Path Block 6 - Bone

• Mineral homeostasis
• House meatopoietic elements
• Provide mechanical support for movement
• Protect viscera
• Determine body size and shape

• Mineral Phase (60%) : Ca, Phos, Mg - stiffness
• Type I Collagen (30%) - tensile strength
• Type V Collagen (1.5%)

• Lamellar (mature)
• Women (immature

Osteoblasts: deposit type I collagen, mineralization, become osteocytes

Osteoclasts: multinucleated giant cells, bone resorption, have dendritic connections to communicate with each other

• Type II collagen
• Hyaline (most abundant)
• Elastic (ear)
• Fibrocartilage (intervertebral discs, tendon attachments)

Transformation of pre-existent mesenchymal tissue into bone

• Intramembranous
• Endochondral

direction transformation of neural crest-derived mesenchymal tissue into bone.

Calvarium and clavicle

Mesenchymal cells first diferentiate into cartilage, later replaced by bone.

Tubular bones, flat bones, epiphysoid bones, irregular bones --> vertebral column, pelvis, extremities.

• 1) Reserve cartilage
• 2) Zone of proliferation
• 3) Zone of hypertrophy
• 4) Zone of degeneration, apoptosis, mineralization
• 5) Zone of ossification (primary spongiosa)

Zone of proliferation - chondrocytes secrete cartilage-specific extracellular matrix.

Chondrocytes cease to divide and hypertrophy - modifying the matrix they produce to allow its mineralization with calcium carbonate.

Invasion of cartilage by blood vessels and subsequent death of hypertrophic chondrocytes through apoptosis - this space becomes BM.

Cells differentiate into osteoblasts - start forming bone matrix (osteoid) in partially degraded cartilage.

New bone is added to the periphery (periosteoum).  THe internal region is reabsorbed to form the BM cavity via osteoclasts.

developmental bone anomalies resulting from localized problems (migration, cellular condensations) - mutations in certain transcription factors

mutations that globally affect cartilage and bone - signaling molecules & matrix components

• FGFR3 mutation
• AD
• 80% from new cases (mostly on paternal allele)

• Shortened proximal extremities with normal trunk length
• Enlarged head w/ bulging forehead and depression of the root of the nose

Thanatophoric dysplasia - curved shape femur seen.

• 40% lethal skeletal dysplasias
• short ribs and extremities
• vertebral bodies with U or H shape on frontal projections
• Frontal bossing and macrocephaly
• Small chest cavity with bell-shaped abdomen
• Respiratory insufficiency

3 different FGFR3 mutations are responsible for 85% of cases.

Transmembrane domain: milder form, achondroplasia

Tyrosine kinase domain or in extracellular domain: lethal form, thanatophoric dysplasia

• blue sclera
• 4 types - lethal form present in 25% skeletal dysplasias
• intrauterine growth retardation
• severe osteopenia
• multiple fractures
• short and curved extremities
• small thorax w/ hypoplastic lungs - respiratory insufficiency 

Defect of synthesis of assembly of procollagen type I osteoblasts

AD - most common inherited disorder of connective tissue

1/10,000-70,000

Reduced bone mass predisposing to fracture

• Localized: disuse
• Entire skeleton: metabolic bone disease

~1 million/year have fracture in US

Genetic factors + nutrient + physical activity = peak bone mass

Menopause: decreased estrogen, increased RANK expression, increased osteoclast activity, increased IL-1, IL-6, TNF

Aging: decreased physical activity, decreased osteoblasts, dedcreased growth factors

Osteoclasts mainly affect bones with increased surface area (vertebral bodies)

Mosaic pattern of Paget Disease - primary bone disorder

• Severe bone deformities
• Predispose to malignant tumors
• Late adulthood (70 yrs)

SQSTM1 mutation - enhances RANK signaling

7X more common in 1st degree relatives

• 1) Osteolytic stage
• 2) Mixed osteoclastic/osteoblastic 
• 3) Burn-out quiescent osteosclerotic stage

Net gain in bone mass, newly formed bone disordered and vulnerable to fracture

Lack of vitamin D or some disturbance in metabolism

Rickets: children

Primary: tumor or hyperplasia

Secondary: prolonged hypocalcemia; increased PTH detected by osteoblasts which increase osteoclastic activity - bone loss predisposes to microfractures.  Hemorrhage + fibrosis tissue = brown tumor

Brown tumor of hyperparathyroidism

Multinucleated osteoclasts in brown tumor of hyperparathyroidism.

Pathologic: break occurs in bone already altered by disease process.

Stress: develops slowly following a period of increased physical activity with repetitive loads.

Pseudoarthrosis: if nonunion allows too much motion, central portion of the callus undergoes cystic degeneration, and the luminal surface can become lined by synovial-like cells, creating a false joint.

Ischemia d/t fracture, idopathic, or corticosteroid administration

• Subchondral: chronic pain
• Medullary: clinically silent

10% of 500K joint replacements/year in U.S.

Avascular necrosis

Hematogenous spread, extension from contiguous site, direct implantation.

Staphylococcus aureus in 80-90% cases of pyogenic osteomyelitis where organism recovered.

Mixed bacterial infections in direct spread or during surgery/open fractures

SCD: Salmonella

50% cases no organism isolated

Osteomyelitis with mixture of fibrosis and inflammatory cells instead of fat.

• Plasma cells: chronic osteomyelitis
• Neutrophils: acute

Fever, chills, malaise, pain over affected region

X-ray: lytic focus surrounded by zone of sclerosis

Blood cultures may be positive

Biopsy and bone cultures may be required to identify pathogen

Antibiotics and surgical drainage

5-25% cases fails to resolve and persists as chronic infection

Acute spontaneous flare-ups with no obvious cause, even after yrs of dormancy.

In US, 3/1000 malignant tumors is a bone tumor.

Incidence: 1/100,000 per year

• Adult > malignancy
• Children > benign

Osteosarcoma, Ewing's Sarcoma

Giant cell tumor

Chondrosarcoma

• 1/2 of osteosarcomas
• Giant cell Tumors
• Non-ossifying fibromas
• >1/3 of ostechondromas

• Chondroblastoma
• Giant cell tumor

• Chondrosarcoma
• 1/2 of osteoblastomas

• Ewing sarcoma
• >1/3 of chondrosarcomas

Exotosis - most common benign tumor of bone

Starts in growth plate and migrates towards metaphysis as patient grows with cartilagenous cap on top.

Malignant transformation rare - EXT-1 is the germline mutation that increases the risk in hereditary multiple exostoses (AD).

Osteochondroma with a mushroom/polypoid appearance with a stalk.

Rarely seen with broad base.

Osteochondroma with cartilagenous cap with endochondral ossification

• Rare, adolescents, M>F
• Epiphysis of knee or proximal humerus
• Benign, but rare metastases

Circumscribed proliferation of chondroblasts with hyaline matrix and chicken-wire calcification.

Tx: curretage, common recurrence

Chondorblasts with chickenwire calcification seen in chondroblastoma.

2nd most common malignant tumor of bone (26%) - bulky tumor of malignant cartilage

Older adults (60s-70s), M>F

Central skeleton (except clear cell variant) - pelvis & ribs, femur, humerus, medullary location

Most low grade (1-3) based on degree of cellularity

Variants: de-differentiated, myxoid, clear cell, mesenchymal, juxtacortical

Survival: 80-90% (1 &2), 29% Gr 3(lung)

Popcorn-like cartilagenous matrix of chondrosarcoma.

• Benign bone forming tumor
• Long bones, femur, tibia
• <2cm
• Night pain
• Responds to aspirin
• Radiolucent lesion w/ sclerotic cortex
• Well circumscribed
• Woven bone trabeculae/osteoid rimmed by osteoblasts (nidus)

Tx: curettage, may recur if not completely removed

• Benign bone forming tumor
• Vertebrae or long bone metaphysis

• >2cm
• painful
• not responsive to aspirin
• expansile radio-lucency with mottling

Nidus: woven bone trabeculae/osteoid rimmed by osteoblasts

See in osteoid osteoma

• Most common malignant bone tumor
• Destructive lesion, Codman's triangle.
• Infiltrative - extending into soft tissue.  Malignant cells producing osteoid.

• Bimodal (15 yrs and 55-80 yrs). M>F. 
• Hematgenous spread to lungs common.

Metaphysis of long bones

Tx: Chemotherapy and surgical ressection

Inherited mutant allele of RB gene - hereditary retinoblastoma: marked increase (1000 fold) in osteosarcoma.

Mutation of p53 suppressor gene - Li-Fraumeni: germinline p53 mutation - bone and soft tissue sarcomas, early onset breast cancer, brain tumors, and leukemia

Prior irradiation

Codman's triangle in osteosarcoma.

Destructive lesion because it is not respecting tissue planes

Telangiectatic osteosarcoma - tumor has tendency to have abundant blood leaks within it.

Osteosarcoma-chondroblastic

tumor cells not only forming osteoid but also cartilage

osteosarcoma- fibroblastic

spindled, elongated cells

surface osteosarcoma

arise from metaphysis, medullary cavity completely spared b/c this tumor arises from surface of long bones

post radiation - osteosarcoma

radiation to scull for squamous cell carcinoma - years later developed aggressive osteosarcoma in that location

Non-ossifying fibroma - metaphyseal fibrous defect

• common developmental cortical defect
• incidental finding or pathologic fracture
• sharply demarcated cellular lesion of fibroblasts and histiocytes

Developmental arrest of bone

Monostotic: most common, adolescents, ribs, mandible, femur

Polyostotic: infancy/childhood, crippling deformities, craniofacial involvement 

Tx: conservative, except polyostotic form

Circumscribed oxteolytic "ground glass" lesion in diaphysis with sclerotic rim

Haphazard curvilinear bone trabeculae (Chinese characters) surrounded by fibroblastic stroma

Polostotic fibrous dysplasia with endocrinopathies and cafe-au-lait spots.

• Rare, F>M
• Activating mutations of GNAS(GTP-binding protein)
• Result in excess cAMP leading to endocrine gland hyperfxn
• Sexual preocicty, acromegaly, and Cushing syndrome

Fibrous dysplasia

• Giant Cell Tumor
• Benign, locally aggressive
• Knee, proximal humerus, epiphysis
• Young adults (skeletally mature)
• F>M
• May destroy cortex and extend to soft tissue
• Tx: Curretage

Multiloculated cyst filled w/ clear to bloody fluid.

Proximal epiphysis humerus (1/2) and femur (1/4)

Tx: Curretage & packing, frequently recurrs

• Any bone, long bone metaphysis and vertebrae
• Adolescents, F>M

X-Ray: lytic well-defined lesion which distorts bone, may extend into soft tissue

Pathology: cavernous blood-filled spaces surrounded by fibrous septae.

Aneurysmal Bone Cyst - normally bone replaced by cystic cavity that contains blood

SEcond most common malignant bone tumor in childhood.

• Adolescents, young adults
• Painful, often enlarging mass
• Diaphysis of long tubular bones, ribs, and pelvis

t(11;22) EWS (22) fused with FLI-I (11)

• Pathology: primitive small round cells with neural phenotype
• Contain abundant glycogen
• Hemorrhage and necrosis common

X-Ray: destructive intramedullary lesion, "onion-skin" pattern of periosteal reaction in response to rapid growth

Tx: chemo and surgery, radiation may be added

• Ewing Sarcoma
• Onion-skin pattern
• Small round blue cell tumor that usually expresses CD99

Adult: prostate, breast, kidney, thyroid, lung

Children: neuroblastoma, Wilms, osteosarcoma,  Ewing sarcoma, rhabdomyosarcoma

Usually multifocal in axial skeleton

Lytic: kidney, lung, thyroid, GI, breast - stimulate osteoclastic bone resoprtion

Blastic: prostate & breast

• Wear and tear and problems with repair
• AKA degenerative joint disease
• Aging & mechanical effects
• Knees and hands: women
• Hips: men

• Chromosomes 2  & 11
• Increased bone density and estrogen increases risk

Heberden's (distant) and Bouchards nodes

• OA
• 1) Eburnated articular surface
• 2) Subchondral cyst
• 3) Residual articular cartilage

• May be disabling
• Hand fxn rarely impaired, even if pain and stiffness remain.
• Pain in knee or hip may decrease even as disease progresses

• chronic systemic inflammatory disorder
• common age 40-70, F>M
• often progresses to destruction of articular cartilage and ankylosis
• may affect many tissues & organs
• autoimmunity
• microbe may start rxn and ultimately cause cross rxn w/ antigens in joints
• affects PIP and MCP

• infiltration of synovial stroma by dense perivascular CD4+ T cells, plasma cells, and macrophages
• increased vascularity d/t vasodilation and angiogenesis
• organizing fibrin covering synovium and floating joint space
• osteoclastic activity in underlying bone forming juxta-articular erosions, subchondral cysts, osteoporosis

RA with lymphoid aggregate and dilated blood vessels

Pannus formation: mass of synovium and stroma, inflammatory cells, granulation tissue and fibroblasts, which grows over and erodes articular cartilage

Pannus may bridge apposing bones, forming fibrous anyklosis, which ossifies and forms bony ankylosis

• Variable clinical course
• Generally small joints affected before larger ones
• No specific diagnostic test: many patients have serum rheumatoid factor: IgM antibody reactive with Fc portion of patients' own IgG - may not be present throughout course of disease

Fatalities usually d/t systemic amyloidosis and vasculitis, or iatrogenic effects to therapy

• Before age 16
• F>M (except in systemic where it is equal)
• Heterogenous group of chronic arthritides
• Fxn disability
• Variants: oligoarticular(<5 joints), polyarticular, systemic

• Genetically predisposed individuals
• Initiated by environmental factors, especially prior infections or exposures
• Manifestations are immune mediated, maybe triggered by T-cell response to unknown antigens

• Clinical variants:
• ankylosing spondylitis (usually affects lumbar spine)
• Reactive arthritis
• Psoriatic arthritis
• Arthritis associated w/ IBD

Overlapping clinical features, many associated with HLA-B27 and triggering infection

• Primary: 
• unknown enzyme defect with increased urate production or decreased urate excretion

• 2ndary:
• increased NA turnover, chronic renal disease, Lesch-Nyhan (increased urate production)

Urates-needle shaped, negative birefringent crystals, tophi (large aggregates of urate crystals surrounded by intense inflammatory rxn)

Acute Gouty Arthritis

needle shaped, negative birefringent crystals

Tophi: large aggregates of urate crystals surrounded by intense inflammatory rxn

Calcium pyrophosphate crystal deposition (chondrocalcinosis)

Etiologies: sporadic, hereditary, secondary

Chalky white friable deposits seen histologically as oval blue-purple aggregates

Individual crystals (.5-5um), weakly positively birefringent, rhomboid shapes

• Neurofibromatosis type 1 (neurofibroma, MPSNT)
• Gardner syndrome (fibromatosis)
• Li-Fraumeni syndrome (soft tissue sarcomas)
• Osler-Weber-Rendu syndrome (telangiectasia)

• Grade: I to III 
• based on degree of differentation/pleomorphism
• average number of mitoses 
• Extent of necrosis

Size (> or < 5cm), depth, stage (metastasis)

superficial have better prognosis than deep lesions

most common soft-tissue tumor of adhulthood

subclassified according to particular morphologic feature

conventional lipomas: 12q14-q15

well encapsulated mass usually cured by simple excision

• 40s-60s
• Proximal extremities & retroperitoneum

• well-differentiated: indolent
• myxoid/round cell: intermediate
• pleomorphic: aggressive

• Superficial: palmar (Dupuytren contracture), plantar, penile (Peyronie disease)
• may stabilize and resolve spontaneously, some recur

Deep-seated(Desmoid tumors): behavior lies btwn benign fibrous tumors and low grade fibrosarcomas.  frequently recur, in teens-30s, some associated with Gardner syndrome, mutations in the APC or beta-catenin genes. 

• Deep soft tissues of extremities
• Recur >50%
• Metastasize >25%
• All markers but vimentin are negatine

• Benign tumors of blood vessels, increased numbers of normal or abnormal vessels
• Very common, infancy/childhood

Capillary: composed of capillaries: congenital, infantile/juvenile, lobular

Cavernous: venous malformations, usually deep-seated

Hemangioma

• Lymphedema: post mastectomy - loss of afferent lymphatics, immunologically privileged site
• Radiation
• Carcinogens: thorotrast, insecticides, vinyl chloride
• AV fistulas, foreign material

cutaneous: most common, head and neck( Scalp and forehead), elderly, beneath hair (sun exposure)

cutaneous angiosarcoma

• HHV-8
• Classic: elder men of Mediterranean descent; skin, indolent
• Africa endemic: young Bantu children of S. Africa; lymph nodes, aggressive
• AIDs-associated: skin or any organ; spreads widely, but usually not lethal

• Adults, F>M
• skin and deep soft tissues of the extremities and retroperitoneum
• superficial = good prognosis
• retroperitoneum = large, cannot be entirely excised, local extension and metastatic spread

Embryonal: 49% RMS, more frequent <10 yrs, head and neck, GU tract, deep soft tissues of extremities, pelvis, retroperitoneum

Alveolar: 32% RMS, age 10-25, deep soft tissues of extremities (less in head, neck, perineum), t(2;13) or t(1;13)

Pleomorphic: older individuals

• Synovial sarcoma
• epithelioid sarcoma
• alveolar soft part sarcoma

• Young adult males
• Deep tissue of extremities, KNEE
• t(X;18)(p11;q11)
• histologically biphasic or monophasic

Grade, size, location (depth), metastases(most important)

lung

8000 and 2500

metastatic carcinoma

multiple myeloma

osteosarcoma

MRI

• longitudinal
• within a single compartment
• made with the definitive resection in mind
• performed by the definitive surgeon