Bone (nontumor and tumor)

Long bones: diaphysis (shaft), epiphysis (ends of bone, partially covered by articular cartilage), metaphysis (junction of diaphysis and epiphysis, represents site of active bone growth, most common site of most primary bone tumors)

Cross section: periosteum, outer cortex (called cortical bone or compact bone), inner spongy region (called medulla, cancellous bone or spongiosa)

Blood supply: diaphysis: cortex supplied by vessels that enter through Volkmann’s canals and communicate with haversian system; a nutrient artery enters medullary canal at center of diaphysis, divides and supplies entire diaphysis; metaphysis is supplied by end arteries from diaphysis that terminate at epiphyseal plate; epiphyses are supplied by network of widely anastomosing vessels

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

Normal histology

Bone: mineralized osteoid; either lamellar bone or woven bone (see below)

Lamellar bone: layered bone, with concentric parallel lamellae; gradually replaces woven bone during growth, stronger than woven bone

Osteoblasts: on bone surface; arise from marrow mesenchymal cells; plump if active, otherwise flat, with perinuclear halo due to prominent Golgi zone; synthesize and transport collagenous matrix, initiate and regulate mineralization, control removal of bone via osteoclasts, express Vitamin D; activity is promoted by physical activity, parathormone (causes stimulation of osteoclasts), fluoride, growth factors; activity suppressed by inactivity and steroid hormones

Positive stains: alkaline phosphatase, estrogen receptors, parathyroid hormone

EM: resemble fibroblasts due to well developed rough endoplasmic reticulum and Golgi

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

EM: numerous mitochondria, rare lysosomes; ruffled edge in area of cell membrane is associated with bone resorption

Osteocytes: osteoblasts 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

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)

Osteon: dense compact cylindrical unit underlying cortical bone; formed in children 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

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

Woven bone: immature bone due to haphazard (random) arrangement of collagen fibers, highlighted with polarized light or reticulin stain; normal in fetal skeleton and growth plates where bone deposition is rapid, but abnormal in adults and associated with fibrous dysplasia or other causes of accelerated bone turnover

Morphometry: measuring bone formation (% active osteoblastic surface, % osteoid surface, % mineralizing surface), bone mineralization (osteoid volume, mineral apposition rate), bone resorption (% total eroded surface, % active osteoclastic surface)

Tetracycline: binds to actively mineralizing surfaces and fluoresces in ultraviolet light

Bone growth

Skeletal patterning is regulated by homeobox genes

Basic multifunctional unit of bone growth is osteoblasts and osteoclasts; balance of bone matrix synthesis and resorption determines skeletal mass at any point in time

Bone is modeled to reach peak bone mass; then 5-10% is remodeled per year

Osteoblasts control osteoclast activity via parathyroid hormone (parathormone), PHRP (Parathyroid hormone related protein), IL-1, TNF

Digestion of bone by osteoclasts releases cytokines and growth factors for osteoblasts

Bone production is identified by well-stained small spicules of bone with lacunar cells present and osteoblasts on bone margins

Bone resorption is identified by numerous osteoclasts in Howship’s lacunae and in bone margins

Cement line: junction between original resorbed surface and new bone; sharp basophilic line on H&E; also called reversal front

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)

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

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

Periosteum: produces osteoblasts, which deposit beginnings of cortex (primary center of ossification); similar process occurs at epiphysis (secondary center of ossification)

Intramembranous bone formation

Cranium, clavicles

Formed from mesenchyme, which differentiates into fibrous tissue containing osteoblasts without an intervening cartilaginous stage

Biopsy

Frozen sections are useful to document adequacy, to allow quicker definitive treatment (if diagnosis can be made), for assessment of margins (by checking marrow), to obtain culture for possible infectious lesions

FNA: helpful for metastatic disease, recurrent tumor or unsuspected malignancy; not helpful for cartilaginous lesions, cystic lesions or obviously benign lesions that require surgical management (chondromyxoid fibroma, giant cell tumor)

References: Archives 2001;125:1463

Developmental abnormalities

Achondrogenesis

Type I: rare, lethal; extreme limb shortening, marked discrepancy between head and trunk size, severely delayed ossification

Type IA: autosomal recessive; rib fractures, no ossification of vertebral pedicles; chondrocytes have inclusion bodies, but cartilage matrix is near normal

Type IB: distinctly abnormal cartilage matrix with rarefaction of ground substance and peculiar ringlike pericellular arrangement of collagen fibers

Achondrogenesis type IB is lethal osteochondrodysplasia due to mutations in transporter gene for diastrophic dysplasia sulfate

Genetic defect causes complex derangement in cartilage matrix assembly; impaired decorin deposition causes lack of development of normal interterritorial matrix, preventing necessary structural substrate for proper endochondral bone formation and severe skeletal phenotype

Case report of type IB in child of consanguineous (first cousins) parents (Archives 2001;125:1375)

Micro: abnormal endochondral bone formation with curved cartilage-bone junction at growth plates, periosteal bony spurs; spongelike cartilage matrix due to lack of interterritorial matrix; epiphyseal cartilage composed of multiple discrete units of chondrocytes encased in territorial capsule and separated from each other by clefts containing fibroblast-like cells; mosaic of chondrocyte units (chondrons) due to breakdown of usual matrix continuity of epiphyseal cartilage

Achondroplastic dwarfism

Major cause of dwarfism

Reduction in chondrocytes at growth plate is due to defect in fibroblastic growth factor receptor 3 gene (FGFR3)

FGFR3 inhibits cartilage proliferation, and is constitutively active in these patients

Autosomal dominant, but 80% of cases are new mutations

Clinical: short proximal extremities, normal trunk, enlarged head (bulging forehead, depression of root of nose)

Normal intramembranous bone formation, so bone cortices seem thickened compared to short bone length

Normal life, IQ, reproductive status

Micro: narrow/disorganized zones of proliferation and hypertrophy in growth plates; chondrocytes in clusters, not columns; base of growth plate has prematurely deposited struts of bone which seal the plate

Fibrodysplasia ossificans progressiva

Rare autosomal dominant disorder with congenital malformation of the great toes and progressive heterotopic ossification in defined anatomic patterns

Early preosseous lesions resemble aggressive juvenile fibromatosis

Pathophysiology: spontaneous and post-traumatic flareups heralded by intense connective tissue edema with perivascular lymphocytic infiltration into skeletal muscle, angiogenic fibroproliferative lesions that spread along muscle planes and evolve through endochondral ossification to form mature lamellar bone; leads to immobilization of joints making movement impossible, later death due to starvation (ankylosis of jaw) or from restrictive disease of chest wall

May be mediated by mast cells (Hum Path 2001;32:842)

Treatment: none; surgical trauma induces further bone formation

References: Hum Path 1997;28:339; UPOJ (with clinical images)

Malformations

Failure of development of a bone (phalanx, rib, clavicle), supernumerary ribs or digits, syndactyly (fusion of adjacent digits) or arachnodactylism (long, spider-like digits)

Craniorachischisis: failure of closure of spinal column and skull; produces meningomyelocoele or meningoencephalocoele

Scoliosis

Abnormal curvature of vertebral column

Kyphoscoliosis: lateral and posterior curvatures

Syndromes

Maffuci’s syndrome: multiple enchondromas and soft tissue hemangiomas; also ovarian carcinoma, brain gliomas

Reference: AJSP 1995;19:1029 (with spindle cell hemangioendotheliomas)

McCune-Albright syndrome: polyostotic fibrous dysplasia, cafe-au-lait skin pigmentation, endocrine abnormalities; almost exclusively women; also see below

Multiple hereditary exostosis: autosomal dominant disorder of multiple osteochondromas diagnosed during childhood; bowing of underlying bones, wide metaphyses; evolution to chondrosarcoma

Multiple osteomas: associated with Gardner syndrome (autosomal dominant, epidermal cysts, fibromatosis, pigmented ocular fundus lesions, multiple colorectal adenomas with carcinoma at ages 35-40 years)

Ollier’s disease: multiple enchondromas, often ovarian sex-cord tumors

Sapho syndrome: see below

Thanatophoric dwarfism

Also called thanatophoric dysplasia

“Thanato”: denoting death

Lethal form of dwarfism, occurs in 1 per 20,000 live births

Type I: short, curved femur; II: straighter femur with cloverleaf skull

Mutation in FGFR3 gene, but different from that in achondroplastic dwarfism

Clinical: micromelia (short limbs), frontal bossing with relative macrocephaly (abnormally large and hyperconvoluted temporal lobes), small chest, bell shaped abdomen

Die at birth or shortly thereafter from respiratory insufficiency due to small thoracic cavity

Case reports: variant in 18 week male fetus (Archives 1993;117:322)

Micro: diminished proliferation of chondrocytes and poor columnization of zone of proliferation

Osteomyelitis

Osteomyelitis-general

Infection of bone or bone marrow

May resemble neoplasms, particularly after antibiotic treatment

Severe osteomyelitis is not associated with grade IV sacral decubitus ulcers in non-septic patients (Archives 2003;127:1599)

May cause secondary AA amyloidosis

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

Amebic osteomyelitis

Case reports: infection of mandibular bone graft by Acanthamoeba castellanii (Hum Path 1981;12:573)

Bacterial osteomyelitis

Rare due to antibiotics

Usually pyogenic

Hematogenous spread common in patients under age 20, often involves lower extremity; may involve metaphyses of neonates, due to its vascularity

In elderly, may affect vertebral column; associated with systemic urinary tract infection, diabetes (affects small bones in feet); in younger adults, associated with immunodeficiency or intravenous drug abuse

50% of cases are due to unknown bacteria

80% of cases with known organisms are due to Staphylococcus aureus, which produces receptors to bone matrix components

Other known organisms are E. coli, Pseudomonas and Klebsiella in intravenous drug addicts (affecting spine or pelvis), organisms causing genitourinary infections (Pseudomonas aeruginosa in spine); also Streptococcus pyogenes and Haemophilus influenzae

Rarely associated with malakoplakia; cases with draining sinus are rarely associated with malignancy (squamous cell carcinoma)

Mixed bacteria: due to trauma, surgery

Group B streptococci: neonates

Salmonella: sickle cell disease patients

Designated as acute, subacute or chronic, based on clinical duration of disease, not inflammatory cells present; chronic disease related to delayed diagnosis, inadequate antibiotics or debridement of dead bone, extensive bone necrosis, weakened host defenses; may produce tuberculoid granules with variable central necrosis (AJSP 1985;9:531)

Pathophysiology: bacteria proliferate in bone, kill osteocytes, cause necrosis, spread along haversian system or medullary cavity within shaft and to periosteum; subperiosteal abscesses impair blood supply, which causes more necrosis and often draining sinuses

Sites: in children, at areas of rapid growth or increased risk of trauma (distal and proximal femur, proximal tibia and humerus, distal radius)

Sequestrum: dead piece of bone; may pass through sinus tract

Involucrum: sleeve of living tissue created by periosteum which is deposited around sequestrum

Brodie abscess: small intraosseous abscess in cortex, walled off by reactive bone with no periosteal reaction

Sclerosing osteomyelitis of Garre': in jaw, associated with extensive new bone formation that obscures underlying osseous structure; also called periostitis ossificans

Xray: lytic bone destruction surrounded by sclerosis; chronic disease may resemble malignant bone tumor due to destructive and regenerative bone changes

Treatment: surgery to remove dead bone (sequestrum), antibiotics

Complications: may develop sinus tract lined by squamous epithelium that forms large epidermal inclusion cyst within bone; rarely transforms to well differentiated squamous cell carcinoma with excellent prognosis

Case reports: 17 month old immunocompetent black girl with disseminated Mycobacterium avium disease (Hum Path 1980;11:476)

Gross: varies with patient age; infants under age 1 year often have permanent joint and epiphyseal damage sparing metaphysis and diaphysis; children 1 year and older have opposite changes (sparing of joint, damage to metaphysis); adults have joint infection and extensive bone involvement; acute disease has pus tracking through bone, periosteal elevation and shell of reactive periosteal bone around necrotic center; chronic disease is accompanied by prominent periosteal bone formation

Micro: neutrophils, 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

Chronic osteomyelitis

Develops in 15-30%

Due to inadequate antibiotic treatment or incomplete surgical debridement of necrotic bone

Chronic multifocal osteomyelitis

Recurrent variant of osteomyelitis in children and young adults of unknown origin

Low grade fever, local swelling and pain; periods of exacerbation and remission over years; negative cultures

Sites: metaphyses of tubular bones, clavicle; multiple asymptomatic sites

Associated skin lesion - pustulosis palmoplantaris

Treatment: non steroidal anti-inflammatory drugs, not antibiotics (since cultures are negative)

Micro: neutrophilic inflammation early; late fibrosis of marrow with chronic inflammatory infiltrate; often plasma cell predominance, fragments of necrotic bone with multinucleated giant cells

DD: rheumatic disease, bacterial osteomyelitis, malignancy

References: Hum Path 1999;30:59

Echinococcus osteomyelitis

Rare; due to infection by larva of Echinococcus tapeworms; usually E. granulosus, also E. multilocularis and E. oligarthrus

Life cycle: tapeworm’s gravid segment breaks off from implantation site in small intestine of dogs, coyotes and wolves (in North America), disintegrates in colon releasing eggs which pass in feces; eggs are ingested by sheep, goats, deer, moose, humans; hatch in small intestine, disseminate via blood; at implantation site, larva secrete hyaline membrane that differentiates into outer acellular laminated structure and inner germinal layer which produces protoscolices; cysts may be ingested by dogs

Cysts may rupture and produce fever, urticaria, anaphylactic shock, dissemination of infection, pathologic fractures if in bone

Sites: 60% liver, 20% lungs, 3% brain, 1% bones (50% in lower vertebrae)

Xray: extensive complex cystic changes

Treatment: excision, albendazole or praziquantel

Case reports: 86 year old woman with draining sinus in tibia (Archives 2002;126:1551)

Gross: ragged surface, multiple cavities filled with red-brown necrotic material and yellow-white cystlike structures

Micro: acellular laminated membranes with germinal layer; rare degenerating scolices and hooklets; intense acute and chronic inflammatory infiltrate may erode bone

Cytology: hydatid sand (free daughter cysts, free scolices)

Positive stains: PAS and GMS (membranes)

Fungal osteomyelitis

Case reports: 41 year old man with injury to lumbar/cervical region and Phialemonium obovatum infection (Archives 1993;117:841), Scedosporium apiospermum (Pseudallescheria boydii) osteomyelitis (Hum Path 1998;29:1266)

Syphilitic osteomyelitis

Caused by Treponema pallidum and T. pertenue (yaws)

Bone involvement more common in congenital syphilis; appears at 5th month of gestation in areas of active endochondral ossification (osteochondritis) and periosteum

Acquired syphilis involves bone in tertiary phase, usually nose, palate, skull, tibia, vertebrae, hands/feet

Xray: reactive periosteal bone deposition (“saber shin” of tibia)

Gross: bone destruction and production; necrotic, well-defined bone defects of cortex and periosteum surrounded by sclerotic bone

Micro: edematous granulation tissue, plasma cells, granulomas, necrotic bone and new bone production

Positive stains: silver stains

Tuberculous osteomyelitis

Usually young adults or children

Sites: vertebrae, hip, knee, ankle, elbow, wrist; usually involves synovium, epiphysis or metaphysis

In US, due to immigrants and immunosuppression

1-3% with tuberculosis have bone infection; usually from focus of acute visceral disease, direct extension or lymphatics

Rarely causes inguinal mass with fluctuant psoas abscess

In AIDS patients, bone infection usually multifocal

Advanced cases are associated with cutaneous sinuses, which cause secondary bacterial infections

Associated with fusion of joint, denudation of cartilage, sequestra of medullary cavity

Can detect in synovial fluid by culture and examination

Pott’s disease: involvement of spine (thoracic/lumbar); extensive necrosis of intervertebral discs with extension into soft tissue; may produce significant deformities or neurologic deficits; difficult to treat

DD: foreign body granuloma post-surgery (AJSP 1997;21:563)

Xanthogranulomatous osteomyelitis

Case reports: two cases with prominent foamy macrophages, neutrophils, plasma cells and fibrin (Archives 1984;108:973)

Non-neoplastic or metabolic disease

Aseptic bone necrosis

Also called avascular bone necrosis, osteonecrosis

Common; affects almost every bone, including tibial tuberosity (Osgood-Schlatter’s disease), proximal femoral epiphysis (Legg-Calve’-Perthes disease)

>50% of cases are multifocal

Causes 10% of joint replacements

Significant cause of arthritis due to fractures through articular surface of hip, knee and other major joints; also due to collapse of necrotic bone segment with resulting reparative granulomas that destroy bone at margin of infarct, may cause detachment of cartilage and secondary degenerative joint disease

Causes: fracture, dislocation, corticosteroids, nitrogen bubbles in dysbarism, vasculitis, radiation, vascular compression, venous hypertension, thrombosis (sickle cell disease), Gaucher’s disease, alcoholism

Pathophysiology: initially necrosis of epiphysis, with variable necrosis of adjacent cartilage; dead bone is resorped by “creeping substitution” over months/years; new bone is soft, may flatten and cause degenerative joint disease

Creeping substitution: dead trabeculae that are not resorbed by osteoclasts serve as scaffolds for deposition of new living bone

Gross: intact articular cartilage except at edge of necrotic area, which exhibits cracking and folding; necrotic area in cross section is yellow, opaque, chalky with hyperemic fibrous tissue at margin; adjacent bone may be thickened; late changes are

Micro: 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)

Black bone

Case reports: 42 year old white woman with black vertebrae after chronic minocycline treatment (Archives 1991;115:939)

Black cartilage

Due to levodopa or methyldopa

Pigment occurs in rib cartilage, rarely in intervertebral disks

Harmless but irreversible

References: Archives 1994;118:531

Cartilaginous rest

Case report in 6 year old boy in neck (Archives 2003;127:e438)

Fracture

See also fracture callus (below)

Break in continuity of bone, often with severance of blood vessels, periosteum or muscle

Complete (bone broken completely) vs. incomplete, closed (intact overlying tissue, also called simple) vs. compound (fracture site communicates with skin surface), displaced (ends of bone not aligned), comminuted (many fragments), pathologic (due to diseased bone) or traumatic

Fractures often due to weakened bone (osteoporosis, tumor, infection) or falls in elderly and children

Types of fractures: spiral configuration through cortex is typical; transverse fractures (like breaking chalk) are associated with Paget’s disease, osteopetrosis or other severe bone disturbances; stress or insufficiency fractures-see below; avulsion fractures are associated with trauma at ligamentous and tendinous insertions, often in pelvis or distal thigh

Osgood-Schlatter’s disease: avulsion fractures of tibial tubercle causing fragmentation, in children

Healing process: hematoma forms between two ends of bone, creates fibrin mesh which seals fracture site, young capillaries enter hematoma, dead bone reabsorption begins at 3 days, periosteal inner layer promotes intramembranous bone growth on each side of fracture, which meets at fracture site to form a primary callus, which anchors ends but doesn’t support weight bearing; this is resorbed and replaced by secondary callus, composed of mature lamellar bone; new bone is laid down along lines of stress

In children, marked bone remodeling occurs, even with gross deformities or shortening of a long bone; open reduction and internal fixation of fractures is usually not needed

Movement along fracture line creates lining of synovial cells and pseudoarthritis; soft tissue must be removed and bone stabilized to promote healing

Fractures may not heal due to improper immobilization, devascularization of bone fragments, persistent infection or interposition of soft tissue between ends of bone

Primary callus: exuberant cartilage and disorderly membranous bone may resemble osteosarcoma; increased callus is present in unstable areas

Noncorrosive nails are isolated from bone substance by fibrous tissue; do not elicit a foreign body giant cell reaction

Pseudoarthrosis: false joint developing after chronic nonunion of a fracture

Case report: sarcoma with leukemoid reaction developing 35 years after uncomplicated fracture (Archives 2003;127:e186)

Micro: 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

Stress fractures

Also called fatigue or insufficiency fractures

Due to physical activity (ballet dancing, long distance running, military training) or metabolic bone disease

Usually lower limbs, especially femoral neck in those with metabolic disease, tibial shaft in joggers or dancers, second or third metatarsal bones in military trainees

May require serial parallel cuts to find evidence of stress fractures

Treatment of subchondral insufficiency fracture: immobilization, no NSAIDs

Gross: white-gray with linear notched zone paralleling subchondral bone end plate

Micro: zonal with necrotic, reparative (fracture callus, granulation tissue) and viable tissue

DD: aseptic bone necrosis (younger patients, wedge shaped infarct, total necrosis of bone trabeculae and bone marrow)

References: AJSP 2000;24:464, more information

Subchondral insufficiency fractures of femoral head

Relatively common in elderly osteoporotic women or renal transplant recipients

Usually resolves after conservative therapy, without surgery

May cause acute onset of hip pain

Xrays: bone marrow edema by MRI

Micro: fracture callus and granulation tissue growing along both edges of fracture line

Giant cystic arachnoid granulations

Arachnoid granulations are pathway for drainage of cerebrospinal fluid from subarachnoid space into dural venous sinus system

Typically produce small, well-defined indentations of inner table of skull

Giant cystic arachnoid granulations may present as destructive-appearing osteolytic lesions, with CSF-containing cysts

References: Hum Path 1993;24:438

Glomus coccygeum

Glomus bodies normally are present near coccyx at caudal end of spinal column; may be misidentified during rectal resection for rectal or uterine carcinoma, treatment of pressure sores or trauma

Not a pathologic finding, but an unusual “normal” finding

Gross: small nodule in soft tissue ventral to tip of coccyx

Micro: 1-4 cm, sharply circumscribed glomus bodies composed of glomus cells without atypia or pleomorphism surrounding vascular channels with fibrous stroma containing nerve fibers; cells are small with moderate cytoplasm and finely dispersed chromatin; no infiltration or expansile growth

Positive stains: vimentin, smooth muscle actin, neuron specific enolase

Negative stains (glomus cells): S100, desmin, CD31, Factor VIII related antigen

EM: small cells with bundles of actin filaments

References: Archives 1999;123:905, AJSP 1990;14:922

Hyperostosis cranii ex vacuo

Also called thickened calvarium

May be due to intracranial hypotension associated with chronic shunting, as skull lacks the outward pressure needed to expand

Case reports: 23 year old woman with long standing ventriculoperitoneal shunt due to shaken baby syndrome (Archives 2003;127:94)

Gross: circumferentially thickened skull, particularly inner table, involvement calvarium and base

Micro: increased cancellous space with normal trabecular bone

DD of thickened calvarium: Paget’s disease, fibrous dysplasia, thalassemia, hyperostosis frontalis interna (inner table has varying thickness of lobulated bone)

References: Hum Path 1994;25:545

Hyperparathyroidism

Only 25% have bone disease, usually bone pain

Presents in young to middle-aged adults with recurring kidney stones, peptic ulcer, nausea, vomiting, weakness, headaches

Affects entire skeleton, cortical bone more than medullary bone

Usually detected early, so osteitis fibrosa cystica (severe changes, also called Recklinghausen’s disease) are rare

Skeletal abnormalities with secondary hyperparathyroidism are typically mild

Causes: parathyroid adenoma of one gland is most common; rarely carcinoma or hyperplasia

Xray: diffuse osteopenia; specific pattern for fingers of cortical cutting cones (erosion of tufts of phalanges, subperiosteal cortical resorption, especially on radial side)

Laboratory: marked hypercalcemia and hypophosphatemia

Gross: thin bone cortices, loss of lamina dura around teeth; rarely associated with brown tumor of hyperparathyroidism

Micro: increased osteoclastic activity with tunneling of osteoclasts into bone matrix (dissecting resorption); also marked increase in bone formation and peritrabecular fibrosis

DD: myelofibrosis (fibrous tissue diffusely throughout marrow, not around trabeculae), acute phase of Paget’s disease (osteoclasts don’t tunnel, have more nuclei, different clinical presentation and laboratory findings)

Hypophosphatasia

Rare genetic disease due to disturbance in synthesis of alkaline phosphatase

Different disorder than hypophosphatemia

Autosomal recessive form: severe disease in infants, rapidly fatal

Autosomal dominant form: may not be identified until adulthood, may be asymptomatic, although associated with short stature, deformity of extremities, rickets-like disorder

Laboratory: reduced levels of alkaline phosphatase in blood, bone, intestines, liver, kidney; normal serum calcium and phosphorus

Micro: infants - increased osteoid, irregular epiphyseal cartilage with lengthened chondrocyte columns; adults - osteomalacia with increased nonmineralized bone but reduced osteoblasts

Infarct

Diaphysometaphyseal infarction: due to infection, vasculitis, sickle cell disease, pheochromocytoma, other vascular disease, Gaucher’s disease, pancreatitis, idiopathic, decompression sickness (historically)

Epiphysometaphyseal infarction: same as above, also fractures and dislocations, corticosteroids for collagen vascular diseases, thromboembolic disease, systemic lupus erythematosus, rheumatoid arthritis, Langerhans cell histiocytosis, osteochondrosis

Medullary infarcts: patchy necrosis involving cancellous bone and marrow; cortex has collateral blood flow

Subchondral infarcts: wedge shaped; cartilage remains viable since nutrients are present in synovial fluid

Sites: femoral head or other convex articular surfaces (see aseptic bone necrosis above)

Xray: no changes until third week; then reduced density in areas of dead bone and increased density due to new bone formation; changes appear irregular / mottled; thick, serpentine border

Complications: large infarcts are rarely associated with osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma; usually adult males in femur / tibia; poor prognosis (Archives 1996;120:482)

Case reports: vertebral infarcts due to staph endocarditis (Hum Path 1982;13:631)

Gross: early (identifiable at autopsy) - elongated pale area with hyperemic border sharply demarcated from adjacent bones, radiologically normal

Micro: early - ghost marrow cells with pyknotic basophilic nucleated red blood cells; irregular cystic spaces due to fat necrosis, focal calcification, dead trabeculae; late - ingrowth of granulation tissue at periphery of lesion, “creeping substitution” of dead bone by layering of new bone on trabecular surfaces at periphery, rim of collagen forms around periphery, often with calcification

Note: osteocytes may be lost even in normal bone due to decalcification

DD: enchondroma (radiologically resembles infarct but lacks its sharp border, has diffuse calcification)

Metal toxicity

Causes: aluminum (from antacids), iron, fluoride

Micro: increased osteoid, but well demarcated mineralization front and minimal osteoblasts

Positive stains: aurintricarboxylic acid highlights aluminum

Mucopolysaccharidoses

Lysosomal storage diseases caused by deficiencies in enzymes degrading heparan sulfate, dermatan sulfate and keratan sulfate

Disorders affect hyaline cartilage since enzymes are produced by chondrocytes

Usually cause short stature, chest wall abnormalities, short bones

Case reports: 19 year old black man with lethal mucopolysaccharidosis VII due to beta-glucuronidase deficiency (Mod Path 1994;7:132)

Necrosis

See aseptic bone necrosis, radiation necrosis

Micro: dead bone stains deeper blue than normal bone, no lacunar cells, margins of bone are ragged; may have osteoclasts on bone margins

Osteogenesis imperfecta

Also called brittle bone disease

One of the most common congenital connective tissue matrix diseases

Disease of type I collagen due to mutations in genes coding for alpha 1-2 collagen chains, usually autosomal dominant

A type of osteoporosis with marked cortical thinning and attenuation of trabeculae, plus other collagen related signs/symptoms

Skeletal abnormalities may be mild (reduced amounts of normal collagen) or severe/lethal (abnormal polypeptide chains cannot form collagen triple helix); associated with short stature and increased fractures (hundreds of minor / major fractures during childhood, usually in lower limb, often involving growth plate fragmentation around knees)

Blue sclera: due to translucent sclera and visualization of choroid

Hearing loss: sensorineural defect and impeded conduction due to abnormalities of middle ear bones

Dental imperfections: small, misshapen, blue-yellow teeth, due to dentin deficiency

Type I: usually acquired mutation, autosomal dominant, normal lifespan with increased fractures during childhood but decreasing after puberty

Type II: usually autosomal recessive, uniformly fatal due to extraordinary bone fragility with multiple intrauterine fractures; unstable triple helix

Type III: autosomal dominant or recessive, growth retardation, but otherwise like type I

Type IV: autosomal dominant, short stature, but otherwise like type I

Xray: nodules of cartilage at growth plate resembling a bag of popcorn; marked swelling of distal femur

Gross: cartilaginous nodules due to fragmentation of growth plate

Micro: severe forms lack an organized trabecular pattern; crowded osteocytes within bone (due to reduced collagen synthesis); large areas of woven bone; less severe forms still have crowded osteocytes with thin lamellar bone

Osteopathia striata

Also called Voorhoeve’s disease

Rare; benign, usually painless

Xray: longitudinal dense striations in affected bones

Osteopetrosis

Also called marble bone disease, Albers-Schonberg’s disease

Rare, hereditary, diffuse and symmetric skeletal sclerosis (increased bone density) caused by osteoclast dysfunction

Bones have "stone-like" quality, but are abnormality brittle and fracture like chalk

One cause is deficiency of carbonic anhydrase II, required by osteoclasts and renal tubular cells to excrete hydrogen ion; deficiency causes failure to solubilize and resorb matrix and failure to acidify urine

Associated with anemia and hepatosplenomegaly since reduced bone marrow

Types: “malignant” - autosomal recessive; detected in utero due to fractures, anemia, hydrocephaly, cranial nerve problems, infections, hepatosplenomegaly; “benign” - autosomal dominant; repeated fractures, mild cranial nerve deficits, anemia

Xray: shortened long bones, loss of metaphyseal flare (Erlenmeyer flask deformity), uniform opacity of pelvis and peripheral bones alternating with normal bone causing a striped appearance; may cause spinal spondylolisthesis

Treatment: bone marrow transplant (reverses many skeletal abnormalities), human interferon gamma

Gross: bones are solid and heavy with no medullary canal, long ends are bulbous, small neural foramina compress nerves

Micro: primarily woven bone since bone is not remodeled; central core of cartilage with dense and irregular bony trabeculae; often abundant osteoclasts; reduced marrow space

EM: osteoclasts lack ruffled borders, lack features of actively resorbing osteoclasts; surface of bone has massive smooth cartilaginous matrix with scattered rough areas of abnormal ossification, but devoid of orderly lamellar haversian system of normal bone; many irregular fracture lines present (Hum Path 1981;12:376)

DD: osteoblastic metastases, myelosclerosis, Paget’s disease

Osteopoikilosis

Usually autosomal dominant with high penetrance

No symptoms, no abnormal labs

Associated with osteosarcoma in affected bone, scleroderma, other conditions

Xray: multiple sclerotic, round lesions of variable size in cancellous bone near joint surfaces

Micro: resembles bone island

Osteoporosis

Reduction in bone mass due to increased bone porosity, which predisposes bones to fracture

Usually refers to postmenopausal or senile loss of bone severe enough to cause fractures

Affects entire skeleton due to metabolic bone disease, but may be localized due to limb disuse

Usually due to increased bone resorption, with normal levels of bone formation

Osteopenia: defined as radiologic decrease in density of skeleton

Primary causes: due to postmenopausal condition, older age (15 million cases in US) or idiopathic

Secondary causes (due to identifiable conditions): endocrine (hyperparathyroidism, thyroid disorders, hypogonadism, pituitary tumors, type I diabetes, Addison’s disease), neoplasms (myeloma, carcinomatosis), gastrointestinal disturbances (malnutrition, deficiency of vitamins C or D), drugs (corticosteroids, chemotherapy), osteogenesis imperfecta, immobilization, homocystinuria, anemia

Menopause: postmenopausal women may lose 2% of cortical bone and 9% of cancellous bone/year; osteoporosis affects women more than men because estrogen deficiency leads to increased osteoclast activity, and osteoblasts cannot keep pace

Age related changes: osteoblasts have reduced reproductive and biosynthetic potential in elderly

Immobilization: important cause because mechanical forces stimulate bone remodeling; zero gravity (astronauts), immobilization cause reduced skeletal mass; athletes have higher bone density; weight training is more effective than jogging in increasing skeletal mass

Genetics: variation in Vitamin D receptor type accounts for 75% of maximal peak bone mass achieved; Vitamin D intake and parathyroid hormone levels are not significant causes, although low calcium intake in women is an important cause

Other risk factors: Whites / Asians, smoking, alcohol abuse

Bone mass: peak bone mass occurs in young adults, based on physical activity, muscle strength, diet, hormones; subsequent remodeling causes small deficit in bone formation with each resorption/formation cycle, which causes bone loss of 0.7% per year

Sites: cancellous compartment of vertebral bone (with high surface area) affected first, causing loss of vertebral height in elderly, leading to dowager’s hump; also thinning of cortex; hip and wrist also affected

Xray: flattening of vertebral bodies, widening and swelling of intervertebral discs, fish-mouth appearance; usually thoracic and upper lumbar spine

Diagnosis: radiographic measurement of bone density, iliac crest biopsy

Prevention/treatment: calcium, Vitamin D and exercise to build up/maintain bone mass; biphosphonates (inhibit post-menopausal bone loss)

Gross: loss of cancellous bone, accentuation of vertical trabeculae in spine

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

Transient osteoporosis

Young patients with bone pain in legs and localized patchy osteopenia by Xray

Usually juxtaarticular

May spontaneously disappear or be migratory (transient migratory osteoporosis)

Micro: disconnected bone trabeculae; variable fat necrosis, increased osteoclastic activity, hypervascularity of marrow

Paget’s disease

Also called osteitis deformans

“Collage of matrix madness”, with furious osteoclastic bone resorption (osteolytic phase), hectic bone formation (mixed osteoclastic/osteoblastic phase), burnt-out osteosclerotic stage (gain in bone mass, but bone is disordered)

90% are over age 55, rare before age 40

More common in whites in US, England (3% at autopsy), France, Austria, Germany, Australia, New Zealand (5-11%); rare in blacks, Scandinavia, China, Japan, Africa

May be due to slow virus infection of paramyxovirus, similar to subacute sclerosis leukoencephalitis (virus identified in osteoblasts)

Sites: 85% of presenting patients are polyostotic (pelvis, spine, skull), 15% monostotic (tibia, ilium, femur, skull, vertebrae, humerus); rare in hands/feet, ribs, fibula [note: polyostotic patients are more likely to seek medical attention; monostotic patients are often asymptomatic, but actually are more common]

Xray: early-radiolucency; late-increased bone density, increased microfractures, loss of distinction between cortex and medulla; may have sharp demarcation between normal and affected bone; may extend into soft tissue if florid disease

Diagnosis: Xray, elevated serum alkaline phosphatase and urinary hydroxyproline (normal serum calcium and phosphorus)

Symptoms: often mild; localized pain due to microfractures and nerve compression; may have secondary osteoarthritis due to weak femur or tibia, chalk-like fractures of tibia, fibula, femur, spinal cord injuries due to spinal fractures; also associated with high output congestive heart failure due to shunting of blood through warm skin (bone is hypervascular and hot)

Leontiasis ossea: cranium too heavy to lift

Platybasia: invagination of base of skull due to weak bone, compression of posterior fossa structures

Associated neoplasms: sarcoma (5% with severe polyostotic disease), giant cell tumor, giant cell granuloma

Treatment: calcitonin, diphosphonates

Micro: diagnostic features are increased osteoclastic and osteoblastic activity with supportive radiologic findings; acutely is primarily woven bone; focal mosaic pattern of lamellar bone, resembles jigsaw puzzle with prominent irregular cement lines; osteoclasts present at surface of bone but don’t tunnel; in osteolytic phase, osteoclasts may have up to 100 nuclei; chronic cases have thick trabeculae and thicker bones; fine fibrosis of marrow

Positive stains: reticulin (highlights disorganization of lamellar bone)

DD of cement lines: radiation therapy, chronic osteomyelitis, reactive bone adjacent to carcinoma, polyostotic fibrous dysplasia (cortical bone has eccentric atrophy)

Radiation necrosis

Major complication of radiation therapy, usually within 3 years of treatment

Micro: necrotic bone, marrow fibrosis, neovascularization, irregular heavily staining cement lines

DD: Paget’s disease

Renal osteodystrophy

Skeletal changes of chronic renal disease (see also hyperparathyroidism)

Increased osteoclastic bone resorption resembling osteitis fibrosa cystica

Associated with osteomalacia, osteosclerosis, growth retardation, osteoporosis

Rickets / osteomalacia

Defect in matrix mineralization due to Vitamin D disturbance (deficiency, abnormal metabolism or calcium deficiency)

Causes accumulation of unmineralized bone matrix

Various causes related to decreased serum calcium or phosphorus, including rare inborn errors of metabolism or common chronic renal failure; also phosphaturic mesenchymal tumor

Associated with vague, generalized bone pain or muscle weakness (due to hypocalcemia)

Rickets: children with irregular, broadened, cup shaped epiphyseal growth plates around knee and wrist

Osteomalacia: adults, bone formed during remodeling is undermineralized, causes osteopenia and fractures

Hypophosphatemia: usually due to renal tubular defect, diuretics, hyperparathyroidism; rarely due to a vascular tumor

Xray: generalized osteopenia with multiple bilateral and symmetrical linear fractures (insufficiency or stress fractures)

Diagnosis: biopsy of long bone or iliac crest

Micro: adults - wide, noncalcified matrix surrounding disorganized bone trabeculae; junction between osteoid and mineralized bone is irregular and granular; may be increased bone volume; children - thickened, poorly defined growth plate, particularly on metaphyseal side; tongues of uncalcified cartilage may extend into metaphysis; wide osteoid seams

Oncogenic osteomalacia

Rare paraneoplastic syndrome of osteomalacia due to phosphate wasting

Bone demineralization is caused by tumor and may be cured by its excision

Most mesenchymal tumors in these patients are phosphaturic mesenchymal tumor (mixed connective tissue variant, see below), AJSP 2004;28:1

Symptoms: bone pain, fractures, renal phosphate wasting, hypophosphatemia, decreased 1,25 Vitamin D3 levels, resistance to Vitamin D supplementation

SAPHO syndrome

Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis

Variable and nonspecific histologic findings

Often peculiar bone lesions of anterior chest wall and pustular dermatoses

Mean age 35 years, range 5-63 years

Micro: early lesions resemble bacterial osteomyelitis with acute inflammation, edema, prominent periosteal bone formation; late lesions have markedly sclerotic bony trabeculae with prominent marrow fibrosis and mild chronic inflammation

References: AJSP 1996;20:1368

Fibrous and Fibroosseous tumors of bone

Cortical irregularities of femur

Formerly called periosteal desmoid, but not neoplastic

No clinical significance

Xray: small irregularities in distal cortex of femur

Micro: bland fibrous tissue

Fibrous dysplasia

Developmental, non-neoplastic disorder of bone-forming mesenchyme, causing bone maturation arrest at the woven bone stage

Usually associated with activating point mutation in some somatic cells (possibly alpha submit of signal transducing G protein) that leads to elevated intracellular cyclic adenosine m