structure; normally loose body is nourished by synovium and continues to grow, has a tree ring appearance.  No clumped atypical chondrocytes; no unevenly distributed chondrocytes. 

Normal anatomy:  The 206 bones in the body can be classified by shape (long bones-femur; flat bones-pelvis or short tubular bones-hands/feet). They can also be classified as axial (vertebrae and girdles) or appendicular, or based on their embryological origin (endochondral-formed via an intermediate cartilage model, or intramembranous-formed directly from mesenchyme without an intermediate cartilage model).

BONE

Blood supply: Diaphysis: a nutrient artery enters medullary canal at center of diaphysis, divides and supplies entire diaphysis; also contributions from vessels within the Volkmann / Haversian system.  Epiphyses: supplied by medullary arteries; sometimes from the epiphysis along additional vessels that traverse the joint.  Metaphysis: supplied by vessels within the medulla that loop back.

Vascular channels: 2 types in compact bone, either haversian (longitudinal) canals or transverse/oblique (Volkmann’s canals).

Bone composition: 35% organic (cells, proteins), 65% calcium hydroxyapatite (contains 99% of body's calcium, 85% of phosphorus, 65% of sodium, also magnesium).  Hydroxyapatite crystal is formed via phase transition; 12 day lag between matrix deposition and mineralization.  Collagen resists tension, hydroxyapatite and proteoglycans in cartilage resist compression.  Thicker cortex in middle of long bones resists bending; cancellous bone at ends of long bones resists compression.

Structure of a long bone

By OpenStax College - Anatomy & Physiology, Connexions Web site. http://cnx.org/content/col11496/1.6/, Jun 19, 2013., CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=30131409

Cross-section details of a long bone

By SEER - U.S. National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) Program (http://training.seer.cancer.gov/index.html)Exact adress, Public Domain, https://commons.wikimedia.org/w/index.php?curid=378948

Micrograph of cancellous bone

cC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=657527

Osteoblasts: Arise from marrow mesenchymal cells; when active, are plump and present on bone surface; eventually are encased within the collagen they produce and get flattened (see osteocytes below); have a perinuclear halo resembling plasma cells in cytologic preparations due to prominent Golgi zone; synthesize and transport collagenous matrix, initiate and regulate mineralization, control removal of bone via osteoclasts, express Vitamin D receptors; activity is promoted by physical activity (Wolf’s law); express parathormone receptors (mediates the activation of osteoclasts).  Osteoblasts control osteoclast activity via parathyroid hormone (parathormone), PHRP (Parathyroid hormone related protein), IL-1, TNF alpha; digestion of bone by osteoclasts releases cytokines and growth factors for osteoblasts.

Positive stains: Alkaline phosphatase, estrogen receptors, parathyroid hormone.

Cement line: Junction between original resorbed surface and new bone; sharp and basophilic with routine staining; also called reversal front activate osteoclastic surface.

Lamellar bone: Layered bone with concentric parallel lamellae; gradually replaces woven bone; normal type of bone found in adult skeleton; stronger than woven bone.

Woven bone: Immature (streamer) bone due to haphazard (random) arrangement of collagen fibers, found during growth, healing, repair, infections or in some neoplasms; highlighted with polarized light or reticulin stain; abnormal in adults and associated with fibrous dysplasia or other causes of accelerated bone turnover.

Osteoblast (Wright Giemsa stain, 100x)

By Gabriel Caponetti - Own work, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=22534751

Osteoblasts lining bone (H&E stain).

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=19542672

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=19552608

Osteoclasts: Cause bone resorption due primarily to remodeling and not calcium homeostasis; derived from monocyte fusion; multinucleated (2-12 nuclei) giant cells, associated with bone surface; use their ruffled borders (with villous extensions) to bind to matrix adhesion proteins, produce resorption pits/bays (shallow concavities) called Howship’s lacunae.  Plasma membrane forms a seal with bone; osteoclast acidifies extracellular area, which solubilizes the mineral and releases enzymes which dissolve the matrix; contains tartrate-resistant acid phosphatase

Light micrograph of an osteoclast displaying typical distinguishing characteristics: a large cell with multiple nuclei and a "foamy" cytosol.

By Robert M. Hunt at English Wikipedia - Transferred from en.wikipedia to Commons by Kauczuk using CommonsHelper., Public Domain, https://commons.wikimedia.org/w/index.php?curid=7168671

Osteocytes: The mature form of osteoblasts after they are surrounded by matrix; most numerous cell in bone; communicate with each other via osteocytic cell processes with gap junctions that travel through canaliculi (bone tunnels); may maintain serum calcium and phosphorus levels; can translate mechanical forces into biologic activity.

Osteocyte

By http://www.visualhistology.com/Visual_Histology_Atlas/VHA_Chpt6_Bone.html, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3642719

Osteoid: Non mineralized bone always present at the formative surface of bone, but usually a very thin layer; resembles hyalinized collagen; composed of type I collagen (90%), acid mucopolysaccharides, noncollagen proteins including bone morphogenetic protein (may initiate bone formation), adhesion proteins (fibronectin, osteopontin, thrombospondin), calcium binding proteins (osteonectin, bone sialoprotein), mineralization proteins (osteocalcin), enzymes (collagenase, alkaline phosphatase). Increased if increased bone formation (fracture callus, Paget’s disease, hyperparathyroidism), if inadequate mineralization or if toxic / inhibitory structures present in bone (aluminum, iron, fluoride).

Light micrograph of osteoid, containing two osteocytes, being synthesized by osteoblasts.

By Robert M. Hunt - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=4230457

Osteon: Dense compact cylindrical unit underlying cortical bone; formed in childhood by ingrowth of periosteal vessels that follow a cutting cone of osteoclasts through the cortex; tunnel is haversian canal, is filled in partially with osteoblast created bone matrix.

Diagram of compact bone from a transverse section of a long bone's cortex.

Osteoprogenitor cells: Mesenchymal stem cells near bony surfaces, can produce osteoblasts.

Periosteum: Outer fibrous layer and inner cellular (cambium) layer of osteoprogenitor cells (fibroblasts and osteoclasts); contains nerve fibers, Sharpey’s fibers/perforating collagenous fibers that penetrate outer layer of bone; may become detached from bone due to benign or malignant processes, causing new bone formation between elevated periosteum and bone and producing radiologic changes.

By OpenStax College - Anatomy & Physiology, Connexions Web site. http://cnx.org/content/col11496/1.6/, Jun 19, 2013., CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=30131412

Bone growth:  Growth plate is responsible for interstitial growth of bone (growth within the bone itself).  Bone growth involves resting chondrocytes as they proliferate, mature, orient in a column and degenerate, leaving newly calcified columns for osteoblasts to migrate into.  Abnormalities in chondrocyte function disrupt this sequence and produce abnormally short and misshapen bones (example: achondroplasia [short stature], may be due to mutation in fibroblast growth factor).  Chondrocytes of the growth plate behave differently than chondrocytes of articular cartilage; are regulated by Indian hedgehog gene.  Limb patterning controls bone development; sonic hedgehog and homeobox genes organize segmentation, anterior-posterior, medial, lateral and longitudional limb patterning during fetal development; gene abnormalities cause extra or missing digits, short or long limbs or congenital amputations.  Bone production is identified by well-stained small spicules of bone with lacunar cells present and osteoblasts on bone margins.  Bones are classified based on embryologic development as endochondral (formed by ossification of cartilaginous anlage, such as long bones) and membranous (formed from connective tissue, such as skull). 

Bone is broken down by osteoclasts, and rebuilt by osteoblasts, both of which communicate through cytokine (TGF-β, IGF) signalling.

Primary center of ossification, or Growth Plate.

By Jn20 Jeppe Achton Nielsen - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=8623436

Epiphyseal growth plate: Site of endochondral bone formation; area between centers of ossification; chondrocytes here have zones of proliferation, hypertrophy, and mineralization, then primary spongiosa; regulated by PHRP; when bone reaches adult length, epiphysis closes by becoming ossified; closed epiphysis is actually more easily invaded by osteosarcoma than open epiphysis with cartilaginous barrier.

Endochondral bone formation:  Primitive mesenchyme differentiates into cartilaginous anlage of future bone, which is degraded, mineralized and removed by osteoclast like cells; allows ingrowth of blood vessels and osteoprogenitor cells; occurs at base of articular cartilage, leading to increase in bone length and diameter.

Light micrograph of epiphyseal plate showing endochondral ossification: healthy chondrocytes (top) become degenerating ones (bottom), characteristically displaying a calcified extracellular matrix.

By Robert M. Hunt - Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=9543639

Intramembranous bone formation:  Cranium, clavicles.  Formed from mesenchyme, which differentiates into fibrous tissue containing osteoblasts without an intervening cartilaginous stage.

Light micrograph of a nidus lined by osteoblasts that are creating rudimentary bone tissue.

By Robert M. Hunt - Own work, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=3809344

Giant cell reparative granuloma: 

Histology:  Areas of multinucleated giant cells are admixed with fibrous tissue and reactive bone. There are several distinctive features of giant cell reparative granuloma. First, the giant cells are smaller than those of a typical giant cell tumor. Second, the giant cells are admixed with extravasated RBCs. Third, there is a zonal pattern of giant cells in the center, which are surrounded by a rim of reactive bone. This zonal pattern indicates that this is a reactive rather than a neoplastic process

Osteoporosis: 

Histology: Thin trabeculae disconnected from each other; increase in osteoclastic activity (may be uneven) or increased percentage of surface with resorptive pitting.

Fracture:

Histology: varies with type of injury; a few days - acute tissue damage and hemorrhage, necrotic bone [empty lacunae, poorly staining bone matrix] at fracture, may be more extensive in patella, femoral neck, carpal scaphoid; 1-2 weeks - hypercellular, hypervascular tissue, often with brisk mitotic activity, resembles sarcoma but without atypia or atypical mitotic figures; reduced callus in midshaft of tibia or other poorly vascularized areas; callus reduced if rigid internal or external surgical fixation.

Fracture callus:

Histology: Spindle cell proliferation with cartilage and bone; may be hypercellular but orderly maturation present.  Procallus = fibrocartilaginous callus = soft callus - the first stage (approximately one week) in the healing of a bone fracture; connective tissue stem cells and capillary blood vessels penetrate the inflamed fracture hematoma and as phagocytes clear the debris from the injury, new fibrous connective tissue matrix, then new cartilage matrix, and finally new bone matrix begin to form; the procallus material usually extends beyond the volume previously occupied by the uninjured bone; it represents the second stage in repair of a bone fracture.  Bony callus = hard callus - the second, final stage (several weeks to months in duration) in the healing of a bone fracture; osteoclasts continue to dissolve away the fibrous and cartilaginous components of the injury site while osteoblasts continue to replace that material with new bone matrix; bone remodeling will continue until the normal dimensions and composition of the bone are recreated; it represents the third and final stage in repair of a bone fracture, though some additional bone remodelling will often follow over time.

DDx: Chondrosarcoma, pathologic fracture.

Aseptic bone necrosis:  AKA avascular bone necrosis, osteonecrosis.

Histology: Dead trabeculae (empty lacunae) stain deeper blue than nonnecrotic bone; have ragged margins with osteoclasts on one side and osteoblasts on the other; lacunae may be enlarged and cystic or normal size with pyknotic nuclei; calcium salts due to necrotic adipocytes; marrow has fat necrosis and calcium deposits (marrow is a more sensitive indicator of necrosis than bone).

Femur head showing a flap of cartilage (osteochondritis dissecans) due to avascular necrosis. Specimen from total hip replacement surgery.

By Steven Fruitsmaak - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=4120118

Osteomyelitis:   usually pyogenic, fungal or tubercular

Xrays: permeative, destructive lesion with periosteal new bone formation; chronic osteomyelitis may produce focal destruction or focal abscess.

Histology: Neutrophils (may persist for weeks), lymphocytes and plasma cells with bone necrosis, reactive new bone formation, capillary proliferation and fibrosis; subtypes include plasma cell osteomyelitis and xanthogranulomatous osteomyelitis (abundant foamy macrophages).  Bone marrow space replaced by inflammatory tissue.

Heterotopic ossification:

XR:  well defined radiodense mass.

Histology:  Osteoid deposition in a cellular fibrous tissue stroma. There is a distinct zonal pattern i.e. the bone is more dense at the periphery of the lesion. The central cellular area shows a distinct “tissue culture-like” appearance. Although the stromal is cellular, there is no evidence of pleomorphism or atypical mitotic figures.

Ddx: a. Osteogenic sarcoma  b. Heterotopic ossification  c. Chondrosarcoma  d. Tumoral calcinosis

Stress fracture:

Histology:  Shows typical characteristics of a fracture callus with granulation tissue, new bone formation, and hyaline cartilage that is undergoing endochondrial ossification. Examination of multiple areas will show a zonal pattern.

DDx: a. Osteosarcoma b. Stress fracture c. Osteoid osteoma

Bone infarct:

XR: a smoke ring pattern of radiodensity.

Histology:  characterized by the absence of osteocytes in lacunae as well as marrow changes. The marrow changes may be either fat necrosis or, in the later stages, fibrosis and calcification.

DDx:  a. Enchondroma b. Bone infarct c. Nonossifying fibroma

Particle disease:  Destruction of bone in the area of a prosthesis due to osteoclastic activity stimulated by the shedding of particles from total joint prosthesis. Particles are usually from the polyethylene component, which are shed and the phogocytosed by histiocytes and stimulate the recruitment of osteoclasts which resorb bone. This bone resorption, which usually leads to loosening of the prosthesis, is known as particle disease.

Histology:  Sheets of histiocytes are present. In addition, multinucleated giant cells containing refracture particles of polyethylene are visible. Polyethylene is easily demonstrated by using polarized light.

Bone island: Benign bone-forming tumor composed of cortical-type bone. 

X-ray: Radiodense lesion(s) that are spiculated and merge with the surrounding cancellous bone.

Histology: Cortical-type bone that is predominately lamellar but may be focally woven, which contains haversian-like canals. The osteoblasts lining the surfaces are flat and quiescent, and the osteocytes are small and cytologically banal. The periphery of lesion blends with the surrounding cancellous bone.

DDx: Well-differentiated intramedullary osteosarcoma.  Osteoblastic metastasis.

Osteoma:

XR: Ovoid, well circumscribed, and radiodense.

Histology: Dense, mature, predominantly lamellar bone rimmed by osteoblasts, surrounded by vascular, loose connective tissue.

DDx: Reactive bone associated with infection, trauma, hemangiomas; parosteal osteosarcoma (for parosteal tumors).

Osteoma

By James Heilman, MD - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=49111499

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Osteoid osteoma:  Similar to osteoblastoma but nidus measures ≤ 1.5-2.0 cm.

Xray: small, round lucency with variable mineralization surrounded by extensive sclerosis.

Histology: Extremely well circumscribed lesion. Central nidus is sharply delimited, composed of anastomosing bony trabeculae with variable mineralization, lined by plump osteoblasts, within vascularized connective tissue; surrounded by sclerotic bone; benign giant cells present; no inflammation.

DDx: Osteomyelitis (Brodie abscess is similar clinically and by Xray, not histologically).

CT scan showing an osteoid osteoma of the fibula with a clearly visible nidus.

By Hellerhoff - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=14523885

Osteoid osteoma composed of haphazardly interconnecting trabeculae of osteoid/woven bone that are lined prominently by osteoblasts. The intervening loose connective tissue is vascular.composed of lace-like pattern of osteoid associated with bland cells, fibrous tissue, and multinucleated giant cells. 

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Osteoblastoma:  Also called giant osteoid osteoma.  Related to osteoid osteoma but larger nidus (> 1.5-2.0 cm), no reactive bone, lack of intense pain (dull, achy), no response to aspirin. 

Xray: may appear malignant due to cortical expansion and destruction, nidus may be identifiable. 

Histology: Resembles osteoid osteoma.  Nidus composed of anastomosing bony trabeculae rimmed by osteoblasts; loose and vascular intratrabecular spaces.  May have scattered bizarre tumor cells (degenerative), rarely produces cartilaginous matrix.  No spindle cells, no infiltration of adjacent soft tissue.  Benign multinucleated giant cells are present.  

DDx: Well differentiated osteosarcoma (infiltrative).

4x Osteoblastoma with well-circumscribed margin from the surrounding bone.

10x

20x Interanastomosing trabeculae of osteoblastoma are rimmed by osteoblasts.

Aggressive osteoblastoma:  Resembles osteoblastoma by Xray but with atypical cytology. 

Histology: Wide and irregular trabeculae, bordered by epithelioid osteoblasts.  Focal lack of trabecular pattern of osteoid proliferation; low mitotic rate, no lace like osteoid, no atypical mitotic figures, no necrosis, no infiltration of adjacent intertrabecular space.  Malignant if permeates surrounding tissues and no peripheral maturation. 

DDx: Osteosarcoma.

Osteosarcoma:

Xray: large, destructive, lytic or blastic mass with permeative margins; may break through cortex and elevate periosteum; sunburst pattern due to new bone formation in soft tissue.  Codman's triangle: shadow between cortex and raised ends of periosteum (due to reactive bone formation), non-specific.

Histology: High grade spindle cell tumor that produces osteoid matrix unconnected by cartilage (by definition).  Tumor cells produce neoplastic bone - basophilic thin trabeculae of neoplastic bone resembling fungal hyphae or neoplastic osteoid - eosinophilic, homogenous, glassy with irregular contours and osteoblastic rimming; destroys or grows around trabeculae; vascular invasion and necrosis common.  May have osteoblastic, fibroblastic (pure spindle cell growth with minimal matrix) or chondroblastic predominance (malignant appearing cartilage with peripheral spindling and osteoid production).  Osteoid may be variable in amount; with bizarre giant cells in stroma or acellular stroma; vessels may have hemangiopericytoma-like features; tumor cells may be spindly, oval or round of variable size; 25% have osteoblast-like multinucleated giant cells; cartilage may be mineralized, immature, myxoid. 

Immunostain:  Positive:  Alkaline phosphatase, vimentin, variable smooth muscle actin and desmin, S100 (if chondroid differentiation), vWF, rarely hCG .  Negative: Keratin, EMA.

DDx: Exuberant fracture callus, myositis ossificans, giant cell tumor (unlikely in metaphysis of young patient).

2x Interanastomosing trabeculae of osteoblastoma are rimmed by osteoblasts.

40x Osteosarcoma containing pleomorphic malignant cells and coarse neoplastic woven bone

4x

10x

20x two major components of this neoplasm: highly pleomorphic cells and haphazard deposits of osteoid. Note that the malignant cells fill the spaces between osteoid deposits

Epithelioid osteosarcoma:  

Xray: highly destructive with variable mineralization.  

Histology: Osteoblastic osteosarcoma with small multinodular growth pattern, lacelike osteoid deposits, hemangiopericytoma-like vessels, rosette-like formation, epithelioid tumor cells.

Immunostains:  Positive:  EMA.

High grade surface osteosarcoma: Site:  Surface of bone.  Same prognosis as conventional osteosarcoma, but poorer prognosis than parosteal (juxtacortical) osteosarcoma. 

Xray: surface tumor with variable mineralization.

Histology: Resembles conventional osteosarcoma.

Low grade intraosseous (central) osteosarcoma:  also known as well differentiated intramedullary osteosarcoma

Sites: usually long bones (femur, tibia). 

Xray: poor margination with cortical disruption and soft tissue extension, variable matrix mineralization, no sclerotic margin. 

Histology: Paucicellular, infiltrates between bone trabeculae composed of interlacing fascicles of spindle cells with mild atypia and rare mitotic figures in heavy collagenous background; variable bone or osteoid production may resemble fibrous dysplasia.

Immunostains: Positive: Ki-67/MIB-1

DDx: fibrous dysplasia (no cortical disruption, no atypia, usually no trabecular bone), paraosteal osteosarcoma (surface location but same histology).

Osteoblastoma-like:  

Histology: Resembles osteoblastoma, but permeation of surrounding host tissue.

Parosteal osteosarcoma:  Also called juxtacortical osteosarcoma (outside of the periosteum).  

Site:  Metaphyses of long bones with  70% occur at posterior aspect of distal femoral shaft, also tibia, humerus; rarely in hands, mandible.  

Xray: prominent extracortical calcified mass that encircles bone; no continuity with bone or marrow.  

Histology: Low grade neoplasm of well formed bony trabeculae, osteoid, variable cartilage and highly fibrous spindle cell stroma in chaotic pattern.  Stroma is hypocellular but malignant with mild atypia.  25% have medullary involvement; 15% have coexisting areas of dedifferentiation; rarely has abundant osteoclast-like giant cells; no/rare mitotic figures; no fatty or hematopoietic marrow.

DDx: Myositis ossificans (orderly maturation, not attached to underlying bone; more active histologically), high grade surface osteosarcomas (may be juxtacortical but different histology), conventional osteosarcoma with periosteal spread, osteochondroma (tumor continuous with bone, fatty or hematopoietic marrow present).

10x

20x Streamers of woven bone surrounded by relatively bland spindle cells in parosteal osteosarcoma.

4x

20x

4x

10x

Periosteal osteosarcoma: 

Sites: usually diaphysis of proximal tibia or femur. 

Xray: small lucent lesions on bone surface with bone spicules perpendicular to shaft and penetrating soft tissues; no medullary involvement (by definition). 

Histology: Intermediate to high grade osteosarcoma with prominent cartilaginous component. Cartilage in lobules with peripheral spindling and central bone formation; malignant osteoid / bone is present, but may be focal.

DDx: Juxtacortical chondrosarcoma (lobules of malignant cartilage with calcification and surface endochondral ossification, no malignant osteoid).

20x There are lobules of cartilage. Neoplastic osteoid is present usually at the most peripheral regions of the cartilage. The cartilage is characterized by atypical chondrocytes separated by some poorly defined bands of fibrous tissue.

Small cell osteosarcoma: 

Histology: Diffuse growth of small, uniform, round/spindle tumor cells, focally produces malignant osteoid, occasionally mixed with cartilage.

Immunostains:  Positive: vimentin, variable S100.   Negative: CD99, keratin, EMA, factor VIII related antigen, desmin, synaptophysin, LeuM1, CD45/LCA.

DDx: Ewing’s sarcoma/PNET, lymphoma.

Telangiectatic osteosarcoma: 

Xray: purely lytic destructive lesion simulating aneursymal bone cyst.  Probably similar prognosis as conventional osteosarcoma

Histology: Prominent blood-filled cysts, malignant stroma in septa separating cysts; minimal osteoid.

DDx: Aneurysmal bone cyst (no malignant cells present within septa).

20x Telangiectatic osteosarcoma with numerous large cystic spaces filled with blood and fibrinous material. The criteria for the diagnosis of telangiectatic osteosarcoma are the following: a) a radiolytic lesion without evidence of intralesional ratiodensity; b) aneurysmal bone cyst histology on low power microscopy; c) high-grade conventional osteoblastic osteosarcoma apparent on high-power microscopy.

Osteochondroma:  Also called exostosis. 

Sites: metaphysis, not medullary cavity; usually distal femur, proximal tibia, proximal humerus; occasionally pelvis, scapula, ribs; rarely digits; not in intramembranous bones. 

Xray: metaphyseal lesions grow in direction opposite to adjacent joint; cortex and medulla are continuous with underlying bone.

Histology: Periosteum appears as pink fibrous capsule; cartilage resembles disorganized growth plate with ossification towards base; medullary cavity merges with that of underlying bone; bony trabeculae appear normal; normal appearing marrow; no spindle cells.

DDx: Secondary chondrosarcoma (see above, usually well differentiated but with invasion into surrounding tissue), parosteal osteosarcoma (spindle cells between bony trabeculae), bizarre parosteal osteochondromatous proliferation.

10x Osteochondroma, showing the outer perichondrium, cartilage cap and underlying stalk. Variable amount of endochondral ossification occurs at the bone/cartilage interface.

Subungual exostosis:  A reactive lesion, probably secondary to trauma, which arises from the distal phalanx of the toes and fingers, most commonly in the toes.

Xray: subungual mass arising from the distal phalanx of the finger or nail and lifting the nail.

Histology:  A zone of reactive new bone arising in the periosteum, which produces a tumefaction under the nail and causing it to detach. There is occasionally a cartilage cap.

DDx: a. Osteochondroma  b. Subungual exostosis  c. Myositis ossificans

Juxtacortical (periosteal) chondroma: 

Site:  Surface of metaphysis or shaft of long bone or small bones of hand/feet.  May arise in zones lacking periosteum such as the femoral neck. 

Xray: well defined, 2-4 cm, sharply scallops outer cortex of underlying bone. 

Histology: Benign hyaline cartilage tumor covered by periosteum or reactive bone.  Hypercellular with variable myxoid features and binucleation.  Does not invade surrounding tissue, no mitotic figures.

DDx: Periosteal chondrosarcoma (patients in 30’s, larger size, infiltrates soft tissues, aggressive appearance on Xray, similar histology), periosteal osteosarcoma (osteoid and spindle shaped malignant cells).

10x Osteochondroma, showing the outer perichondrium, cartilage cap and underlying stalk. Variable amount of endochondral ossification occurs at the bone/cartilage interface.

10x

4x

4x

4x

Soft tissue (extraskeletal) chondromas: 

Site:  hands and feet

Histology: Lobulated on low power; clusters of plump tumor cells with fine punctate calcification; nuclear hyperchromasia and binucleation common; may have focal fibrosis; may have osteoclast-like giant cells, histiocyte-like cells, vacuoles resembling lipoblasts.

DDx: Chondrosarcoma (rare in hands and feet), calcifying aponeurotic fibroma.

10x Osteochondroma, showing the outer perichondrium, cartilage cap and underlying stalk. Variable amount of endochondral ossification occurs at the bone/cartilage interface.

4x

Enchondroma: 

Sites: Usually small bones of hands and feet (rare in thumb or ribs).   Enchondromas of long bones is rare and is usually at the metaphysis or diaphysis with flecks of calcification. 

Variants:  Enchondroma protuberans: rare, exaggeratedly eccentric enchondroma resembling radiographically an osteochondroma. Calcifying enchondroma:  Metaphysis of long bones with massive tumoral calcification.  Multiple enchondromas may produce severe deformities and more likely associated with chondrosarcomatous transformation.  Maffuci’s syndrome: multiple enchondromas and soft tissue hemangiomas; also ovarian carcinoma, brain gliomas.  Ollier’s disease: nonhereditary disease of multiple enchondromas of long bones and flat bones (up to 50% of skeleton) with associated skeletal deformities, and often ovarian sex-cord tumors. 

Xray: thinning but preservation of cortex, O ring sign, no penetration into soft tissue, pathologic fractures common. 

Histology: Lobules of hyaline cartilage encased by bone and covered by perichondrium (fibrous tissue).  Resembles low grade chondrosarcoma due to hypercellularity, binucleation, myxoid change but radiographically is benign; also calcification, endochondral ossification.  Necrosis common in benign lesions due to avascular cartilage.  Tongues of bone extend into cartilage (vs. sharp interface at growth plate).  More atypia present with Ollier’s disease and Maffuci’s syndrome, but histologic features of low grade chondrosarcoma should be ignored if radiographically benign; most lesions regress when skeleton matures;

DDx: low grade chondrosarcoma (breaks through or erodes cortex, marked myxoid change, large tumors occupy marrow space and entrap bony trabeculae), epiphyseal dysplasia (in babies, affects multiple joints).   

4x The border of an enchondroma with the surrounding cortex is sharp.

10x Enchondromas of the small bones of the hands and feet often demonstrate increased cellularity and nuclear atypia.

20x Clustered and scattered chondrocytes with small, uniform, darkly stained nuclei. Occasional bi-nucleated chondrocytes are present. Importantly, there were no mitotic figures.

Chondroblastoma: 

Sites: distal femur, proximal humerus, proximal tibia, pelvis, ribs, feet, scapula; usually epiphysis (open) or apophysis such as iliac crest; may extend into metaphysis; also skull in older patients. 

Xray: extremely well circumscribed tumor of epiphysis with spotty calcifications in patient with open epiphysis. 

Histology: Varies with time - early hypercellularity, followed by necrosis, followed by fibrous or chondroid areas with occasional spindle cells.  Compact polyhedral chondroblasts with abundant pink cytoplasm and variable pigment, well defined cell borders and hyperlobulated nuclei with grooves in mineralized, chicken-wire matrix that surrounds chondroblasts; chondroid differentiation almost always present (pink vs. blue matrix).  May have marked cellularity, intracytoplasmic glycogen granules, mitotic figures, necrosis, osteoclast-type giant cells; 25%-50% have secondary aneurysmal bone cyst; hyaline cartilage is rarely seen; no significant nuclear atypia.

Immunostain:  Positive: S100, vimentin, low molecular weight keratin (LMWK), PAS with diastase (glycogen), reticulin (surrounds each cell), neuron specific enolase, occasionally muscle specific actin.

DDx: Giant cell tumor (metaphyseal or epiphyseal in patients with closed epiphysis, clustered giant cells that are larger and more numerous than chondroblastoma, no chondroid differentiation, no chicken wire matrix), chondromyxoid fibroma (metaphyseal, myxoid with pseudolobular pattern with pleomorphic stellate cells).

20x Chondroblastoma demonstrates sheets of round to ovoid cells admixed with osteoclast-like giant cells. The delicate pericellular calcification of the matrix has been described as chicken wire.

40x  The mononuclear cells in chondroblastoma show eccentric, round to ovoid nuclei with occasional nuclear grooves.

10x

2x

4x

Chondromyxoid fibroma:

Site: metaphysis of long tubular bones, small bones of feet or any bone, skull base (clivus). 

Xray: extremely well circumscribed, lytic defect with scalloped, sclerotic margin similar to metaphyseal fibrous defect.  Treatment: Benign, 25% recur after curettage; fewer recurrences after en bloc excision; may erode through cortex but no distant metastases.

Histology: Well circumscribed, hypocellular lobules of poorly formed hyaline cartilage composed of chondroblasts with abundant pink cytoplasm and myxoid tissue with fibrous septae containing spindle cells and osteoclasts.  More cellular at periphery of nodules.  Tumor cells present in lacunae in myxoid areas, stellate in myxoid areas with long delicate cell processes that approach other cells.  Atypia is common, including large, hyperchromatic nuclei; scattered calcification and osteoclast-like giant cells, although fewer giant cells in old tumors; extensive vascularity is present in peripheral areas.  No/rare mitotic activity.

Immunostains: Positive: S100 (variable).  Negative stains (chondroid areas): muscle specific actin (MSA), smooth muscle actin (SMA), desmin, CD34 (but vessels stain)

DDx: Fibromyxoma (similar to chondromyxoid fibroma but no cartilaginous areas, usually older adults), chondroblastoma (cells are similar but not lobulated), chondrosarcoma (similar histology but malignant radiologically, no hypocellular center, infiltrates surrounding tissue), fibrous dysplasia with myxoid change (not lobulated)

2x  chondromyxoid fibroma has a lobulated growth pattern.

10x  Lobules of chondromyxoid fibroma have increased cellularity at the periphery and loose myxoid stroma centrally.

4x

20x  The cells of chondromyxoid fibroma within the lobules have spindled to stellate cytoplasm and small round to polygonal nuclei with fine chromatin and eosinophilic cytoplasmic extensions.

Chondrosarcoma-conventional: 

Sites: large bones - pelvis, ribs, femur, humerus, vertebrae; unusual in hands, feet, jaw, skull. 

Xray: presume malignant if large tumor of long bones or grows rapidly during adolescence to 8 cm or more; have fluffy calcification, poorly defined margins, erosion or thickening of cortex; usually no periosteal new bone formation. 

Histology: Tumor cells produce cartilaginous matrix; either well, moderate or poorly differentiated; may have only minor or focal atypia, but consider malignant if malignant radiologic features (see above); no direct osteoid or bone formation by tumor cells (if present, classify as osteosarcoma, although may be non-neoplastic bone).  Intracytoplasmic hyaline globules common in low grade tumors.  Grading: Based on cellularity and nuclear changes in chondrocytes.  Well, moderate or poorly differentiated correspond to grades 1-3; grade 4 is spindled tumor representing either chondroblastic osteosarcoma or dedifferentiated chondrosarcoma. 

Grade 1 (low-grade):  Very similar to enchondroma. However, the cellularity is higher, and there is mild cellular pleomorphism. The nuclei are small but often show open chromatin pattern and small nucleoli. Binucleated cells are frequent. Mitoses are very rare. Grade 1 chondrosarcomas are locally aggressive and prone to recurrences, but usually do not metastasize.

Immunostains:  Positive: S100 (nuclear and cytoplasmic); staining resembles adult cartilage in well differentiated tumors or fetal cartilage in poorly differentiated tumors; high grade tumors may be p53+.  Negative: Neural-type cadherin.

DDx: Chondroma vs. well differentiated chondrosarcoma (Xray is determinative, for chondrosarcoma must see permeation of tumor through cortex into soft tissue), osteosarcoma (tumor cells make bone).

Grade 1 chondrosarcoma shows only mildly increased cellularity and minimal atypia compared with normal cartilage. The morphology overlaps substantially with enchondroma.

Grade 2 (low-grade):  The cellularity is higher than in Grade 1 tumors. Characteristic findings are moderate cellular pleomorphism, plump nuclei, frequent bi-nucleated cells, and occasional bizarre cells. Mitoses are rare. Foci of myxoid change may be seen. Unlike Grade 1 tumors, about 10% to 15% of Grade 2 chondrosarcomas produce metastases.

10x Chondrosarcoma permeates bone as a single, confluent mass entrapping existing bony trabeculae. 

Grade 3 (high-grade):  Characteristic findings are high cellularity, marked cellular pleomorphism, high N/C ratio, many bizarre cells and frequent mitoses (> 1 per hpf). These are high grade tumors with significant metastatic potential.

Grade 3 chondrosarcoma demonstrates diffuse hypercellularity, pleomorphic chondrocytes with nuclear hyperchromasia, irregular nuclear membranes, and necrosis. Mitotic activity is present in this case, but mitoses may be rare even in grade 3 tumors.

Chondrosarcoma-clear cell: 

Sites: Proximal femur or humerus. 

Xray: Lytic lesion, slightly expansile, sharply marginated, may appear benign, may be heavily mineralized.

Histology: Lobules of tumor cells with sharply defined borders, clear or ground-glass cytoplasm with vacuoles, central nuclei with occasional prominent nucleoli, numerous osteoclast-type giant cells, often mixed with small trabeculae of reactive bone. 50% also contain conventional low-grade chondrosarcoma; may have secondary aneurysmal bone cyst changes.

Immunostain:  Positive: S100.

DDx: Chondroblastoma.

Clear cell chodrosarcoma of the chest wall.

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Chondrosarcoma-dedifferentiated:  Coexistence of well differentiated (low grade) cartilaginous component and high grade anaplastic component.  More common in recurrent versus primary tumors. 

Site: Often in pelvic and shoulder girdles.  

Xray: Resembles chondrosarcoma with areas of highly aggressive tumor. 

Histology: High grade spindle cell sarcoma at periphery of typical low grade chondrosarcoma with abrupt change, usually central. Has features of malignant fibrous histiocytoma, rhabdomyosarcoma, fibrosarcoma, osteosarcoma, undifferentiated sarcoma (different from pre-existing chondrosarcoma).

Immunostain:  Positive: Alpha-1-antichymotrypsin, actin, desmin, myoglobin, p53, variable S100.  Negative:  Keratin (usually).

DDx: Chondroblastic osteosarcoma (gradual transition from high grade cartilaginous tumor to spindle cell sarcoma, young patients).

Dedifferentiated chondrosarcoma is characteristically a biphasic tumor with broad zones of hyaline cartilage juxtaposed with a second high-grade sarcoma. The dedifferentiated component consists of a high-grade sarcoma such as malignant fibrous histiocytoma, as in this example, or osteosarcoma.

2x

Chondrosarcoma-mesenchymal:  Cartilaginous tumor with primitive component composed of mesenchymal cells at condensation stage. 

Sites: diaphysis of jaw, pelvis, femur, ribs, spine; often involves extraosseous structures such as orbit, paraspinal region, meninges, extremity soft tissue.  Xray: Resembles conventional chondrosarcoma.

Histology: Dimorphic pattern of well differentiated cartilage with abrupt boundary from undifferentiated stroma composed of small round/oval cells resembling lymphoma, hemangiopericytoma or Ewing’s sarcoma/PNET; occasional spindle cells; minimal pleomorphism, no/rare mitotic figures.

Immunostain:  Positive: Vimentin, CD57/Leu7, neuron specific enolase, CD99/MIC2 in small round blue cells.  Negative stains: S100 (positive only in chondroid areas), desmin, actin, cytokeratin, EMA, synaptophysin.

DDx: Small blue cell tumors (Ewing’s/PNET, lymphoma, small cell osteosarcoma; all usually lack chondroid lobules).

2x At low power, mesenchymal chondrosarcoma is a biphasic tumor composed of hyaline cartilage and small round blue cells. Hemangiopericytoma-like vessels may be prominent.

4x A, The cellularity of the cartilage areas of mesenchymal chondrosarcoma is lower than the round cell areas and typically displays low grade features. 

20x The round cell component of mesenchymal chondrosarcoma shows hemangiopericytoma-like vasculature and dense sheets of monomorphic round to oval cells.

Metaphyseal fibrous defect:  Also called fibrous cortical defect.  Called nonossifying fibroma if loose, > 5 cm and associated with intramedullary component. 

Sites: usually metaphysis of distal femur, tibia; 50% are multiple; often < 1 cm.  Xray: sharply demarcated radiolucencies surrounded by thin zone of sclerosis without a periosteal reaction.  Treatment: usually none; curettage and bone grafts if large and at risk for pathologic fracture.

Histology: Storiform pattern of fibroblasts with scattered benign giant cells, foamy histiocytes, cholesterol crystals, hemosiderin; mitotic figures common; rarely has bizarre (degenerative) nuclear features; resembles fibrous histiocytoma.

DDx: Giant cell tumor (older patients, usually epiphyseal, lytic, no sclerosis, diffuse giant cells with 40+ nuclei), benign fibrous histiocytoma (painful, in pelvic and long bones, similar histology).

2x Nonossifying fibroma: histologic appearance. Low-power view photomicrograph showing bland spindle cells admixed with multinucleated giant cells. The spindle cells assume a storiform pattern. 

2x Nonossifying fibroma: histologic features. The spindle cells are often numerous and contain plump vesicular nuclei.

20x Nonossifying fibroma:  Lesions often contain large numbers of hemosiderin-laden macrophages and foam cells. These features have led some pathologists to the name fibroxanthoma.

Desmoplastic fibroma: 

Sites: metaphysis of long bones (56%), mandible (26%), pelvis (14%). 

Xray: lytic and honeycombed (“soap bubble” appearance) metaphyseal lesions, cortical thinning with soft tissue extension.  Treatment: wide local excision to prevent otherwise frequent recurrences.  Causes local destruction, no metastases.

Histology: Mature, bland fibroblasts separated by abundant collagen with thin walled, dilated vascular channels; may infiltrate into soft tissue; no necrosis, no pleomorphism or atypia, no mitotic activity.

DDx: Fibrous dysplasia, low grade fibrosarcoma.

10x Desmoplastic fibroma of bone: histologic features. Bland spindle cells are present in a heavy collagenized matrix.

20x Desmoplastic fibroma of bone: histologic features. The spindle cells show no atypia, and mitotic figures are extremely rare.

Fibrosarcoma of bone:

Sites: medulla of metaphysis of long bones, usually distal femur or proximal tibia, jaw.  Often secondary to infarct, Paget’s disease, radiation.  Occasionally is multicentric, but metastatic sarcomatoid carcinoma (kidney or other sites) is more likely. 

Xray: osteolytic, soap-bubble appearance; invasive or well-defined margins depending on differentiation of tumor. 

Histology: Resembles soft tissue fibrosarcoma with herringbone pattern of spindle cells with variable anaplasia.  No malignant osteoid; classify as malignant fibrous histiocytoma if prominent pleomorphism.  Well differentiated tumors are hypo- or hypercellular with mitotic figures and atypia; high grade tumors have more hyperchromasia and mitotic figures; may have small cells simulating Ewing’s/PNET; other variants are sclerosing epithelioid and myofibroblastic.

DDx: Desmoplastic fibroma, fibroblastic osteosarcoma, metastatic sarcomatoid carcinoma.

Benign fibrous histiocytoma of bone: 

Sites: pelvic bones, other unusual sites. 

Xray: small, lytic lesions with sharply defined margins and a sclerotic rim. 

Histology: Storiform pattern of spindled cells with frequent foam cells and variable benign multinucleated giant cells; resembles cutaneous counterpart.

DDx: Metaphyseal fibrous defect / nonossifying fibroma (similar histology but characteristic radiologic findings, usually younger than age 20 years, metaphysis of long bones), fibrous cortical defect, xanthoma, low grade fibrosarcoma, giant cell tumor of bone.

4x Fibrosarcoma of bone: histologic features. Lesions consist of a cellular population of spindle cells that often assumes a “herringbone” pattern.

10x Fibrosarcoma of bone: histologic features. Lesions consist of a cellular population of spindle cells that often assumes a “herringbone” pattern.

20x Fibrosarcoma of bone: histologic features. The spindle cells usually show mild nuclear atypia.

20x Fibrosarcoma of bone: histologic features. The spindle cells usually show mild nuclear atypia.

Plump, foamy histiocytic cells in a benign, fibrous, spindled matrix; hemorrhage may be present along with giant cells.  Storiform arrangement of cells 

Malignant fibrous histiocytoma (MFH):

Sites: metaphysis of long bones, jaw. 

Xray: lytic process with destruction of cortex.

Histology: Resembles similar soft tissue tumor; storiform pattern of malignant appearing fibroblasts and myofibroblasts with benign or malignant giant cells.  No areas typical of osteosarcoma or chondrosarcoma (by definition).

DDx: Fibrosarcoma (less pleomorphism, no giant cells), fibroblastic osteosarcoma (matrix production), lymphoma, metastatic sarcomatoid carcinoma (must rule out in patients age 60+ years).

Malignant fibrous histiocytoma: histologic features. Most commonly, lesions show pleomorphic, spindle cells in a storiform pattern.

Ewing’s sarcoma / primitive or peripheral neuroectodermal tumor (PNET):  Molecular: t(11,22)(q24;q12) in 85%

Sites: marrow of femur, tibia, humerus, fibula, pelvis, ribs, vertebra, mandible, clavicle; may permeate cortex and invade soft tissue. 

Xray: destructive, lytic tumor with reactive periosteal bone resembling onion skin; widening of medullary canal. 

Histology: Sheets of small, round, uniform cells 10-15 microns (larger than lymphocytes) with scant clear cytoplasm, divided into irregular lobules by fibrous strands; indistinct cell membranes; round nuclei with indentations, small nucleoli; may have Homer-Wright rosettes (central fibrillary space) or pseudorosettes (cells arrange themselves around vessels), hemorrhage and necrosis, prominent vasculature, variable mitotic figures, may have large pleomorphic cells, organoid pattern, filigree pattern (large areas of perivascular tumor necrosis with “ghost cells”); little stroma, no spindling; may have adamantinoma-like features.  Post-treatment: marked pleomorphism, tumor giant cells.

Immunostains:  Positive: CD99 (O13, MIC2), usually PAS+ diastase sensitive (glycogen), NSE, Leu7/CD57, FLI1 protein, vimentin; variable low molecular weight keratin, variable synaptophysin.  Negative: S100, CD45/LCA, muscle markers, vascular markers.

DDx: Metastatic neuroblastoma (patients younger than 5 years, primary should be evident), lymphoma (CD20+, older patients, polymorphic infiltrate), desmoplastic small round cell tumor, embryonal rhabdomyosarcoma.

2x Permeation of intertrabecular spaces with displacement of normal marrow fat demonstrates the local invasive potential of the tumor.

10x Ewing sarcoma. Another high-power field demonstrates monotonous and uniformly appearing nuclei with solid groupings of viable tumor cells with central necrosis.

20x Ewing sarcoma. Monotonous and uniformly appearing nuclei

Myeloma of bone:  Also called multiple myeloma, plasma cell myeloma. 

Sites: multifocal involving vertebral column, ribs, skull, pelvis, sternum; begins in medulla, then erodes cortical bone.  Can spread to skin, lymph nodes. 

Xray: multiple, punched out defects, associated with generalized osteoporosis, not associated with sclerosis. 

Histology: Plasma cells to plasmablasts; all cells have large nuclei, may be multinucleated; often with prominent nucleoli, perinuclear hof (due to prominent Golgi apparatus), Mott Cells (blue grapelike inclusions), Russell bodies (cytoplasmic crystalline rods), Dutcher bodies (intranuclear crystalline rods), hyaline inclusions, vacuoles or granules; also sinusoidal vascular pattern. 10% have amyloid in vessel walls or as masses.  “Flaming” plasma cells: fiery fringes formed by pseudopodic cytoplasmic projections that are carmine red after Wright-Giemsa staining; peripheral cytoplasm has numerous dilated endoplasmic reticulum cisterns distended with immunoglobulin that may fragment and appear around the cell; associated with IgA myelomas. Bone marrow biopsies should have >10% plasma cells to diagnose myeloma.

Immunostains:   Positive: Kappa or lambda light chains (usually one markedly more than the other), CD38 (plasma cells), CD79a, CD138, variable EMA, variable CD10.  Negative: keratin, CD45 / LCA, CD19, CD20.

DDx: Reactive synovitis with Dutcher bodies, osteomyelitis with plasma cell predominance (other inflammatory cells, capillary proliferation, plasma cells not monoclonal), metastatic carcinoma, lymphoma.

20x Histologic features of well-differentiated myeloma are characterized by cells easily recognizable as plasma cells.

20x Characteristic lesion of amyloid in a patient with plasma cell dyscrasia. This is AL amyloid and will show the characteristic apple green birefringence in polarized light.

Lymphoma-general: 

Xray: destructive permeative process involves extensive areas of bone with lytic and sclerotic lesions. 

Histology: Diffusely infiltrates marrow, sparing trabeculae; often significant crush artifact; usually diffuse large B cell type.

DDx: chronic osteomyelitis (has granulation tissue, no atypia), granulocytic sarcoma (CD45+, CD43+, myeloperoxidase+, lysozyme+, CD20-), carcinoma (keratin+, clinical history).

20x Collections of large (2x size of normal lymphocytes) centroblastic and immunoblastic cells

2x Many primary lymphomas of bone have areas of fibrosis and reactive bone formation.

4x Extensive crush artifact oftentimes obscures the cytologic features of the lymphoid cells in malignant lymphomas of bone.

Hodgkin’s lymphoma: 

Sites: vertebrae, pelvis, ribs, sternum, femur; also nodal involvement (often paraaortic). 

Xray: osteolytic, osteoblastic, mixed; vertebral lesions often osteoblastic.

Histology: Mixed cell infiltrate with rare pleomorphic cells.

Immunostains:  Positive: CD15, CD30.  Negative: CD45(LCA), CD20

Hemangioma of bone:

Xray: sunburst appearance due to trabecular bone, particularly in spine and skull; nonspecific in long bones.  Sites for clinically significant hemangiomas: skull, vertebrae (causing spinal cord compression), jaw; occur in marrow.

Histology: Thick walled lattice-like pattern of vessels; either capillary or cavernous; often with reactive new bone formation; no endothelial atypia.

DDx: Osteoblastoma, hemangioendothelioma.

20x  cavernous hemangioma demonstrates growth pattern with gaping vascular spaces replacing marrow cavity between trabeculae.

4x  cavernous hemangioma demonstrates growth pattern with gaping vascular spaces replacing marrow cavity between trabeculae.

Epithelioid hemangioma:  also known as angiolymphoid hyperplasia with eosinophilia

Site:  usually affects long tubular and flat bones, but may occur in any bone.  Also occurs in skin and subcutis. 

Xray: lytic or blastic, well defined or poorly circumscribed margins. 

Histology: Replaces marrow, surrounds bony trabeculae, erodes cortex, may have soft tissue component; lobular growth pattern.   Epithelioid cells line well formed vessels, but may also grow in sheets and cords.  Nuclei are grooved, vesicular, may have prominent nucleoli; no severe nuclear atypia; abundant eosinophilic cytoplasm, often with vacuoles. < 5 mitotic figures/10 HPF.  Stroma is loose connective tissue with lymphocytes, eosinophils, extravasated red blood cells.

Immunostains: Positive: EMA, factor VIII related antigen, Ulex europeus; variable CD31, CD34, keratin.

DDx: Epithelioid hemangioendothelioma.

4x  Epithelioid hemangiomas demonstrate predominantly cuboidal endothelial cells but still confined to a single layer around well-formed vascular channels. Cytologic atypia and mitotic activity are not prominent.

40x Some examples of epithelioid hemangioma of bone may show a prominent lymphoeosinophilic infiltrate between vascular channels in a pattern similar to the analogous lesion in soft tissue (angiolymphoid hyperplasia with eosinophilia).

Epithelioid hemangioendothelioma: 

Sites: femur, occasionally vertebrae.

Xray: osteolytic appearance without bony expansion, may have peripheral sclerosis; infiltration is associated with higher-grade lesions.

Histology: Cohesive growth pattern of cells with eosinophilic and often cytoplasmic vacuolization, some vacuoles contain erythrocytes; vesicular nuclei, some with prominent grooves, mild atypia; recent and old hemorrhage; variable eosinophils, vasoformative features may be primitive and accompanied by myxohyaline stroma; no/rare mitotic activity, no anastomosing channels.

Immunostains: Positive: CD31, CD34, Fli-1 (nuclear stain), factor VIII related antigen.  Negative: Mucin (Alcian blue, mucicarmine, PAS), S100, cytokeratin.

DDx: Metastatic carcinoma, chordoma (destructive lobulated pattern and multivacuolated physaliferous cells, keratin+, S100+), epithelioid hemangioma (well formed vascular spaces).

20x Epithelioid hemangioendothelioma usually contains myxoid or hyalinzed stroma and epithelioid cells in nests.

20x Occasional cells of epithelioid hemangioendothelioma contain intracytoplasmic lumina (so-called blister cells) that may mimic adenocarcinoma.

20x Example of a high-grade epithelioid hemangioendothelioma with more striking nuclear pleomorphism and increased cellularity.

Angiosarcoma: 

Site:  1/3 affect long tubular bones, but any bone may be affected. 

Xray: Lytic areas of destruction, with minimal/no reactive new bone formation.

Histology: Obvious atypia of tumor cells, solid areas alternating with irregular, anastomosing vascular channels; necrosis and hemorrhage, brisk mitotic activity; variable differentiation often within same tumor; may be epithelioid or histiocytic; may have benign giant cells, eosinophils, occasionally reactive bone formation.  Graded 1-3 based on atypia of endothelial cells.  Grade 1 have excellent prognosis vs. poor prognosis for grade 3.

Immunostains:  Positive stains: Factor VIII related antigen, CD31. 

DDx: Telangiectatic osteosarcoma, metastatic renal cell or other carcinoma, hemangioma (no atypia).

10x  low-power view, angiosarcoma has a destructive, vasoformative growth pattern of anastomosing channels and extensive hemorrhage.

20x Grade 1 angiosarcoma typically shows only mild cytologic atypia. Mitotic activity, though present in this case, may be relatively low. 

20x angiosarcoma demonstrates more marked cytologic atypia with at least some cells lining vascular spaces.

Giant cell tumor:  Also called osteoclastoma. 

Sites: Knee is common site (distal femur, proximal tibia), distal radius, sacrum but can affect any bone, usually at epiphysis, may spread into metaphysis; uncommon in hand/feet, jaw, vertebrae other than sacrum. 

Xray: lytic, expansile lesion of epiphysis extending to articular cartilage, usually without peripheral bone sclerosis, periosteal reaction or mineralization within the lesion; within soft tissues usually produces eggshell ossification at periphery. 

Histology: Regular and uniform distribution of stromal cells and giant cells.  Stromal cells are mononuclear, resemble macrophages.  Giant cells are large, multinucleated (10-50 nuclei) with similar nuclei as stromal cells, resemble osteoclasts; also necrosis, hemorrhage, hemosiderin, reactive bone; mitotic figures (not atypical); 1/3 have focal deposition of osteoid or bone; may have aneurysmal bone cyst component, foam cells with spindling of mononuclear cells; no chondroid differentiation, no atypia.

Immunostains:  Positive: giant cells - acid phosphatase, lysozyme, alpha-1-antitrypsin, alpha-1-antichymotrypsin, cyclin D1, estrogen receptor (50%); mononuclear cells - Ki-67.

DDx: other giant cell tumors (giant cells usually only focal): brown tumor of hyperthyroidism, giant cell granuloma, pigmented villonodular synovitis, chondroblastoma, aneurysmal bone cyst; osteosarcoma, metaphyseal fibrous defect / nonossifying fibroma, chondromyxoid fibroma, Langerhans’ cell histiocytosis, solitary bone cyst, osteoid osteoma, osteoblastoma.

10x sheets of spindled or ovoid cells interspersed with multinucleated giant cells. Both cell populations have eosinophilic cytoplasm and the same fairly regular, oval nuclei with a distinct membrane and one or two small nucleoli

Benign metastasizing giant cell tumor:  Cannot predict which benign appearing tumors will metastasize (rate is 1-10%).  Good prognosis after resection of metastasis, although may undergo sarcomatoid transformation.

Histology: Evenly distributed multinucleated giant cells in hemorrhagic background of mononuclear cells, spindle cells and inflammatory cells; also reactive bone formation, 2-3 mitotic figures/HPF.

2x

4x

10x

20x

Malignant giant cell tumor:  Very uncommon.  To diagnose, must document either prior or coexisting benign giant cell tumor at same location as spindle cell sarcoma.  Usually due to prior giant cell tumor and radiation therapy.  Older age than for benign giant cell tumors, same sites.

Histology: Resembles high grade sarcoma (osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma).

Chordoma: 

Sites: 50% sacrococcygeal (ages 40-59 years), 35% spheno-occipital / clivus (particularly children), 15% thoraco-lumbar spine.  Sacrococcygeal: sacrum destroyed by osteolytic tumor; tumor may extend into retroperitoneum, presents as palpable extrarectal mass.  Spheno-occipital: presents as nasal, paranasal or nasopharyngeal mass involving cranial nerves.  Posterior mediastinum: Xray presentation is well-circumscribed, encapsulated soft tissue mass separate from spine. Poor prognostic factors: large tumor size, positive surgical margins, tumor necrosis, high proliferative activity, areas of dedifferentiation; also up regulation of N cadherin and down regulation of E cadherin. 

Histology: Cords and lobules of physaliferous (having bubbles or vacuoles) cells separated by fibrous septa with extensive myxoid stroma.  Cells may be very large, with vacuolated cytoplasm, prominent vesicular nucleus.  Also small tumor cells with small nucleus; rare mitotic figures.  

Immunostains:  Positive: S100, keratin (CK 8/18, CK19, AE1-AE3), EMA, 5' nucleotidase, glycogen, neural-type cadherin, variable CK903, vimentin, CEA, lysozyme, synaptophysin.  Negative: CK7, CK20, chromogranin.

DDx: Metastatic renal cell carcinoma (prominent vascularity, not lobulated, S100 negative) or other carcinoma, chondrosarcoma (not midline, no fibrous septa, EMA and keratin negative), signet cell adenocarcinoma of rectum, myxopapillary ependymoma (negative for epithelial markers), parachordoma (soft tissue tumor composed of epithelioid cells, smaller “glomoid” cells and spindle cells, negative for CK7, CK19, CK20, CEA).

10x

20x

2x Chordoma: lobular growth pattern 

10x Chordoma: the cells in chordoma grow in cords, strands, and clusters amid a loose myxoid stroma. 

20x Chordoma:  cells of chordoma demonstrate pale eosinophilic to somewhat foamy cytoplasm with central ovoid to round and cytologically bland nuclei.

20x Chordoma:  Two types of cells can be appreciated: smaller ovoid cells and the larger cells with numerous cytoplasmic vacuoles. The latter are the hallmark of this tumor and are called "physaliphorous cells". Occasional mitotic figures were identified. However, no atypical mitoses were found. These tumors often demonstrate significant cellular pleomorphism that is, probably, of no prognostic significance.

Benign notochordal cell tumors:  Not notochordal rests or hamartomas. 

Sites: At autopsy, found in 14% of spinal columns and 11.5% of clivus’s

Histology: Well demarcated but unencapsulated.   Sheets of adipocyte-like vacuolated or eosinophilic cells with fewer vacuoles; often cytoplasmic eosinophilic hyaline globules; bland round nuclei with mild pleomorphism; may contain colloid-like material; bone trabeculae often sclerotic but no bony destruction; no intercellular myxoid matrix, no necrosis, no mitotic figures.

Immunostains:  Positive: PAS+ diastase resistant eosinophilic hyaline globules.

DDx: Chordomas (osteolytic, lobules are separate by thin fibrous septa, lobules contain cords, strands or sheets of physaliphorous cells with myxoid matrix, cells have mild to marked nuclear atypia), notochordal vestiges (cords or strands of notochordal cells within myxoid background, cells have eosinophilic cytoplasm with small vacuoles, pyknotic round nuclei, CK18 negative, usually replaced by fibrocartilage by age 1-3 years).

Adamantinoma of long bones:

Site:  Common in tibia, usually shaft,

Xray: single or multiple lytic lesions of shaft (cortex or medulla) with marked surrounding sclerosis.

Histology: Three forms: (a) osteofibrous dysplasia-like form with scattered epithelial elements, (b) classic form with large groups of bland epithelial cells in clusters with peripheral palisading in fibrous stroma with haphazard osteoid deposition, (c) sarcomatoid transformation with highly pleomorphic cells, high mitotic count, deposition of osteoid and chondroid matrix, no epithelial features.  Squamous differentiation and keratin production is uncommon.

Immunostains:  Positive: Keratin (epithelial and spindle cells).

DDx: Metastatic carcinoma (unusual below knee, older patients, more malignant cytology, no osteofibrous dysplasia-like areas).

2x Adamantinoma. Tubular variant. Small, tubular spaces lined by cuboidal cells embedded in a spindle cell stroma. 

10x Adamantinoma. Tubular variant. The spaces are nearly filled with the cuboidal cells in this area of the same tumor.

10x Adamantinoma. Spindle cell variant. Histologically, the broad solid nests of tumor cells resemble other types of spindle-cell sarcomas and may be so misdiagnosed. 

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10x Adamantinoma. Adamantinoma. Squamous variant. Nests of epithelial cells with squamous differentiation within a spindle cell stroma.

Fibrous dysplasia:   Types: monostotic, polyostotic, McCune-Albright syndrome, Mazabraud's syndrome. 

Site:  Monostotic: ribs, femur (causes crook neck deformity of neck resembling candy cane, also called Shepherd’s crook), tibia, jaw.  Polyostotic: femur, skull, tibia; craniofacial involvement in 100% with extensive skeletal disease, 50% otherwise; usually unilateral. 

Sites: femur, skull, tibia; craniofacial involvement in 100% with extensive skeletal disease, 50% otherwise; usually unilateral. 

Gross: Well circumscribed, intramedullary; tan-white-yellow, gritty; large lesions distort bone; cortical bone often thin and expanded.

Histology: Curvilinear trabeculae (Chinese letters) of metaplastic woven bone (never matures) in hypocellular, fibroblastic stroma; no osteoblastic rimming (due to maturation arrest), 20% of cases have cartilaginous nodules (particularly in femoral neck region); also myxoid areas, rapidly growing secondary aneurysmal bone cysts, hemorrhage, foamy macrophages, calcified spherules (similar to cementifying fibromas), cellular areas, focal hyaline cartilage or cystic areas; usually abrupt transition of normal to abnormal bone; no/rare mitotic figures, no atypia (rarely is degenerative); overall resembles endochondral ossification in skull.

Immunostains:  Negative: keratin.

DDx: Well differentiated osteosarcoma (has lacy, malignant bone; intramedullary extension, cortical violation, soft tissue extension).

Fibrous dysplasia:   Types: monostotic, polyostotic, McCune-Albright syndrome, Mazabraud's syndrome. 

Site:  Monostotic: ribs, femur (causes crook neck deformity of neck resembling candy cane, also called Shepherd’s crook), tibia, jaw.  Polyostotic: femur, skull, tibia; craniofacial involvement in 100% with extensive skeletal disease, 50% otherwise; usually unilateral. 

Histology: Curvilinear trabeculae (Chinese letters) of metaplastic woven bone (never matures) in hypocellular, fibroblastic stroma; no osteoblastic rimming (due to maturation arrest), 20% of cases have cartilaginous nodules (particularly in femoral neck region); also myxoid areas, rapidly growing secondary aneurysmal bone cysts, hemorrhage, foamy macrophages, calcified spherules (similar to cementifying fibromas), cellular areas, focal hyaline cartilage or cystic areas; usually abrupt transition of normal to abnormal bone; no/rare mitotic figures, no atypia (rarely is degenerative); overall resembles endochondral ossification in skull.

Immunostains:  Negative: keratin.

DDx: Well differentiated osteosarcoma (has lacy, malignant bone; intramedullary extension, cortical violation, soft tissue extension).

4x Low-power view shows bony trabeculae with a curvilinear branching appearance, so-called Chinese characters, hockey stick, or C, S, and Y shapes, within a fibrous stroma

20x Trabeculae of immature woven bone are devoid of a plump lining osteoblast layer and lie within a fibrous stroma comprising bland stromal cells arranged in a whorled or storiform manner

Osteofibrous dysplasia: Also called fibroosseous dysplasia, ossifying fibroma of long bones, Campanacci’s lesion. 

Site: diaphysis of tibia or fibula of children. 

Xray: no medullary involvement.

Histology: Spindle cell proliferation with production of woven bone trabeculae with prominent osteoblastic rimming; loose, slightly myxoid stroma.  Closely related to fibrous dysplasia but is a cortical (not medullary) lesion with osteoblastic rimming of bone and lamellar bone that does mature. 

Immunostains:  Positive: keratin in spindle cells (not seen in fibrous dysplasia), S100, Leu7/CD57.

DDx: well differentiated osteosarcoma.

Aneurysmal bone cyst (ABC):

Sites: metaphysis of posterior vertebrae (often multiple), flat bones, shaft of long bones

Xray: eccentric expansion of bone, cortical erosion and destruction, small peripheral area of periosteal bone formation; fluid levels detectable by CT; MRI shows honeycomb appearance with fluid levels. 

Histology: Large cystic spaces filled with blood and separated by fibrous septa, alternating with solid areas.  Cysts and septa lined by fibroblasts, myofibroblasts and histiocytes but not endothelium; clusters of osteoclast-like multinucleated giant cells with loose spindly stroma to cellular stroma, reactive woven bone, degenerated calcifying fibromyxoid tissue; variable mitotic figures and hemosiderin; no malignant osteoid, no atypia.

DDx: Solitary bone cyst, giant cell tumor (lacks fibroblastic cells), hemangioma, telangiectatic osteosarcoma (more atypia), giant cell reparative granuloma (if in jaw), low grade osteosarcoma (hypocellular).

4x Aneurysmal bone cyst. At low power, multiple variably sized spaces are present, traversed by thin fibrous membranes with a peripheral shell of bone

20x Aneurysmal bone cyst. Clusters of osteoclast-like giant cells are frequently seen within a fibrohistiocytic stroma.  Small spaces with osteoclasts are also seen.  

10x Aneurysmal bone cyst. osteoclast-like giant cells are often numerous. D, Reactive bony trabeculae bordered by plump osteoblasts are common

40x Aneurysmal bone cyst. Intermingled trabeculae of reactive bone bordered by plump osteoblasts

Unicameral bone cyst:  a development lesion

Site: proximal humerus (mostly) or proximal femur. Most lesions occur in the proximal humerus. They develop at the proximal epiphyseal plate over a period of years and involved in metaphysis.

Imaging:  They are filled with fluid which can be demonstrated on an MRI. The fluid cavity is generally a single chamber.

Histology:  Fibrous membrane shows blood, fibrous tissue admixed with spicules of reactive bone. Often there is a cementum-like amorphous material in the wall of the cyst. This cementum-like material is diagnostic of unicameral bone cyst.

DDx:   a. Aneurysmal bone cyst (expansion of the bone and the multiple locules are not present. Indeed, this case showed a single locule. Aneurysmal bone cyst is a reactive lesion composed of multiple cystic spaces filled with blood) b. Unicameral bone cyst c. Fibrous dysplasia

Ganglion cyst of bone: Within bone, but close to a joint space at ends of long bones

Site:  often in distal tibia or proximal humerus.  May be an extension of soft tissue ganglion. 

Histology: Cystic space with no epithelial lining; may be filled with mucoid material or foamy macrophages.

DDx: solitary bone cyst, periarticular cyst associated with degenerative joint disease.

Langerhans cell histiocytosis (LCH):  Formerly called Histiocytosis X.

Imaging: lytic masses that may extend into soft tissue.  Either solitary bone involvement, multiple bone involvement (variable skin involvement) or multiple organ involvement (bone, liver, spleen, other sites).

Sites: skull, jaw, humerus, rib, femur; metaphysis or diaphysis. 

Histology: Infiltration by Langerhans cells (polygonal cells with eosinophilic cytoplasm, oval nuclei with longitudinal grooves resembling coffee beans); also eosinophils, giant cells, neutrophils, foam cells, lymphocytes, plasma cells, fibrosis, necrosis; may have typical and atypical mitotic figures.

Immunostains:  Positive: CD1a, S100; also vimentin, Langerin, variable CD68. Negative: HAM56, CD21, CD35

Molecular: often loss of DNA sequences involving several chromosomes and 1p.

DDx: Osteomyelitis, sinus histiocytosis with massive lymphadenopathy, lymphoma (lacks nuclear features), macrophages, mastocytosis, monocytic leukemia.

10x Langerhans cell histiocytosis.  At low power, an intense inflammatory cell infiltrate is usually lying within loose granulation tissue. Abundant eosinophils are present.

40x Langerhans cell histiocytosis. Langerhans cells have irregular, indented nuclei with somewhat poorly demarcated eosinophilic cytoplasm.   Binucleated form and admixed eosinophils and neutrophils are present.

Erdheim-Chester disease:

Site: Diaphysis and metaphysis of long bone, usually lower extremities.  Occasionally involves axial skeletal, retroperitoneum, lungs, kidney, hypothalamus / posterior pituitary (causing diabetes insipidus), retroorbital space, heart, skin.

Imaging:  Bilateral and symmetric osteosclerosis of long bones (diaphysis and metaphysis)

Histology: Diffuse infiltration with large, foamy histiocytes, lymphoid aggregates, fibrosis, rare Touton-like giant cells.

Immunostains:  Positive stain: CD68 and factor XIIIa (strong), S100 (weak or negative).  Negative: CD1a.

By Dra marina - Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3437529

Metastases to bone:  Most common malignant bone tumor is metastatic carcinoma.  In adults, 80% from prostate, breast, kidney, lung or thyroid.  In children, from neuroblastoma, Wilm’s tumor, osteosarcoma, Ewing’s/PNET or rhabdomyosarcoma.  Intraspinal seeding may occur along Batson’s plexus of veins. 

Sites: Common sites: axial skeleton, proximal femur, proximal humerus; usually marrow; very rare to be distal to elbow or knee.  Solitary metastases: kidney, thyroid.  Small bones of hands and feet: colon, lung, kidney.  Blastic lesions: prostate, carcinoid tumor, neuroendocrine tumors. 

Imaging: Positive isotope bone scans (versus myeloma). 

DDx: myeloma (negative isotope bone scan, monoclonal protein in serum or urine).

Hyperparathyroidism: It is not normal to see osteoclastic resorption in bone. If extensive osteoclastic resorption can be seen by light microscopy, the diagnosis of hyperparathyroidism, either primary or secondary, must be strongly suspected.

Sites: Most commonly in the femoral head

Imaging:  XR of the hand shows subperiosteal resorption, consistent with tunneling resorption

Histology: Increased osteoclastic activity in the pattern of tunneling resorption. This pattern of tunneling resorption is diagnostic of hyperparathyroidism, either primary or secondary.

DDx: a. Osteoporosis (findings of osteoporosis include thinning of bone trabeculae, but subperiosteal or "tunneling resorption" is not a feature of osteoporosis)

                                                                                                                                       JOINT & BONE PATHOLOGY

Joint:

-       Normal anatomy:  synovial joint, nonsynovial joints, bursae, menisci, synoviocytes, hyaline cartilage, chondrocytes, tendons, ligaments, fascia, collagen

-       Diseases of the joints: 

o   Nonneoplastic:  synovial hyperplasia, ganglion cyst, synovial cyst, rheumatoid arthritis, degenerative joint disease, metastatic calcification, gout and gouty arthritis, calcium pyrophosphate crystal deposition disease (pseudogout, chondrocalcinosis),  detritic synovitis:

o   Neoplastic:  pigmented villonodular synovitis (PVNS), malignant giant cell tumor of tendon sheath-diffuse type, hemosiderotic synovitis, synovial lipomatosis, fibroma of tendon sheath, synovial chondromatosis, giant cell reparative granuloma, loose bodies

Bone:

-       Normal anatomy: parts of a long bones, blood supply, bone composition,

-       Normal histology: cement line, lamellar bone, woven bone, osteoblasts, osteoclasts, osteocytes, osteoid, osteon, osteoprogenitor cells, periosteum, endochondral bone formation, epiphyseal growth plate, intramembranous bone formation,

-       Diseases of the bones:

o   Nonneoplastic:  giant cell reparative granuloma osteoporosis, fracture, fracture callus: aseptic bone necrosis, osteomyelitis, stress fracture, bone infarct, particle disease, bone island, osteoma

o   Neoplastitic:  osteoid osteoma, osteoblastoma, aggressive osteoblastoma, osteosarcoma, epithelioid osteosarcoma, high grade surface osteosarcoma, low grade intraosseous (central) osteosarcoma, parosteal osteosarcoma, periosteal osteosarcoma, telangiectatic osteosarcoma, osteochondroma, subungual exostosis, juxtacortical (periosteal) chondroma, soft tissue (extraskeletal) chondromas, enchondroma, chondroblastoma, chondrosarcoma-conventional, chondrosarcoma-clear cell, chondrosarcoma-dedifferentiated, chondrosarcoma-mesenchymal, Chondrosarcoma-myxoid (chordoid), metaphyseal fibrous defect, desmoplastic fibroma, fibrosarcoma of bone, benign fibrous histiocytoma, malignant fibrous histiocytoma (MFH), Ewing’s sarcoma / primitive or peripheral neuroectodermal tumor (PNET), myeloma of bone, lymphoma-general, Hodgkin’s lymphoma, hemangioma of bone, epithelioid hemangioma, epithelioid hemangioendothelioma, angiosarcoma, giant cell tumor, benign metastasizing giant cell tumor, malignant giant cell tumor, chordoma, benign notochordal cell tumors, adamantinoma of long bones, fibrous dysplasia, osteofibrous dysplasia, aneurysmal bone cyst (ABC), unicameral bone cyst, ganglion cyst of bone, Langerhans cell histiocytosis, Erdheim-Chester disease, metastases to bone, distal femoral cortical erosion syndrome, florid reactive periositis, hyperparathyroidism: